Method and composition for treating CNS disorders

Abstract

Compositions and methods for treating a range of Central Nervous System (CNS) disorders and diseases such as amyloidosis, protein folding diseases, tauopathy, and specifically Alzheimer's Disease and Parkinson's Disease, among others, in humans and in veterinary animals, by administering to a subject in need thereof a formulation comprising of melatonin, curcumin, and cannabis, specifically THC alone or with CBD.

Claims

1. Composition for treating symptoms of Alzheimer's disease; the composition comprising: (i) tetrahydrocannabinol (THC) in a dose amount per 70 kg patient from 1.0 mg to 3.0 mg, (ii) melatonin in a dose amount per 70 kg patient from about 14 g to about 77.0 mg, and (iii) curcumin in a dose amount per 70 kg patient from about 0.35 mg up to 0.5 mg.

2. Composition of claim 1 which is a 1 mL oral suspension.

3. Composition of claim 1 wherein the dose amount of the THC is 1.0 mg up to 2.5 mg and the dose amount of the melatonin is 14 g up to 1.5 mg.

4. Composition of claim 3 which is a 1 mL oral suspension.

5. Composition of claim 1 wherein the THC is selected from the group consisting of dronabinol, 9-THC, 8-THC, and THC Acid (THCA).

6. Composition of claim 1 wherein the curcumin is selected from the group consisting of turmeric, and mixtures thereof.

7. Composition of claim 1 in a liquid carrier further comprising a non-ionic emulsifier in an amount sufficient to maintain stability and solubility of the composition.

8. Composition of claim 7, wherein the non-ionic emulsifier is selected from the group consisting of soy lecithin, sunflower lecithin, polysorbate 80, and D--tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS).

9. Composition of claim 1 further comprising an anti-fungal agent.

10. Composition of claim 9, wherein the anti-fungal agent is a natural anti-fungal agent.

11. Composition for treating a human suffering from Alzheimer's disease; the composition comprising dose amounts per 70 kg-person weight as follows: (i) tetrahydrocannabinol (THC) from about 2.0 mg up to 2.5 mg, (ii) melatonin from about 0.7 mg to about 10.0 mg, and (iii) curcumin up to 0.5 mg.

12. Composition of claim 11 further comprising polysorbate 80, D--tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), ethanol, and water.

13. Composition of claim 11 which is a 1 mL oral suspension.

Description

DESCRIPTION

(1) The invention provides a method and compositions for treating central nervous system (CNS) disorders in humans and animals which involves treating a patient with a CNS disorder such as Alzheimer's or Parkinson's with a composition including (i) tetrahydrocannabinol (THC) in an ultra-low dose amount per 70 kg patient of from about 14 g to about 2.0 mg without severe psychological impairments and side effects associated with higher doses of THC; (ii) melatonin in a dose amount per 70 kg patient of from about 14 g to about 77.0 mg; and (iii) curcumin in a dose amount per 70 kg patient of about 7 mg to about 100 mg.

(2) In a preferred embodiment, cannabidiol (CBD) in a dose amount per 70 kg patient of from about 14 g to about 100 mg is administered to a patient along with THC, melatonin, and curcumin.

(3) In another preferred embodiment, the composition of the invention is administered orally in a liquid carrier which includes a non-ionic emulsifier in an amount sufficient to maintain stability and solubility of the composition components. Suitable non-ionic emulsifiers include lecithin from soy or sunflower, Tween 80 (polysorbate 80), and vitamin E TPGS (d--tocopheryl polyethylene glycol 1000 succinate).

(4) This invention provides a method for treating certain CNS disorders and symptoms, and diseases classified broadly as amyloidosis, protein folding diseases, tauopathy, and specifically for example Alzheimer's Disease (AD), among others, in humans and veterinary animals which includes administering to a subject in need thereof a composition including (i) an effective amount of melatonin, (ii) an effective amount of curcumin, and (iii) a cannabis compound containing THC in a micro dosage amount that is sufficient to provide efficacy while not inducing side effects commonly associated with cannabis, melatonin or curcumin.

(5) Compositions of the invention for treating Alzheimer's and related CNS diseases in humans and veterinary animals include: (i) an effective amount of melatonin, (ii) an effective amount of curcumin, and (iii) a cannabis compound containing THC in an amount that is sufficient to provide efficacy while not inducing side effects commonly associated with cannabis, melatonin or curcumin. The composition is administered orally in a suitable carrier.

