WO2020234650A1 - Compositions pharmaceutiques comprenant des compositions de cbd et de terpène - Google Patents

Compositions pharmaceutiques comprenant des compositions de cbd et de terpène Download PDF

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Publication number
WO2020234650A1
WO2020234650A1 PCT/IB2020/000402 IB2020000402W WO2020234650A1 WO 2020234650 A1 WO2020234650 A1 WO 2020234650A1 IB 2020000402 W IB2020000402 W IB 2020000402W WO 2020234650 A1 WO2020234650 A1 WO 2020234650A1
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composition
oil
caryophyllene
linalool
cbd
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PCT/IB2020/000402
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English (en)
Inventor
Courtney BETTY
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Timeless Herbal Care (Canada) Ltd.
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Publication of WO2020234650A1 publication Critical patent/WO2020234650A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present Application is related to compositions and methods for reducing pain, inflammation, and dependencies on opioid compounds in mammals.
  • the opioid compounds Preferably, the
  • compositions comprise cannabidiol (CBD) and one or more terpene molecules within a carrier and are provided in an effective amount so as to reduce pain, anxiety, inflammation, and the dependency on opioid compounds in a mammal.
  • CBD cannabidiol
  • Opioid pain medications have been widely prescribed to treat severe and chronic pain.
  • a significant increase in opioid prescriptions began in the 1990s and has continued to increase dramatically through the current day.
  • the number of prescriptions for opioid painkillers jumped from 76 million to approximately 207 million between 1991 and 2013.
  • prescription opioids work to dampen pain signals from the body, but the ensuing psychological effects, like euphoria and extreme relaxation, can lead to abuse and addiction. The summation of these effects proves intensely rewarding to those abusing them, eliciting persistent alterations in brain chemistry that may further compel an individual to use the drug beyond the prescribed use of treating pain.
  • This dependency and recreational use of prescription opioids has reached epidemic levels, with an estimated 130 people a day dying from opioid related overdoses in the United States.
  • Applicant has identified new compositions that utilize components from cannabis including CBD, THC, cannabinoids as a class of compounds, and terpenes to treat opioid use disorder, to reduce the dependency on opioids, to provide pain relief, reduce anxiety, reduce inflammation, provide vascular combination, and be synergistic or in competition with opioid receptors.
  • compositions and methods of treatment using the same for treating pain, inflammation, anxiety, and reducing dependencies on opioid therapeutics through new compositions and formulations comprising certain cannabinoid compounds combined with one or more of additional terpenes or curcumin.
  • composition for treating anxiety related to opioid withdrawal comprising: at least 5% cannabidiol, at least 2% b-caryophyllene, at least
  • linalool at least one emulsifying agent comprising between 50% and 80% by weight of the composition, at least one oil comprising between 1% and 10% by weight of the composition, at least one cosurfactant comprising between 1% and 10% by weight of the composition, and at least one antioxidant comprising between 1% and 10% of the composition, wherein the composition is suitable for oral dosage to a mammal.
  • a composition for treatment of addiction comprising: at least 5% cannabidiol, at least 2% b-caryophyllene, at least 2% linalool, at least one emulsifying agent comprising between 50% and 80% by weight of the composition, at least one oil comprising between 1% and 10% by weight of the composition, at least one cosurfactant comprising between 1% and 10% by weight of the composition, and at least one antioxidant comprising between 1% and 10% of the composition, wherein the composition is suitable for oral dosage to a mammal.
  • composition provided as a dose of greater than 50 mg of the cannabidiol, greater than 20 mg of the b-caryophyllene, and greater than 20 mg of the linalool.
  • the oil is a long chain fatty acid.
  • composition wherein the oil is a medium chain fatty acid or a long chain fatty acid.
  • composition admixed with a protective colloidal material.
  • the composition wherein the active composition is microencapsulated.
  • the composition formed as a liquid or sublingual oral dose.
  • composition further comprising at least 1% of a piperine compound.
  • b-caryophyllene, and linalool are generated from an extract of a cannabis plant.
  • the composition wherein the b-caryophyllene and linalool are derived from any plant.
