CANNABINOID FORMULATION INCLUDING A VASODILATOR AND OCULAR DELIVERY OF THE SAME

Abstract

A cannabinoid formulation and method for ocular or nasal delivery. The method of administration includes providing eye drops that comprise an aqueous solution of at least one water soluble cannabinoid, saline, and a vasodilator; and administering the eye drops topically to an eye of the subject. In an alternate method the cannabinoid formulation is a nasal spray delivered through the nose of a subject. Preferably, the vasodilator is 0.9% methylsulfonylmethane (MSM) in a MSM solution so that the MSM solution has a concentration of 5-15% in the overall formulation. Additionally, the at least one water soluble cannabinoid is encapsulated with a phospholipid liposome.

Claims

1. Formulated cannabinoid eye drops comprising: an aqueous solution of at least one water soluble cannabinoid; saline, and a vasodilator.

2. The formulated cannabinoid eye drops of claim 1, wherein the vasodilator is methylsulfonylmethane (MSM), defined by the formula: ##STR00003##

3. The formulated cannabinoid eye drops of claim 1, wherein the vasodilator is an oxide of sulphur.

4. The formulated cannabinoid eye drops of claim 1, wherein the vasodilator is methylsulfonylmethane (MSM) and the concentration of the at least one water soluble cannabinoid is less than 0.1 mg/ml.

5. The formulated cannabinoid eye drops of claim 1, wherein the vasodilator is methylsulfonylmethane (MSM), the concentration of the water soluble cannabinoid is less than 0.1 mg/ml, and the at least one water soluble cannabinoid is encapsulated with a liposome.

6. The formulated cannabinoid eye drops of claim 1, wherein the vasodilator is Methylsulfonylmethane (MSM), and the at least one water soluble cannabinoid is encapsulated with a phospholipid liposome.

7. A method of treating a subject comprising: providing eye drops comprising an aqueous solution of at least one water soluble cannabinoid, saline, and a vasodilator; administering the eye drops topically to an eye of the subject.

8. The method of claim 7, wherein the vasodilator is methylsulfonylmethane (MSM).

9. The method of claim 7, wherein the vasodilator is includes a compound including sulphur.

10. The method of claim 7, wherein the vasodilator is methylsulfonylmethane (MSM) and the concentration of the at least one water soluble cannabinoid is less than 0.1 mg/ml.

11. The method of claim 7, wherein the vasodilator is methylsulfonylmethane (MSM), the concentration of the water soluble cannabinoid is less than 0.1 mg/ml, and the at least one water soluble cannabinoid is encapsulated with a liposome.

12. The method of claim 7, wherein the vasodilator is methylsulfonylmethane (MSM), and the at least one water soluble cannabinoid is encapsulated with a phospholipid liposome.

13. The method of claim 7, wherein the method treats cataracts.

14. The method of claim 7, wherein the method treats glioblastoma.

15. The method of claim 7, wherein the method treats locked-in-syndrome.

16. The method of claim 7, wherein the subject it a canine.

17. The method of claim 7, wherein the subject it a feline.

18. The method of claim 7, wherein the method treats a seizure.

19. The method of claim 7, wherein the method treats myopia.

20. The method of claim 7, wherein the method treats eye strain.

Description

DESCRIPTION OF THE DRAWING

[0017] FIG. 1 is a liposome.

DETAILED DESCRIPTION

[0018] The present invention is particularly useful for treating cataracts and other eye conditions including infections, myopia, hyperopia, eyestrain, retinal detachment, tumors, and glaucoma. These conditions are examples, and many other conditions can be treated in accordance with the present invention including diabetes, and asthma when delivered nasally

[0019] The present invention is also particularly useful for treating neurological conditions including seizures, and locked-in-syndrome. These are just two of many possibilities of neurological conditions that can be treated.

[0020] In an embodiment of the invention, the formulation is administered as eye drops to an animal such as livestock, or a pet such as a dog or cat. 1-5 eye drops are administered.

[0021] Accordingly, the present invention includes methods of treatment of the diseases disclosed herein as well as other diseases that have been remedied by the use of cannabinoids. The present invention is particularly useful for treating diseases of the eye, and for delivering cannabinoids into the optic nerve, the brain, and the vasculature of a subject. This enables many treatment possibilities, particularly for those suffering with glioblastoma. Since the present invention delivers cannabinoids rapidly and directly to the vasculature of the brain, the present invention is also optimal for treatment of seizures as they occur. In one embodiment, the present invention is delivered in the form of a nasal spray to administer to a subject when the subject is having a seizure.