(6) Compositions of the invention for treating Alzheimer's and related CNS diseases in humans and veterinary animals include: (i) an effective amount of melatonin, (ii) an effective amount of curcumin, (iii) a cannabis compound containing THC, and (iv) a cannabis compound containing CBD, in an amount that is sufficient to provide efficacy while not inducing side effects commonly associated with cannabis, melatonin or curcumin. The composition is administered orally in a suitable carrier.

(7) Compositions of the invention for treating Alzheimer's and related CNS diseases in humans and veterinary animals include: (i) an effective amount of melatonin, (ii) an effective amount of curcumin, and (iii) a cannabis compound containing CBD, in an amount that is sufficient to provide efficacy while not inducing side effects commonly associated with cannabis, melatonin or curcumin. The composition is administered orally in a suitable carrier.

(8) Compositions of the invention for treating Alzheimer's and related CNS diseases in humans and veterinary animals include: (i) an effective amount of melatonin and (ii) an effective amount of curcumin in an amount that is sufficient to provide efficacy while not inducing side effects commonly associated with higher doses of melatonin and curcumin. The composition is administered orally in a suitable carrier.

(9) Cannabis compounds can be synthetic (chemically synthesized) or extracted from cannabis plants such as sativa, indica, hemp, or hybrid strains of sativa and indica. A preferred source of tetrahydrocannabinol (THC) is so-called organic THC, which is extracted from cannabis and contains minor amounts of other cannabinoids such as CBD. Full-spectrum cannabis oil, full-spectrum hemp oil, and full-spectrum marijuana are extracted from hemp

(10) This invention provides a method for treating certain disorders, symptoms, and diseases classified broadly as amyloidosis, protein folding diseases, tauopathy, and specifically, for example, Alzheimer's Disease (AD), among others, in mammals by administering to a subject in need thereof a composition including: (i) an effective amount of melatonin, (ii) an effective amount of curcumin, and (iii) a cannabis compound in an amount that is sufficient to provide efficacy while not inducing side effects commonly associated with cannabis.

(11) A preferred 1 ml oral suspension for a 70-kg human is administered once a day, twice a day, thrice a day or four times a day depending on the severity of the symptoms and comprises up to 2.5 mg of THC, up to 1.5 mg of melatonin, and up to 0.5 mg curcumin.

(12) A preferred 1 ml oral suspension for a 70-kg human is administered once a day, twice a day, thrice a day or four times a day depending on the severity of the symptoms and comprises up to 2.5 mg of THC, up to 1.5 mg of melatonin, and up to 200 mg CBD.

(13) Dose ranges for the components of the inventive composition follow.

(14) THC is administered with the other inventive components in dose amounts as follows: Per kg of patient weight: from about 0.2 g to about 0.14 mg Per 70 kg patient: from about 14 g to about 10 mg Preferred per kg of patient weight: from about 0.2 g to about 0.03 mg. Preferred per 70 kg patient: from about 14 g to about 2.0 mg.

(15) Melatonin is administered with the other inventive components in dose amounts as follows: Per kg of patient weight: from about 0.02 mg to about 0.3 mg. Per 70 kg patient: from about 1.4 mg to about 20 mg. Preferred per kg of patient weight: from about 0.01 mg to about 0.15 mg. Preferred per 70 kg patient: from about 0.7 mg to about 10 mg.

(16) CBD is administered with the other inventive components in dose amounts as follows: Per kg of patient weight: from about 0.2 g to about 3.0 mg. Per 70 kg patient: from about 14 g to about 200 mg. Preferred per kg of patient weight: from about 0.03 mg to about 3.0 mg. Preferred per 70 kg patient: from about 2.0 mg to about 200 mg. Also preferred per kg of patient weight: from about 0.02 g to about 0.036 mg. Also preferred per 70 kg patient: from about 14 g to about 2.5 mg.

(17) Curcumin is administered with the other inventive components in dose amounts as follows: Per kg of patient weight: from about 0.005 mg to about 7.0 mg. Per 70 kg patient: from about 0.35 mg to about 500 mg. Preferred per kg of patient weight: from about 0.01 mg to about 3.5 mg. Preferred per 70 kg patient: from about 0.7 mg to about 250 mg.