  • the composition wherein the b-caryophyllene and linalool are derived from a fruit.
  • composition further comprising between 0.01% and 0.3% THC.
  • composition wherein the cannabidiol is provided from a combination of an extract from Cannabis sativa and Cannabis indica.
  • the composition wherein the Cannabis sativa is combined with the Cannabis indica at a ratio of between 100: 1 and 1 : 100.
  • either composition comprising between 1% and 10% by weight of curcumin.
  • composition wherein the emulsifying agent is a combination of Kolliphor EL, Tween 80 and Phosal 50 PG, wherein the cosurfactant is propylene glycol and wherein the oil is an MCT oil, and wherein the antioxidant is vitamin E.
  • the composition wherein the components of the composition
  • the emulsifying agent comprises between 30% and 40% of Kolliphor EL, between 25% and 35% of Tween 80 and between 5% and 10% of Phosal 50 PG, between 5% and 10% of the co-surfactant as propylene glycol, and between 1% and 5% of the oil as an MCT oil, and wherein the antioxidant is between 1% and 5% and is vitamin E.
  • a method of forming an oral composition comprising:
  • the method comprising one or more additional excipients.
  • the method wherein the composition is administered orally, oral mucosally. In a further embodiment, the method wherein the composition is administered orally to the mouth for contact with the oral mucosa. In a further embodiment, the method wherein the composition is administered to the nasal mucosa as a gel, liquid, or aerosol. [0020] In a further embodiment, the method wherein the emulsifying agents are Kolliphor EL, Tween 80, and Phosal 50 PG.
  • the method wherien the composition comprises between 30% and 40% Kolliphor EL, between 25% and 35% Tween 80, and between 5% and
  • composition wherein the composition’s cosurfactant is propylene glycol and wherein the antioxidant is vitamin E.
  • the compositon formulated as a 50, 100, 200, or 400 mg dose of cannabidiol.
  • a composition comprising an active composition made up of at least 5% CBD, and two of: at least 1% b-caryophyllene, greater than 0.2% Linalool, greater than 0.4% borneol, and greater than 0.01 percent of each of Limonene and Nerolidol; wherein said composition is formed as an oral dosage form for mammalian consumption.
  • composition comprises about 2% by weight of b-caryophyllene, and about 2% by weight of Linalool.
  • composition is admixed with a long chain fatty acid or a medium chain fatty acid.
  • composition is admixed with a protective colloidal material.
  • the composition wherein the active composition is microencapsulated.
  • the composition is formed as a liquid dose.
  • the composition is formed as a sublingual dose.
  • the composition further comprises at least one excipient, and at least one binding agent.
  • CBD and terpene molecules are generated from an extract of a cannabis plant.
  • terpene molecules are derived from any plant.
  • terpenes are derived from a fruit.
  • CBD is generated from an extract of a cannabis plant and the terpene molecules are derived from a combination of mango extract and cannabis extract.
  • the active composition is admixed into a carrier oil and absorbed into a food material; wherein the carrier oil and food material are freeze- dried to form an oral dosage material.
  • composition further comprising between 0.01% and 0.3% THC.
  • the composition wherein the cannabis extract is a combination of an extract from Cannabis sativa and Cannabis indica.
  • the Cannabis sativa is combined with the Cannabis indica at a ratio of between 100: 1 and 1 : 100.
  • a method of forming an oral CBD formulation comprising combining a portion of CBD extract with a portion of mango extract; and admixing said extracts with a carrier oil.
  • a method of forming an oral food material composition comprising CBD and terpenes; comprising combining a portion of CBD extract with a portion of mango extract; admixing said extracts with a carrier oil; admixing said carrier oil and extracts with a food material; freeze-drying said food material and extracts; grinding the freeze-dried material and forming the food material.
  • the method further comprising one or more additional excipients.
  • a carrier is selected from the group consisting of an emulsion, a lipid, an alcohol, and nonpolar organic solvents.
  • a composition for treatment of pain comprising: an effective amount of CBD; an effective amount of a terpene formulation selected from the group consisting of: b-caryophyllene, Linalool, Borneol, Limonene, Nerolidol, and combinations thereof.
