WO2017160923A1

WO2017160923A1 - Formulations of argan oil and cannabidiol

Info

Publication number: WO2017160923A1
Application number: PCT/US2017/022431
Authority: WO
Inventors: Michael Edward SHEMANSKI
Original assignee: Royal Oil Colorado Llc
Priority date: 2016-03-15
Filing date: 2017-03-15
Publication date: 2017-09-21

Abstract

The present invention relates to formulations of Argan oil and Cannabidiol (CBD). The Formulations of the present invention are useful in treating inflammatory disorders including arthritis. More specifically, the compositions provide synergistic results when used in topical administration to affected areas such as joints or on the skin.

Description

FORMULATIONS OF ARGAN OIL AND CANNABIDIOL

Field

[0001] The present invention relates to formulations of Argan oil and Cannabidiol (CBD). The formulations of the present invention are useful in treating inflammatory disorders including arthritis. More specifically, the compositions provide synergistic results when used in topical administration to affected areas such as joints or on the skin.

Background

[0002] Argan oil is an extract from the Moroccan Argan tree, particularly its kernels (Argania spinosa L.). Patent applications, such as French Patent Publications 2,553,788, and 2,756,183, United States Patent Publication 2008/0193399 and International Patent Publication WO 01/37792 describe methods for preparing argan extracts and combinations including a lipidic extract of argan fruit, pharmaceutical or cosmetic compositions of argan oil with aloe vera extracts, and dermatological compositions thereof for softening and rehydrating skin and reducing wrinkles and age spots.

[0003] Cannabidiol is one of at least 85 active cannabinoids identified from the cannabis plant. It is a major phytocannabinoid, accounting for up to 40% of the plant's extract. CBD is considered to have a wider scope of medical applications than tetrahydrocannabinol. An orally- administered liquid containing CBD has received orphan drug status in the United States for use as a treatment for Dravet syndrome, under the brand name Epidiolex.

[0004] Oral formulations of CBD have been reported to have activity against arthritis and other disorders. PNAS vol. 97 no. 17, A. M. Malfait, 9561-9566, DOI: 10.1073/PNAS. 160105897. [0005] The present formulations are topical applications with enhanced properties relative to prior art formulations including the surprising property of facilitating penetration of an effective amount of the active CBD through the skin into a distressed tissue.

Summary

[0006] The present invention relates to a formulation of Argan oil and Cannabidiol (CBD).

[0007] More specifically, the formulations of the present invention are useful in treating inflammatory disorders including arthritis including rheumatoid arthritis and osteoarthritis; dermatitis including eczema, psoriasis, dry skin, skin inflammations (such as those caused by tattoo, insect bites, poison ivy and jellyfish), allergic dermatitis, contact dermatitis, atopic dermatitis, and psoriasis; ulcerative colitis, and Crohn's disease. More specifically, the compositions provide synergistic results when used in topical administration to affected areas such as joints or on the skin.

[0008] One embodiment of the present invention is directed to a composition of about 28 grams (25 to 35 grams, 28.3495 grams or 1 ounce is most preferred) of Argan oil and 50-150mg, more preferably lOOmg, of Cannabidiol oil (CBD).

Detailed Description

[0009] Argan oil is extracted from the fruits of the Argan tree (Argania spinosa, sapotaceae family), more specifically kernels or seeds from the Argan. This tree is little known outside of Morocco since its growth is limited to the south-west region of Morocco. Currently, it is estimates that over 700,000-800,000 hectares are in cultivation.

[0010] The fruits of the Argan tree are green. They resemble an olive but are larger and more round. Inside is a nut whose shell is very hard. This represents approximately one quarter of the weight of the fruit. The nut may contain up to three argan seeds, from which argan oil will be extracted by means of mechanical cold compression.

[0011] Argan oil is extracted traditionally from a paste manufactured from the crushed

"almonds" of pear-form fruits of Argania Spinosa. The Argan oil is non-saponifiable (which contributes to its recognized high quality), soluble in chloroform or hexane, slightly soluble in ethanol but non-miscible with water. This oil is known to possess some pharmaceutical activity and is under investigation for the treatment of cancer and other disorders.