(18) The preferred oral dose is in the range of 1 ml of an oral suspension, for a 70-Kg human, once a day, twice a day, thrice a day, or four times a day depending on the severity of the symptoms comprising of a cannabis compound with up to 2.5 mg of THC, but less than the amount which causes psychological impairments and side effects associated with higher doses of THC, up to 1.5 mg of melatonin, and up to 0.5 mg curcumin.

(19) A preferred 1 ml oral suspension, for a 70-Kg human, once a day, twice a day, thrice a day, or four times a day depending on the severity of the symptoms comprises THC in the range from about 14 g to about 10 mg, melatonin in the range from about 0.02 mg to about 0.3 mg, curcumin in the range from about 0.35 mg to about 500 mg, and CBD in the range from about 14 g to about 200 mg, but with THC, less than the amount which causes psychological impairments and side effects associated with higher doses of THC, melatonin, curcumin, and CBD.

(20) The preferred oral dose is in the range of 1 ml of an oral suspension, for a 70-Kg human, once a day, twice a day, thrice a day, or four times a day depending on the severity of the symptoms comprising of THC in the range shown in Table 1, CBD in the range shown in Table 1 but with THC, less than the amount which causes psychological impairments and side effects associated with higher doses of THC, and CBD.

(21) The combination of melatonin, curcumin, and cannabis is believed to work along several pathways in controlling various endpoints and the hallmarks of Alzheimer's Disease as well as diseases classified broadly as amyloidosis, protein folding diseases, and/or tauopathy. It is believed that the dosing in the formulation does not cause any of the side effects commonly associated with cannabis, melatonin, or turmeric. The dosing of cannabis prescribed in the formulation herein is below the 5 mg levels prescribed by the FDA for dronabinol and well below the 50 micromolar level used in the Eubanks 2006 study (Eubanks L m, Rogers C J, Beuscher A E 4.sup.th, Koob G F, Olson A J, Dickerson T J, Janda K D. A molecular link between the active component of marijuana and Alzheimer's disease pathology. Mol Pharm. 2006 November-December 3(6): 773-777). Using time-release formulations for any of the components, can further enhance bioavailability.

(22) The combination of lower dose of melatonin, curcumin, and cannabis compounds unexpectedly leads to (i) a reduction of side effects, such as transient, acute psychotic reactions, anxiety, impaired neuropsychological performance, memory impairments, executive functioning disorder, mitochondrial dysfunction, and (ii) other side effects like headache, dizziness, nausea, drowsiness, depression, anxiety, tremor, cramps, irritability, confusion, hypotension, rash, yellow stool, among others, otherwise present with higher doses of melatonin, curcumin, and cannabis compounds, or when each of melatonin, curcumin, and or cannabis is used alone.

(23) Suitable pharmaceutically acceptable cannabis compounds include cannabis extract, which includes phytocannabinoids such as tetrahydrocannabinol THC (9-Tetrahydrocannabinol (9-THC), 8-tetrahydrocannabinol (8-THC) and 9-THC Acid), cannabidiol (CBD), other phytocannabinoids such as cannabinol (CBN), cannabichromene (CBC), cannabigerol (CBG) among others, terpenoids and flavonoids. Standardized cannabis extract (SCE) consists of mostly THC, CBD, and CBN. Organic THC consists of solvent-extracted THC from cannabis with lesser or trace amounts of other cannabinoids and terpenoids. Synthetic or pure THC is free of CBD and other compounds is a preferred cannabis compound.

(24) THC and CBD can be extracted from a Cannabis indica dominant strain using, for example, high pressure and carbon dioxide or ethanol as a solvent in a 1500-20 L subcritical/supercritical CO2 system made by Apeks Super Critical Systems, 14381 Blamer Rd., Johnstown, Ohio, 43031.

