DISORDERS

Ramachandra MUKUNDA

Ranga Chelva KRISHNA

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] The present application claims priority on prior U.S. Provisional Application S.N. 62/141 ,438, filed April 1 , 2015, which is hereby incorporated herein in its entirety by reference.

FIELD OF THE INVENTION

[0002] This invention relates to compositions and methods for treating seizure disorders such as epilepsy in humans and animals (mammals) using a non-barbiturate anti-epileptic drug (NAED), phytocannabinoid cannabidio! (CBD); and a lipophilic fatty acid.

SUMMARY OF THE INVENTION

[0003] The invention provides compositions and methods for treating seizure disorders such as epilepsy in humans and animals using, the combination of a non-barbiturate anti-epileptic drug (NAED), phytocannabinoid cannabidiol (CBD); and a lipophilic fatty acid.

[0004] Patients who are subject to seizure disorders such as epilepsy are treated to control and reduce the frequency of seizures by administering the drug combination described above in accordance with further details of the invention that are disclosed herein.

DETAILED DESCRIPTION OF THE PREFERRED E BODIMENT(S)

OF THE INVENTION

[0005] Non-barbiturate anti-epileptic drugs (NAEDs) include:

[0008] acetozolamide

[0007] brivaracetam

[0008] carbamazepine

[0009] c!obazarn

[0010] clonazepam

[0011] ethosuximide

[0012] eslicarbazepine acetate

[0013] felbamate

[0014] flurofelbamate

[0015] gabapentin

[0016] lacosarnide

[0017] lamotriquine [0018] levetriacetam

[0019] oxcarbazepine

[0020] perarnpanel

[0021] phenytoin

[0022] piracetam

[0023] pregabalin

[0024] primidone

[0025] rufinamide

[0026] seletracetam

[0027] sodium valproate

[0028] tiagabine

[0029] topiramate

[0030] valproate

[0031] vigabatrin

[0032] zonisamide

[0033] A preferred group of NAEDs bind to glyprotein SV2A and includes levetriacetam (LEV) and derivatives or analogs thereof with anti- epileptic drug activity such as brivaracetam (BVA) and seletracetam (SEA).

[0034] Preferred drugs such as Leveritacetam and analogs or derivatives thereof bind to glycoprotein SV2A and act by modulating the release of calcium by inhibiting pre-synaptic calcium channels. This results in reducing the release of excitatory neurotransmitters across the synaptic cleft, thereby reducing the excitatory post-synaptic potential discharges, [0035] The lipophilic fatty acid component increases the amount of NAED and CBD crossing the blood brain barrier thereby increasing the bioavailability of the NAED and CBD while decreasing or eliminating undesirable side effects. [0036] The preferred fatty acid is alpha linolenic acid ("ALA") or a lipophilic mixture high in alpha linolenic acid. One such source is hempseed oil extracted from the seed of the hemp plant (Cannabis Sativa). Hempseed oil is essentially free of CBD and tetrahydrocannabinol (THC) and is to be distinguished from hemp oil extracted from the glandular structure of the hemp plant which contains CBD but not THC.

[0037] CBD can be used in its pure form or as a mixture of compounds that result from extracting cannabis plants. Such mixtures contain CBD, THC or tetrahydrocannabinol (which in turn is a mixture comprising 9-tetrahydrocannabinol (delta-9 THC), 8-tetrahydrocannabinol (delta-8 THC) and 9-THC Acid), Cannabinol (CBN), Cannabichromene (CBC), Cannabigerol (CBG), terpenoids and flavonoids. [0038] The preferred CBD mixture is extracted from a Cannabis Indica, the composition of which is known. The use of CBD from Cannabis Indica, which can contain up to 50% THC (based on the amount of CBD), is preferred. See, for example, Qureshi et al, World Applied Sciences Journal 19 (7): 918-923, 2012 ISSN 1818-4952, IDOSI Publications, 2012, disclosing an Indicia extraction containing 54% CBD and 24% THC. Preferred mixtures for use in the invention contain at least 50% by weight CBD wherein the weight ratio of CBD to THC is at least 2:1 , preferably at least 3:1 .