[0022] Phytocannabinoids employed by the present invention preferably include any combination of the following classical cannabinoids derived from Cannabis Sativa: [0023] THC (Tetrahydrocannabinol) [0024] THCA (Tetrahydrocannabinolic acid) [0025] CBD (Cannabidiol) [0026] CBDA (Cannabidiolic Acid) [0027] CBN (Cannabinol) [0028] CBG (Cannabigerol) [0029] CBC (Cannabichromene) [0030] CBL (Cannabicyclol) [0031] CBV (Cannabivarin) [0032] THCV (Tetrahydrocannabivarin) [0033] CBDV (Cannabidivarin) [0034] CBCV (Cannabichromevarin) [0035] CBGV (Cannabigerovarin) [0036] CBGM (Cannabigerol Monomethyl Ether) [0037] CBE (Cannabielsoin) [0038] CBT (Cannabicitran)

[0039] In one embodiment, the present invention includes solely acid forms of cannabinoids to minimize psychoactive effects associated with THC. In another embodiment, the cannabinoids are solely CBD to minimize psychoactive effects. In another embodiment, a combination of THC-A and CBD are formulated together. It can be appreciated that any combination of the classical cannabinoids and other cannabinoids can be used in accordance with the present invention.

[0040] While the present invention describes the use of isolated cannabinoids, preferably having an 80-99.9% purity, the present invention can also be optimized using a whole plant extract having a cannabinoid profile roughly paralleling the cannabinoid profile in a substrate plant material.

[0041] When using isolated cannabinoids, isolated cannabinoids are formulated to be water soluble with sufficient water solubility to remain suspended in an aqueous solution for a desired shelf life, e.g. two years.

[0042] FIG. 1 shows one embodiment wherein the cannabinoids are encapsulated with nano-sized (less than 1 micron) liposomes. The liposomes define a core housing cannabinoids in an aqueous solution. The cannabinoids are adapted to be sufficiently soluble to achieve suspension in an aqueous solution that is encapsulated by liposomes.

[0043] In one embodiment the liposome encapsulated cannabinoid (e.g. CBD) includes an isolated cannabinoid core surrounded by a hydrophobic membrane. This yields a lipid bilayer. The cannabinoid in the core does not readily pass through the bilayer. Since the cannabinoids are typically hydrophobic, they associate with the bilayer.

[0044] In delivering the cannabinoids to a site of action, the lipid bilayer can interact with other bilayers such as the cell membrane of a vascular cell, and more easily enter into the blood stream. This is particular useful when combined in cooperation with a vasodilator that improves the flow of blood in the region of delivery.

[0045] In an alternate embodiment, the vasodilator is encapsulated by the liposome bilayer using an appropriate liposome, and is delivered simultaneously in a mixture with liposome encapsulated cannabinoids. In another embodiment, the vasodilator and the cannabinoid are both encapsulated by the same liposome bilayer. It can be appreciated that although a liposome bilayer is utilized by the present invention, a liposome monolayer can be employed with lipophilic cannabinoids including THC and CBD.

[0046] Thus it is possible not only to deliver the liposome core contents to the blood stream, the liposome layer(s) can be designed to optimally deliver the liposome core contents directly to the neurons. This is especially effective where ocular delivery is utilized.

[0047] In an alternate embodiment, the liposomes used are designed to deliver cannabinoids via alternate pathways such as diffusion. WE speculate that liposomes that contain low (or high) pH can be constructed to use electrical charge to further optimize delivery to the blood stream, or to a particular site of action i.e. the brain. As the pH naturally neutralizes within the liposome (protons can pass through some membranes), the charged cannabinoids will also be neutralized, allowing it to freely pass through a membrane. These liposomes work to deliver drug by diffusion rather than by direct cell fusion.

[0048] Preferably, a raw phospholipid liposome used in the formulation is derived from lecithin. Phosphatidylcholine is a specific example of a liposome that is useful for the purposes described herein. The formulation can be adapted to alternate liposomes to create homogeneous liposome particle sizes that are stable and hold their encapsulated payload of cannabinoids in the core for a pre-determined period, or until they reach the most desirable point of delivery.

[0049] Encapsulating the cannabinoids, vasodilators or other molecules used herein i.e. MSM, is accomplished by supplying energy to a dispersion of phospholipids in a polar solvent, such as water, to break down multilamellar aggregates into oligolamellar bilayer vesicles. The vasodilator is an oxide of sulphur, having two double-bonded oxygen molecules.