  • a terpene formulation selected from the group consisting of: b-caryophyllene, Linalool, Borneol, Limonene, Nerolidol, and combinations thereof.
  • the composition comprises at least 1% by weight of
  • composition is administered orally, oral mucosally, nasally, topically, or inhaled.
  • composition is administered to the nasal mucosa as a gel, liquid, or aerosol.
  • the composition is burned or vaporized and inhaled.
  • the composition comprising a medium chain triglyceride oil (MCT), at least one emulsifying agent, a surfactant, and at least one antioxidant agent.
  • MCT medium chain triglyceride oil
  • Applicant proposes new therapeutic materials comprising a carrier, and an admixture of cannabinoid and terpene compounds that together form a novel combination with synergistic impacts to treat addiction specifically related to opioid use disorder, including treatment of reducing anxiety, reducing cravings, and reducing pain and inflammation.
  • opioid use disorder a key target of the compositions described herein is the treatment of opioid use disorder.
  • Opioids have long been used for their therapeutic properties, namely reduction of pain, but they have also been abused for centuries for their ability to induce euphoria. Their use and abuse modernly and historically are a scourge. Today, nearly 50,000 deaths each year are attributed to opioid overdoses in the United States alone.
  • Treatment for opioid use disorder often includes therapy with one of methadone or buprenorphine. Additional options include the use of naltrexone, though its use for long-term treatment is under review. Therapeutics are needed to provide new and improved treatment options, as relapse with any of the prior art drugs is prevalent and some even become addicted to the treatment drugs.
  • a key issue in treatment remains the reduction of a series of maladies including pain, inflammation, depression, and anxiety. Applicant has created a new formulation that seeks to treat several of these maladies in order to create a superior composition for long term opioid use disorder treatment.
  • the term“about” means plus or minus 5% of the numerical value of the number with which it is being used. Therefore, about 50% means in the range of 45%-55%.
  • administering when used in conjunction with a therapeutic means to administer a therapeutic directly to a subject, whereby the agent positively impacts the target.
  • administering the therapeutic drug or compound may be accomplished by, for example, injection, oral administration, topical administration, or by these methods in combination with other known techniques. Such combination techniques include heating, radiation, ultrasound, and the use of delivery agents.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutical composition is intended to encompass a product comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation, or aggregation of any two or more of the ingredients or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • compositions of the present invention encompass any composition made by admixing a compound or compounds of the present invention and a pharmaceutically acceptable carrier.
  • therapeutic mean a compound or composition utilized to treat, combat, ameliorate, prevent, or improve an unwanted condition or disease of a patient.
  • agent “active agent,”“therapeutic agent,” or“therapeutic” encompass a combination of, for example, CBD, one or more terpene compounds, and/or additional agents as described in the present invention.
  • A“therapeutically effective amount” or“effective amount” of a composition is a predetermined amount calculated to achieve the desired effect, i.e., to inhibit, block, or reverse the activation, migration, proliferation, alteration of cellular function, and to preserve the normal function of cells.
  • the activity contemplated by the methods described herein includes both medical therapeutic and/or prophylactic treatment, as appropriate, and the compositions of the invention may be used to provide improvement in any of the conditions described. It is also contemplated that the compositions described herein may be administered to healthy subjects or individuals not exhibiting symptoms but who may be at risk of developing a particular disorder.
  • a therapeutically effective amount of compound of this invention is typically an amount such that when it is administered in a physiologically tolerable excipient composition, it is sufficient to achieve an effective systemic concentration or local concentration in the tissue in the amounts described in the embodiments.
  • the terms“treat,”“treated,” or“treating” as used herein refer to both therapeutic treatment and prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or to obtain beneficial or desired clinical results.
  • beneficial or desired results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder, or disease; stabilization (i.e., not worsening) of the state of the condition, disorder, or disease; delay in onset or slowing of the progression of the condition, disorder, or disease; amelioration of the condition, disorder, or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder, or disease.
  • CBD extract refers to an extract of a cannabis or hemp plant having at least 1% of CBD.