[0039] The preferred CBD mixture is extracted from a Cannabis Indica dominant strain using high pressure and carbon dioxide as a solvent in a 1500-20L subcritical/supercritical C02 system made by Apeks Super Critical Systems, 14381 Biamer Rd., Johnstown, Ohio, 43031 . See http://www.apekssupercritical.com/botanical-extraction-syste ms/.

[0040] Apeks Systems use valveless expansion technology with no constrictions or regulating valves to cause clogging in the system between the extraction vessel and the C02 expansion separator. Flow of liquid C02 and dissolved oil travels from the extraction vessel into the separator, and the oil is separated from the C02 in the separator/collection vessel. C02 is recycled during the extraction process and recovered and regenerative heat capture methods are used to increase efficiency.

[0041] A further process using solvents can be used to remove THC from the mixture leaving either pure CBD or so-called "Organic CBD" containing CBD, CBN, CBC, CBG CBN, terpenoids and fiavonoids. The use of essentially THC-free Organic CBD from Cannabis Indica is more preferred. [0042] Another source of CBD essentially free of THC is the CBD mixture obtained by extracting hemp oil from the glandular structure of the hemp plant (Cannabis Sativa). See Leizer et al, J. Nutraceuticals, Functional and Medical Foods, Vol. 2(4) 2000, The Haworth Press, Inc. Hemp oil is to be distinguished from hempseed oil which contains neither CBD nor THC.

[0043] NAEDs have been used to treat epilepsy and seizure disorders. The addition of CBD creates an additional path to treat epilepsy and or seizures wherein the overall impact of using the combination is higher than those if treaded with each drug individually. Because the use of a lipophilic fatty acid increases the amount of NAED and CBD crossing the blood brain barrier which in turn increases the bioavailability of the NAED and CBD, lower dosage amounts of NAED can be used to decreasing or eliminating undesirable side effects.

[0044] Patients being treated for seizure disorders will receive a NAED in an amount to provide from about 14 to about 40 micrograms of said drug per milliliter of blood serum in a patient. To obtain these levels, the daily dosage of a NAED will be about 4 mg/kg to 60mg/kg of patient weight divided into two doses a day. For adults to neonates, the dosing will be titrated to tolerability and efficacy not to exceed a total adult daily dose of about 6000 mg/day. The daily dosage amount of CBD to be used with a NAED is from about 0.5 to about 1 .0 mg/kg of patient weight. The daily dosage of a fatty acid such as ALA will be about from 1 to 8 grams per day depending on the body mass index of the patient. [0045] Candidates to be treated according to the invention will generally present with symptoms or signs associated with seizure disorders such as recurrent loss of consciousness, recurrent seizures and/or a prior diagnoses of medically refractory epilepsy. The invention is especially useful in treating patients who have had recurrent and/or poorly controlled seizures or epilepsy in spite of being treated with one or more know anticonvulsant drugs. [0046] The expected response in patients treated according to the invention is a reduction in seizure intensity and/or frequency once a steady state of the active pharmaceutical components is achieved. Up to 14 or more days of treatment may be required before benefits can be achieved.

[0047] Patients with allergies, cardiac rhythm disturbances, metabolic syndrome, renal failure, on dialysis, or with a history of Cannabis abuse are not candidates to be treated according to the invention. [0048] Animals, especially dogs and cats, can be treated according to the invention. Seizures in dogs and cats are caused by abnormal brain activity; they can be subtle or cause violent convulsions. Some seizures only occur once but repeated seizures require treatment to prevent larger areas of the brain from becoming affected. Dosage amounts and serum levels of drug are the same as disclosed above for human patients.

[0049] While this invention has been described as having preferred sequences, ranges, ratios, steps, order of steps, materials, structures, symbols, indicia, 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.