[0012] Although the present inventors do not wish to be limited to one particular theory, they have surprisingly found that the Argan oil as used herein affects skin permeability and transport mechanisms such that effective amounts of topically applied CBD may be detected

subcutaneously in tissues and joints of patients treated according to the invention. Other compounds have been known to possess such permeability and penetration properties such as dimethyl sulfoxide. See Kara Capriotti and Joseph A. Capriotti, Dimethyl Sulfoxide, History, Chemistry, and Clinical Utility in Dermatology, J. Clin. Aesthet. Dermatol., 2012 Sep; 5(9): 24- 26. Mechanistically it is not clear why the present formulations possess such permeability and penetration activity but the results of therapy in individuals in need of anti-inflammatory, arthritic or immunological treatment is unexpected. Patients in need of treatment report improved outcomes after as little as two weeks of treatment.

[0013] The formulations of the present invention are also useful in the treatment of lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, cancer, atopic dermatitis, autoimmune thyroid disorders, ankylosing spondylitis, juvenile idiopathic arthritis, Crohn's disease, psoriatic arthritis, Alzheimer's disease, and Leukemia. [0014] The formulations of the present invention are useful in the treatment of pain and swelling associated with inflammation in transient conditions and chronic diseases in which inflammation plays a critical role. Transient conditions include treatment of inflammation associated with minor abrasions, sunburn or contact dermatitis, as well as, the relief of pain associated with tension and migraine headaches and menstrual cramps. Applications for chronic conditions include arthritic diseases, such as rheumatoid arthritis and osteoarthritis. Although, rheumatoid arthritis is largely an autoimmune disease and osteoarthritis is caused by the degradation of cartilage in joints, reducing the inflammation associated with each provides a significant increase in the quality of life for those suffering from these diseases.

[0015] In addition to rheumatoid arthritis, inflammation is a component of rheumatic diseases in general. Diseases include systemic lupus erythromatosus (SLE), as well as, rheumatic skin conditions, such as scleroderma. The formulations are also effective for the relief of

inflammatory skin conditions that are not of rheumatic origin, such as psoriasis, in which reducing the inflammation resulting from the over production of prostaglandins could provide a direct benefit.

[0016] Inflammation and/or pain is associated with a skeletal or muscular disease or condition selected from the group consisting of: musculoskeletal sprains, musculoskeletal strains, tendonopathy, peripheral radiculopathy, osteoarthritis, degenerative joint disease, juvenile arthritis, gout, ankylosing spondylitis, psoriatic arthritis, system lupus erythematosus, costochondritis, tendonitis, bursitis, temporomandibular joint syndrome, and fibromyalgia.

[0017] Inflammation is a process by which pathogenic vectors such as microbes or tissue injury induce the release of cytokines and chemokines from various cell types producing increased blood vessel permeability, upregulation of endothelial receptors, and thus increased egress of various cells of the innate and adaptive immune system which enter surrounding tissue and produce the classical symptoms of inflammation, i.e. redness, swelling, heat and pain.

[0018] Inflammation is a localized reaction of live tissue due to an injury, which may be caused by various endogenous and exogenous factors. The exogenous factors include physical, chemical, and biological factors. The endogenous factors include inflammatory mediators, antigens, and antibodies. Endogenous factors often develop under the influence of an exogenous damage. An inflammatory reaction is often followed by an altered structure and penetrability of the cellular membrane. Endogenous factors, such as mediators and antigens define the nature and type of an inflammatory reaction, especially its course in the zone of injury. In the case where tissue damage is limited to the creation of mediators, an acute form of inflammation develops. If immunologic reactions are also involved in the process, through the interaction of antigens, antibodies, and autoantigens, a long-term inflammatory process will develop. Various exogenous agents, for example, infection, injury, radiation, also provide the course of inflammatory process on a molecular level by damaging cellular membranes which initiate biochemical reactions.

[0019] Pain that can be treated with the formulations of the invention can be divided into three types: nociceptive, neuropathic, and mix-type.