##STR00002##

[0050] Liposomes can hence be created by sonicating a dispersion of amphipatic lipids, such as phospholipids, in water. Sonication is one method of preparation. Extrusion and the Mozafari method may also be employed to produce liposomes for encapsulating cannabinoids. In one embodiment phosphatidylcholine is used. It can be appreciated that other lipids can be used liposome preparation.

[0051] Various vasodilators have been studied that have the desired effect of increasing the rate of delivery of cannabinoids to a desired site of action. While the following classes of vasodilators may be utilized with the present invention, MSM has proven to be sufficiently effective, and also functions as a preservative to improve shelf life. The classes of vasodilators that may be substituted for the MSM of the present invention either in a preferred combination or in isolation. These classes include: [0052] Alpha-adrenoceptor antagonists (alpha-blockers) [0053] Angiotensin converting enzyme (ACE) inhibitors [0054] Angiotensin receptor blockers (ARBs) [0055] Beta.sub.2-adrenoceptor agonists (β.sub.2-agonists) [0056] Calcium-channel blockers (CCBs) [0057] Centrally acting sympatholytics [0058] Direct acting vasodilators [0059] Endothelin receptor antagonists [0060] Ganglionic blockers [0061] Nitrodilators [0062] Phosphodiesterase inhibitors [0063] Potassium-channel openers [0064] Renin inhibitors

[0065] Various examples of preferred formulation manufacturing methods and formulation components are provided as follows:

Example Formulation Method #1

[0066] Producing a 30 ml batch with: [0067] 10 ml purified water; [0068] 2.5 mg of isolated THC in a water-soluble form. [0069] 2 ml Opti-MSM® methylsulfonylmethane 0.9% solution [0070] 20 ml of 0.9% saline solution [0071] Mixing and heating the mixture at 210° F. for one hour in a flask with a magnetic stirrer. [0072] Filtering with a 5 micron filter [0073] Packaging in five 6 ml glass eyedropper bottles.

Example Formulation Method #2

[0074] Producing a 30 ml batch with: [0075] 8 ml purified water; [0076] 2.5 mg of liposome encapsulated CBD (the CBD having 99% purity) [0077] 2 ml Opti-MSM® methylsulfonylmethane 0.9% solution [0078] 20 ml of 0.9% saline solution [0079] Mixing and heating the mixture at 210° F. for one hour in a flask with a magnetic stirrer. [0080] Filtering with a 5 micron filter [0081] Packaging in a glass eyedropper bottle.

Example Formulation Method #3

[0082] Producing a 30 ml batch with: [0083] 10 ml purified water; [0084] 0.5 mg of liposome encapsulated CBD (80% purity powder) [0085] 4 ml methylsulfonylmethane 0.9% solution [0086] 16 ml of 0.9% saline solution [0087] Mixing and heating the mixture at 210° F. for one hour in a flask with a magnetic stirrer. [0088] Filtering with a 5 micron filter [0089] Packaging in a glass eyedropper bottle.

Example Formulation Method #4

[0090] Producing a 30 ml batch with: [0091] 10 ml purified water; [0092] 0.5 mg of liposome encapsulated CBG [0093] 2 ml methylsulfonylmethane 0.9% solution [0094] 18 ml of 0.9% saline solution [0095] Heating the mixture at 210° F. for one hour in a flask. [0096] Stirring with a magnetic stirrer for three hours. [0097] Filtering with a 5 micron filter [0098] Packaging in a nasal spray dispenser.

Example Formulation Method #5

[0099] Producing a 30 ml batch with: [0100] 10 ml purified water; [0101] 2.5 mg of whole plant extract of cannabinoids (80% cannabinoid content) [0102] 4.5 ml Opti-MSM® Methylsulfonylmethane 0.9% solution [0103] 18 ml of 0.9% saline solution [0104] Heating the mixture at 210° F. for one hour in a flask. [0105] Stirring with a magnetic stirrer for three hours. [0106] Filtering with a 5 micron filter [0107] Packaging in an eye drop dispenser.

[0108] The present invention envisions transmucosal administration of the present invention via the ocular or nasal routes. For ocular delivery, the number of drops is between (1-5). For nasal delivery, the same volume in the form of a mist is administered. The nature of administration and formulation reduces the need for administering a large volume of cannabinoids. To compare, an orally administered therapeutic dose of THC, for example, via an edible product can be 10-25 mg. In accordance with the present invention, 0.1 mg or less can be therapeutic. Subjective testing indicates that the present invention may be more than 100× more potent than traditional oral deliver via an edible product.

[0109] The product and methods of the present invention also can be employed through delivery via the ears, sublingually and topically.