(25) The cannabis plant in its natural form contains THCA. The resin called shatter is extracted from the cannabis flower using any of a variety of methods including CO2 extraction as described herein. Shatter is produced using a three-step process: kief separation, extraction, and winterization. Cannabis flower is introduced into a steel tumbler over a mesh sieve with dry ice. Flower is frozen and broken while tumbled with dry ice chunks allowing fine THCA-bearing particles (kief) to fall through the sieve. THCA is then extracted from kief using supercritical extraction. A solvent such as CO2 and kief are introduced into a chamber. That sealed chamber is pressurized to approximately 2800 psi and heated to 53 C. Supercritical CO2 is then allowed to flow out of the pressurized chamber into a vile at room temperature and pressure (while more CO2 is introduced to maintain pressure in the chamber). As the CO2 vaporizes in the collector vial, it deposits shatter. In the third, optional step, called winterization, the CO2 oil is dissolved in ethanol ( ounce shatter dissolved in 400 ml ethanol). This mixture is then poured through a filter (such as a coffee filter) frozen for 48 hours, then warmed, filtered again, and then spun with heat to evaporate off the ethanol. The remaining resin contains a combination of THCA, THC, and other cannabis compounds. The resin is heated for 60 minutes at 240 F. An HPLC test is run to determine the amount of THC and THCA present in the resin. 45 mg of the resin containing 99% THC (as determined by HPLC) is dissolved in 1 ml of ethyl alcohol. The dissolved resin is transferred and mixed with the solution of curcumin-honey-ascorbic acid-melatonin solution. The solution is filtered and sterilized using a 0.2-micron PES Nalgene filtration unit under constant pressure in a sterilized environment. The filtered 30 ml solution is transferred to and stored in an amber glass bottle that is autoclaved in an aseptic condition.

(26) Animals, especially dogs and cats, can be treated according to the invention. Dosage amounts and serum levels of drug are the same as disclosed above for human patients.

(27) The term about as used herein is intended to allow for variations in formulations of plus or minus 1 g or 1 mg.

(28) The transitional term comprising is synonymous with including, containing, or characterized by, is inclusive or open-ended, and does not exclude additional, unrecited elements or method steps. The transitional phrase consisting essentially of is intended to embrace only specified components or ingredients or steps, and those that do not materially affect the basic and novel characteristics of the claimed invention. In other words, elements or ingredients which materially affect the essence of the invention are excluded by the phrase consisting essentially of.

Example 1: General Method of Preparation

(29) The following example sets out a method for preparing the formulation. One dose of the liquid formulation is measured at 1 ml, comprising of 70% of water, 20% honey, and 10% ethyl alcohol, 1.5 mg THC, 1.5 mg melatonin, 1 mg turmeric, 1 mg ascorbic acid as an anti-oxidative agent, and 0.1% sodium benzoate as an anti-fungal agent. Food-grade solvents and carriers include, among others, DMSO and polyethylene glycol. Food-grade, anti-oxidative agents include, among others, carotenoids and tocopherols. Food-grade agents with anti-fungal properties include flavonoids among others.

(30) The following is a list of ingredients for making 30 ml of the formulation: Melatonin procured from Bulk Inc: 45 mg. Curcumin procured from Bulk Inc: 30 m. Ascorbic acid: 30 mg Ethyl alcohol 200 proof: 3 ml. Water (USP grade RMBI): 21 ml Honey (KirklandCostco): 6 ml THC procured as shatter: 45 mg Sodium benzoate USP, 33 mg

(31) Weigh 30 mg of curcumin in a digital weighing machine and place it in a glass beaker containing 1 ml ethyl alcohol (200 proof). Add 21 ml of water to the curcumin alcohol mixture. Boil the water and curcumin mixture for 10 minutes on the hot plate, and stir the mixture using a magnetic stirrer. After the mixture cools to room temperature, add 6 ml of honey to the curcumin mixture slowly with stirring. Weigh 30 mg of ascorbic acid and add to the curcumin-honey mixture. Weigh 45 mg of melatonin and dissolve it in 1 ml of ethyl alcohol. Once melatonin is completely dissolved in alcohol, transfer the melatonin mixture to curcumin-honey-ascorbic solution.

(32) A further embodiments of Example 1 comprises of replacing turmeric with any of, or a combination of curcumin, nano-curcumin, and turmeric.

Example 2

(33) An Alzheimer's patient exhibiting slight anxiety and/or agitation is given 1 ml of the formulation set out in Example 1, in the morning on an empty stomach, prior to breakfast, and 1 ml prior to dinner in the evening. The patient exhibits reduced anxiety and agitation.

Example 3

(34) An advanced-stage Alzheimer's patient exhibiting moderate to severe anxiety, sleep disorder, and/or agitation is given 1 ml of the formulation three to four times a day, morning afternoon and evening, prior to meals. The patient exhibits reduced anxiety and agitation vastly improving the distress caused to the caregivers.