[0020] Nociceptive pain is the term for pain that is detected by specialized sensory nerves called nociceptors. These nerves are located throughout the soft tissues, such as muscles and skin, as well as the internal organs. There are two types of nociceptive pain: somatic pain and visceral pain. Visceral pain comes from the internal organs. Deep somatic pain is initiated by stimulation of nociceptors in ligaments, tendons, bones, blood vessels, fasciae and muscles, and is dull, aching, poorly localized pain. Examples include sprains and broken bones. Superficial pain is initiated by activation of nociceptors in the skin or other superficial tissue, and is sharp, well- defined and clearly located. Examples of injuries that produce superficial somatic pain include minor wounds and minor (first degree) burns. Nociceptive pain is usually short in duration and end when the damage recovers. Examples of nociceptive pain include postoperative pain, sprains, bone fractures, burns, bumps, bruises, and inflammatory pain.

[0021] Neuropathic pain is pain caused by damage or disease that affects the somatosensory system. Neuropathic pain is originated from spontaneous ectopic neuron discharge in the nervous system either in central or in peripheral. Due to the underlying etiologies are usually irreversible, most of neuropathic pain are chronic pain. Most people describe neuropathic pain as shooting, burning, tingling, lancinating, electric shock qualities, numbness, and persistent allodynia. The nomenclature of neuropathic pain is based on the site of initiating nervous system with the etiology; for examples, central post-stroke pain, diabetes peripheral neuropathy, post-herpetic (or post-shingles) neuralgia, terminal cancer pain, phantom limb pain.

[0022] Mix-type pain is featured by the coexistence of both nociceptive and neuropathic pain. For example, muscle pain trigger central or peripheral neuron sensitization leading to chronic low back pain, migraine, and myofacial pain.

[0023] Connective tissues are subjected to a constant barrage of stress and injury that can be affected by treatment with the formulations of the invention. Acute or chronic impacts and the natural progression of various degenerative diseases all produce painful inflammation in joint regions, such as the neck, back, arms, hips, ankles and feet.

[0024] Additional combination therapy is envisioned such as addition into the formulation of corticosteroids, COX-2 inhibitors or NSAIDS. [0025] There is a need for a composition and a method for treating inflammation, inflammatory- related disorders, and pain. The composition should be economic and easy to manufacture, and the method should be effective and possess reduced side effects as compared to current therapies.

[0026] Other pharmaceutically acceptable carriers that can be combined in the formulations of the invention include inactive ingredients such as non-aqueous based solutions, suspensions, emulsions, microemulsions, micellar solutions, gels, and ointments. The pharmaceutically acceptable carriers may also contain ingredients that include, but are not limited to, saline and aqueous electrolyte solutions; ionic and nonionic osmotic agents such as sodium chloride, potassium chloride, glycerol, and dextrose; pH adjusters and buffers such as salts of hydroxide, phosphate, citrate, acetate, borate; and trolamine; antioxidants such as salts, acids and/or bases of bisulfite, sulfite, metabisulfite, thiosulfite, ascorbic acid, acetyl cysteine, cysteine, glutathione, butylated hydroxyanisole, butylated hydroxytoluene, tocopherols, and ascorbyl palmitate;

surfactants such as lecithin, phospholipids, including but not limited to phosphatidylcholine, phosphatidylethanolamine and phosphatidyl inositiol; poloxamers and poloxamines, polysorbates such as polysorbate 80, polysorbate 60, and polysorbate 20, polyethers such as polyethylene glycols and polypropylene glycols; polyvinyls such as polyvinyl alcohol and povidone; cellulose derivatives such as methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose and hydroxypropyl methylcellulose and their salts; petroleum

derivatives such as mineral oil and white petrolatum; fats such as lanolin, peanut oil, palm oil, soybean oil; mono-, di-, and triglycerides; polymers of acrylic acid such as

carboxypolymethylene gel, and hydrophobically modified cross-linked acrylate copolymer; polysaccharides such as dextrans and glycosaminoglycans such as sodium hyaluronate. Such pharmaceutically acceptable carriers may be preserved against bacterial contamination using well-known preservatives, these include, but are not limited to, benzalkonium chloride, ethylenediaminetetraacetic acid and its salts, benzethonium chloride, chlorhexidine,

chlorobutanol, methylparaben, thimerosal, and phenylethyl alcohol, or may be formulated as a non-preserved formulation for either single or multiple use.