  • the CBD extract comprises at least 10% CBD, and more preferably more than 25%, more than 50%, more than 75%, and more than 95%.
  • Selective extraction procedures can be utilized by those of ordinary skill in the art to create extracts that are high in certain cannabinoid compounds, such as CBD.
  • the cannabis plant is a flowering plant in the family cannabaceae, which is an annual dioecious, flowering herb.
  • the leaves are palmately compound or digitate with a well-known serrated leaflet.
  • the first pair of leaves usually have a single leaflet, the number gradually increasing up to a maximum of about 13.
  • the leaves have a striking orientation and pattern that enables even persons vaguely familiar with the plant to distinguish a cannabis leaf from unrelated species.
  • Cannabis plants are predominately dioecious, having male and female flowers occurring on separate plants. There are several different species that are cultivated, with the two most common being C. sativa and C. indica. Of these, the C.
  • sativa plant typically grows larger and results in greater biomass for use in extracting cannabinoid molecules, and for growing biomass for use in hemp-based products.
  • the term“cannabis plant” refers to all varietals of cannabis including those high and low in either THC or CBD concentrations, and including industrial hemp.
  • the cannabis plant produces a group of chemicals called cannabinoids, among which is A 9 -tetrahydrocannabinol (THC), which is a psychoactive compound having receptors in the mammalian body.
  • cannabinoids A 9 -tetrahydrocannabinol (THC)
  • THC tetrahydrocannabinol
  • cannabinoids has been hampered by the psychoactive properties of some compounds (e.g., Dronabinol) as well as their low bioavailability when administered orally.
  • Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters systemic circulation, thereby accessing the site of action.
  • the low bioavailability of orally ingested cannabinoids (from about 6% to 20%; Adams & Martin (1996) Addiction 91 : 1585-614; Agurell et al. (1986) Pharmacol. Rev. 38: 21-43; Grotenhermen (2003) Clin. Pharmacokinet.
  • Cannabinoids are a heteromorphic group of chemicals which directly or indirectly activate the body’s cannabinoid receptors.
  • cannabinoids There are three main types of cannabinoids: herbal cannabinoids that occur uniquely in the cannabis plant, synthetic cannabinoids that are manufactured, and endogenous cannabinoids that are produced in vivo.
  • Herbal cannabinoids are nearly insoluble in water but soluble in lipids, alcohol, and nonpolar organic solvents, and can also be suspended in emulsions. These natural cannabinoids are concentrated in a viscous resin that is produced in glandular structures known as trichomes. In addition to cannabinoids, the resin is rich in terpenes, which are largely responsible for the odor of the cannabis plant. These materials are also present in additional tissues of the plant, most notably in the flowers and leaves of the plants.
  • Cannabinoid research has increased tremendously in recent years since the discovery of cannabinoid receptors and the endogenous ligands for these receptors.
  • the receptors include CB1, predominantly expressed in the brain, and CB2, primarily found on the cells of the immune system.
  • Cannabinoid receptors belong to a superfamily of G protein- coupled receptors. They are single polypeptides with seven transmembrane a-helices, and have an extracellular, glycosylated N-terminus and intracellular C-terminus. Both CB1 and CB2 cannabinoid receptors are linked to Gl/0 proteins.
  • ligands for these receptors capable of mimicking the pharmacological actions of THC have also been discovered.
  • Such ligands were designated endocannabinoids and included anandamide and 2-arachidonoyl glycerol (2-AG).
  • Anandamide is produced in the brain and peripheral immune tissues such as the spleen.
  • cannabidiol Unlike THC, which exerts its action by binding to CB1 and CB2, cannabidiol (CBD) does not readily bind to these receptors and hence has no psychotropic activity. Instead, cannabidiol indirectly stimulates endogenous cannabinoid signaling by suppressing the enzyme that breaks down anandamide (fatty acid amide hydroxylase,“FAAH”). Cannabidiol also stimulates the release of 2-AG. Cannabidiol has been reported to have immunomodulating and anti-inflammatory properties; to exhibit anticonvulsive, antianxiety, and antipsychotic activity; and to function as an efficient neuroprotective antioxidant.