Example 4

(35) The formulation in Example 1, is supplemented with 50 mg of Cannabidiol (CBD) dissolved in 1 ml of ethyl alcohol and added to the overall solution of Example 1. A moderate-stage Parkinson's patient exhibiting levodopa-induced dyskinesia, stammering, anxiety, gait, sleep disorder, and/or agitation is given 1 ml of the formulation of Example 4, three to four times a day, morning afternoon and evening, prior to meals. The patient exhibits reduced symptoms.

Example 5

(36) The formulation of Example 4, without the THC component, is administered three times a day prior to meals to a moderate-stage Parkinson's patient exhibiting levodopa-induced dyskinesia, stammering, anxiety, gait, sleep disorder, and/or agitation. The patient exhibits reduced symptoms.

Example 6

(37) The formulation and dosing in Example 4, is administered to a patient with moderate incontinence, two times a day, morning and evening, prior to meals. The patient exhibits reduced symptoms.

Example 7

(38) The formulation and dosing in Example 1, is administered, once a day, twice a day, to an individual exhibiting early signs of Alzheimer's disease, including plaques and tangles, as determined by a PET scan, as a prophylactic. The patient exhibits a slowdown in the buildup of plaques and tangles.

Example 8

(39) The formulation and dosing in Example 1, without the THC component is administered to a patient with mild symptoms of Alzheimer's disease two times a day, morning and evening, prior to meals as a prophylactic. The patient exhibits reduced symptoms.

Example 9

(40) To address the solubility and stability of THC in an alcohol/water mixture, the following active ingredients were combined in 30 ml solution: Turmeric: 30 mg Melatonin: 45 mg THC: 45 mg Honey: 6 ml Water: 21 ml Ascorbic acid (THC antioxidant): 30 mg Rutin (antifungal agent): 33 mg Ethyl alcohol: 3 ml Polysorbate-80

(41) A non-ionic emulsifier is preferably added to increase the solubility of THC and other active ingredients in the solution. Nonionic emulsifiers include lecithin from soy and sunflower, polysorbate 80, and vitamin E TPGS (d--tocopheryl polyethylene glycol 1000 succinate). Polysorbate 80 is a nonionic surfactant and emulsifier derived from polyethoxylated sorbitan and oleic acid.

(42) Preferred emulsifiers are from 1-3% polysorbate-80, 2-5% vitamin E TPGS and a combination of 1% polysorbate-80 and 1-2.5% Vitamin E TPGS.

(43) Sodium benzoate in Example 1 serves as an antifungal agent and natural antifungal agents such as rutin are also suitable. Natural antifungal agents with broad-spectrum antifungal properties are more potent and less toxic compared to sodium benzoate.

(44) Rutin, also called rutoside, quercetin-3-O-rutinoside, and sophorin, is a glycoside combining the flavonol quercetin and the disaccharide rutinose. It is a citrus flavonoid found in a wide variety of plants including citrus fruit.

Example 10

(45) A preferred formulation in a 30 ml solution which maintains THC and the other components in a stable solution is as follows: Curcumin: 0.05% Melatonin: 0.15% THC: 0.25% Honey: 20% Water: 65 to 55% Ascorbic acid: 1% Rutin: 0.05% Ethyl alcohol: 12% Polysorbate-80 (1%) and Vitamin E-TPGS (1 to 2.5%). CBD: 0.25% to 5%

(46) It is preferred to use 20-30% honey and/or 12% alcohol to increase the solubility of THC. The use of 1% of an antioxidant such as ascorbic acid is also preferred to counter degradation of THC when exposed to atmospheric oxygen.

(47) While this invention has been described as having preferred sequences, ranges, ratios, steps, order of steps, materials, structures, symbols, indica, sativa, hemp, graphics, color scheme(s), shapes, configurations, features, components, or designs, it is understood that it is capable of further modifications, uses and/or adaptations of the invention following in general the principle of the invention, and including such departures from the present disclosure as those come within the known or customary practice in the art to which the invention pertains, and as may be applied to the central features hereinbefore set forth, and fall within the scope of the invention and of the limits of the claims appended hereto or presented later. The invention, therefore, is not limited to the preferred embodiment(s) shown/described herein