[0027] Topical formulations can be in a form of gel, cream, lotion, liquid, emulsion, ointment, spray, solution, and suspension. The inactive ingredients in the topical formulations for example additionally include, but not limited to, lauryl lactate (emollient/permeation enhancer), diethylene glycol monoethyl ether (emollient/permeation enhancer), DMSO (solubility enhancer), silicone elastomer (rheology/texture modifier), caprylic/capric triglyceride,

(emollient), octisalate, (emollient/UV filter), silicone fluid (emollient/diluent), squalene

(emollient), sunflower oil (emollient), and silicone dioxide (thickening agent).

[0028] The present invention is directed to a method of treating inflammation and/or pain.

[0029] The method comprises the steps of first identifying a subject suffering from inflammation and/or pain, and administering to the subject a topical formulation of the active CBD compound, in an amount effective to treat inflammation and/or pain. "An effective amount," as used herein, is the amount effective to treat a disease by ameliorating the pathological condition or reducing the symptoms of the disease. One therapy involves treating the affected area with a formulation of 28 grams (25 to 35 grams, 28.3495 grams or 1 ounce is most preferred) of Argan oil and 50- 150mg, more preferably lOOmg, of Cannabidiol oil (CBD) which may be rubbed into the affected area and may be covered with a gauze to prevent the oil from being rubbed away.

Treatment may be continued one to three times daily for one to two weeks or until the patient achieves the desired remission of symptoms. [0030] In one embodiment, the method reduces or alleviates the symptoms associated with inflammation. The present invention provides a method to treat localized manifestations of inflammation characterized by acute or chronic swelling, pain, redness, increased temperature, or loss of function in some cases.

[0031] In another embodiment, the present invention provides a method to alleviate the symptoms of pain regardless of the cause of the pain. The general term "pain" treatable by the present method includes nociceptive, neuropathic, and mix-type. The present invention reduces pain of varying severity, i.e. mild, moderate and severe pain; acute and chronic pain. The present invention is effective in treating joint pain, muscle pain, tendon pain, burn pain, and pain caused by inflammation such as rheumatoid arthritis.

[0032] In one embodiment, the present invention is useful in treating inflammation and/or pain associated in a musculoskeletal system or on the skin. The highly innervated, musculoskeletal and skin systems have a high capacity for demonstration of pain. In addition, the musculoskeletal system has a high capacity for tissue swelling, and the skin has a high capacity for redness, swelling, and heat. In musculoskeletal and skin systems, the degree of tissue damage is frequently magnified out of proportion to the resulting inflammatory response.

[0033] The present invention provides a method for treating inflammation and/or pain associated with inflammatory skeletal or muscular diseases or conditions. The method comprises the steps of identifying a subject in need thereof, and administering to the subject a formulation of the invention, in an amount effective to treat inflammation and/or pain. The skeletal or muscular diseases or conditions include musculoskeletal sprains, musculoskeletal strains, tendonopathy, peripheral radiculopathy, osteoarthritis, joint degenerative disease, polymyalgia rheumatica, juvenile arthritis, gout, ankylosing spondylitis, psoriatic arthritis, systemic lupus erythematosus, costochondritis, tendonitis, bursitis, such as the common lateral epicondylitis (tennis elbow), medial epichondylitis (pitchers elbow) and trochanteric bursitis, temporomandibular joint syndrome, and fibromyalgia.

[0034] The present invention provides a method for treating inflammation and/or pain associated with inflammatory skin diseases such as dermatitis, psoriasis, and acne. The method comprises the steps of identifying a subject in need thereof, and administering to the subject a formulation of the invention, in an amount effective to treat inflammation and/or pain.

[0035] The present invention further provides a method for treating inflammatory skin diseases such as dermatitis, psoriasis, and acne (Acne vulgaris). The method comprises the steps of identifying a subject in need thereof, and administering to the subject a formulation of the invention, in an amount effective to reduce or eliminate the symptoms of the disease.

[0036] Skin is highly reactive to environmental stimuli and the epidermal component of keratinocytes is a very rich source of both arachidonic acid and pro-inflammatory cytokines of IL-1 and TNF. The skin dendritic cells, Langerhans cells, recognize and process antigens for further immune response of various lymphocytes and all of these cells are primarily regulated by cytokines through their specific cell surface receptors.