  • FAAH fatty acid amide hydroxylase
  • Cannabinoids in cannabis are often inhaled via smoking but may also be ingested.
  • Smoked or inhaled cannabinoids have reported bioavailabilities ranging from 2-56%, with an average of about 30% (Huestis (2007) Chem. Biodivers. 4: 1770-1804; McGilveray (2005) Pain Res. Manag. 10 Suppl. A: 15A-22A). This variability is mainly due to differences in smoking dynamics.
  • Cannabinoids that are absorbed through the mucous membranes in the mouth have bioavailabilities of around 13% (Karschner et al. (2011) Clin. Chem. 57:66-75).
  • CBD is generally considered to be safe and has been used medicinally and in nutraceutical applications. The mechanism of action of CBD is multifold.
  • CB1 and CB2 receptors Two cannabinoid receptors are known to exist in the human body, including CB1 and CB2 receptors, but THC, and not CBD, binds to these receptors.
  • the CB1 receptors are located mainly in the brain and modulate neurotransmitter release in a manner that prevents excessive neuronal activity.
  • the modulation of these neurotransmitters may be implicated in the calming effect and reduction in anxiety that is defined by CBD.
  • CBD also has the ability to regulate and reduce pain; reduce inflammation; and regulate movement, sensory perception, and cognitive function.
  • An endogenous ligand, anandamide which is naturally occurring in the human body, binds to the CB1 receptor though the G protein coupling system.
  • CBD has an indirect effect on the CB1 receptor by stopping the enzymatic breakdown of anandamide, allowing it to stay in the system longer and thus providing certain benefits.
  • CBD has a mild effect on the CB2 receptors, which are located in the periphery in lymphoid tissue. Accordingly, CBD helps to mediate the release of cytokines from immune cells in a manner that helps to reduce inflammation and pain. Indeed, cannabinoids such as CBD also induce apoptosis and inhibit cell proliferation, in addition to the suppression of cytokine production, while also inducing regulatory T cells (Tregs).
  • cannabinoids such as CBD also induce apoptosis and inhibit cell proliferation, in addition to the suppression of cytokine production, while also inducing regulatory T cells (Tregs).
  • CBD can protect certain cells, for example within the central nervous system, from certain autoimmune conditions such as MS.
  • CBD also plays a modulation role.
  • Cytokines are signaling proteins synthesized and secreted by immune cells upon stimulation. These factors balance the initiation and resolution of inflammation. Accordingly, one of the possible mechanisms of immune control by CBD is by perturbing the balance between cytokines produced by T helper subsets, Thl and Th2. In certain prior studies, both anti-inflammatory and proinflammatory effects were shown.
  • THC During chronic inflammation, IL-6 suppression can decrease tissue injury.
  • THC has been shown to decrease IL-6, TNFa, GM-CSF, and IFNy. Accordingly, THC may be a necessary component in certain applications when a combined effect is necessary to reduce inflammation and decrease pain. Low doses of THC may be suitable to provide these therapeutic effects.
  • CBD is also known to stimulate vanilloid pain receptors (TRPV-1 receptor), which are known to mediate pain perception, inflammation, and body temperature. CBD may also impact certain adenosine receptors, which play a significant role in cardiovascular function and broadly impact anti-inflammatory effects throughout the body as well as regulate and decrease anxiety and depression and increase the sense of well-being.
  • TRPV-1 receptor vanilloid pain receptors
  • Generating THC as a pure compound is performed by extracting the compound from green material from the cannabis plant, typically leaves, flowers, and buds. However, in the extraction process, a number of other cannabinoid compounds are also extracted, and there are at least 85 different cannabinoids that have been isolated from the plant, and some have reported 483 identifiable chemical constituents known to exist in the cannabis plant.
  • Terpenes are a large class of organic compounds produced by a wide number of plants including conifers and other leafy plants, such as cannabis. The chemicals often have a strong and readily identifiable odor. Terpenes are the primary constituent of many essential oils of many types of plants and flowers, typically used for their aromatic boutique, but also for their medicinal properties.