[0037] Dermatitis (also called eczema) is generic inflammation of the skin. Specific types of dermatitis include atopic, contact, nummular, and photo-induced.

[0038] Contact dermatitis is an inflammatory condition of the skin either of irritant exposure to the skin without specific adaptive immunologic pathogenesis or of allergic sensitization and subsequent exposure of the skin to the sensitizing allergen with specific adaptive immunologic pathogenesis. Both involve innate and acquired immune system response including arachidonic acid and cytokine components that initiate and propagate the disease through cell to cell messaging by eicosanoid and/or cytokine moieties produced by epidermal cells, macrophages, dendritic cells, neutrophils, eosinophils, and various T and B lymphocytes. Contact dermatitis may be either acute or chronic. The acute forms are pruritic with erythema, edema, and micro or macrovesiculation in the areas of skin contact by the initiating factor. The chronic forms are pruritic with milder erythema, scaling, lichenification, and possibly Assuring particularly on the hands.

[0039] The formulations of the invention are effective in treating atopic dermatitis and alleviating one or more symptoms selected from the group consisting of erythema, induration, lichenification, scaling, and oozing and crusting.

[0040] The formulations of the invention are effective in treating rosacea and alleviating one or more symptoms selected from the group consisting of erythema, telangiectasia, red domed papules and pustules, red gritty eyes, and burning and stinging sensations.

[0041] Since the present invention has an aspect that relates to the treatment of the

disease/conditions described herein, the invention also relates to kits comprising one or more pharmaceutical compositions (I.e. different dosage amounts) with application and clean-up materials.

[0042] An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (oils, emulsions, tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the capsules or formulations to be packed. Next, the formulations are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the formulations are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the formulations can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The formulation can then be removed via said opening or using the backing as a delivery means or when an oil may be squeezed onto the affected area.

[0043] It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the packs whereby the numbers correspond with the days of the regimen which the oils, emulsions, tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday,

Tuesday, etc.... Second Week, Monday, Tuesday,..." etc. Other variations of memory aids will be readily apparent. A "daily dose" can be a single capsule or film to be taken on a given day.

[0044] In another specific embodiment of the invention, a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.

[0045] Argan oil is commercially available. Preferably, Argan Oil is isolated by cold press of freshly harvested seeds from the Argania Spinosa tree and kept cold in an inert environment free of oxidizing agents. [0046] Cannabidiol is commercially available. Cannabidiol may also be prepared from plant material such as described in EP 1542952 Al (WO2004026802A1) in substantially pure form starting from plant material having a chromatographic purity of 95% or greater.

[0047] Formulations of the invention include effective amounts of cannabidol such as lOmg to lOOOmg in Argan oil preferably 1ml to 10 ounces of Argan oil. One embodiment of the invention is 100 mg CBD in minimal Argan oil (1-10 ml). Another embodiment comprises lOOmg CBD in 0.5 to 30 grams (more preferably 28.3495 grams, 1 ounce) of Argan oil.

Example 1

[0048] Formulations of the invention are prepared by mixing lOOmg of CBD and 28.3495 grams Argan Oil and placing the mixture in a mold followed by gently heating the mold at 110°C for 1 hr. The product is isolated as a capsulate that when applied to the affected area melts with the body temperature of the hand/finger and dissolves into the patient within 10-15 minutes of application.

Example 2

[0049] Ten patients suffering from joint pain are randomly assigned to a treatment group versus an indomethacin control group. Topical treatment (3 times daily) comprising rubbing a formulation according to Example 1 around the painful joint area as the formulation melts until absorption is complete. Patients reported that the treatment was more efficacious than 50 mg oral indomethacin taken 3 times daily. There were no reports of gastrointestinal discomfort in the experimental group.

Claims

1. A formulation comprising Argan oil and Cannabidiol (CBD).

2. A formulation according to claim 1 wherein the Argan Oil comprises 28.3 grams.

3. A formulation according to claim 1 wherein the CBD comprises lOOmg.

4. A method of treating inflammation in a mammal (preferably a human) in need of such treatment comprising topically administering an effective amount of CBD and Argan Oil.