  • Applicant has advantageously identified that therapeutic properties are enhanced through selective inclusion of certain terpene compounds admixed into a pharmaceutical composition with CBD. Specifically, it is advantageous to admix b-caryophyllene and Linalool in concentrations much greater than found in typical full spectrum extracts. Accordingly, it would be advantageous to add in these molecules as individualized and specific extracts in order to reach about 2% total weight of the formulation for each of the b-caryophyllene and Linalool. The inclusion of these terpene molecules increases the bioavailability of the CBD, as well as targets certain receptors in the body to impact pain, inflammation, and anxiety. These are particularly important in the wholistic treatment of opioid use disorder.
  • Curcumin is derived from the Curcuma longa plant and is the principal curcuminoid of turmeric, a member of the ginger family Zingiberaceae . Curcumin is widely panned as a molecule that shows positive results in drug screening but leads to undue experimental attention while failing to advance as a viable drug or drug lead.
  • Curcumin when admixed with certain other molecules, can lead to surprising synergistic effects, specifically when used with cannabinoids such as THC or specifically with CBD, and also with certain terpenes or terpenes mixed with CBD. Accordingly, an inclusion of between 1% and 10% by weight of curcumin to a composition as described herein can increase certain therapeutic effects.
  • Curcumin has certain medicinal properties, including with regard to pain relief and reduction in inflammation. Unlike analgesic drugs, curcumin does not neutralize the pain sensation for a few hours. Instead, curcumin impacts pain sensation by reduction in
  • inflammation which in turn reduces impacts on the body that are causing pain. Accordingly, the reduction in inflammation is also helpful as an antiarthritic agent and for osteoarthritis.
  • Cannabinoid compounds of the present disclosure are highly lipophilic, meaning that they are soluble in lipids and some organic solvents while being substantially insoluble or only sparsely soluble in water.
  • the poor water solubility of these lipophilic agents often results in major difficulties in formulation.
  • lipophilic compounds When administered in the form of an oil solution or some kind of water and/or oil suspension or emulsion, lipophilic compounds usually show poor bioavailability.
  • micellar solubilization by means of surface-active agents (i.e., the use of surfactant micelles to solubilize and transport the therapeutic agent).
  • micelles can incorporate lipophilic therapeutic agents in the hydrocarbon core of the micelle or can entangle the agents at various positions within the micelle walls.
  • formulations is limited by the solubility of the therapeutic agent in the micelle surfactant. For many lipophilic therapeutic agents, such solubility is too low to offer formulations that can deliver therapeutically effective doses.
  • Another method consists of preparing a derivative or an analog of the lipophilic compound having a better solubility in water than the original compound.
  • this derivative may be a water-soluble salt of the compound that usually retains the original biological activity.
  • this approach is applicable only to compounds having acidic or basic properties. If more substantial modifications are introduced into the original compound to improve its solubility, a decrease or even a complete loss of the original bioactivity of the compound is frequently observed.
  • Another approach consists of preparing a water-soluble prodrug capable of liberating the original bioactive compound under physiological conditions.
  • prodrugs usually improve bioavailability of the compound and can ensure a targeted delivery of the compound or its sustained release over a period of time.
  • the use of prodrugs is not universally applicable since they usually require the presence of certain functional groups in the original compound.
  • synthetic methods of improving solubility of a compound by chemical modifications are relatively complicated and expensive.
  • chelating agents such as citric acid, tartaric acid, amino acids, thioglycolic acid, and edetate disodium.
  • buffering agents such as acetate, citrate, glutamate, and phosphate salts.
  • buffers and chelating agents have been implicated in imparting high levels of aluminum in products, leading to adverse side effects.
  • certain chelating agents such as EDTA have been implicated in adverse events such nephrotoxicity and renal tubular necrosis.
  • colloids examples include polypeptides (such as gelatin, casein, and caseinate), polysaccharides (such as starch, dextrin, dextran, pectin, and gum arabic), as well as whole milk, skimmed milk, milk powder, or mixtures of these.
  • polyvinyl alcohol and vinyl polymers for example polyvinylpyrrolidone, (meth)acrylic acid polymers and copolymers, methylcellulose, carboxymethylcellulose, hydroxypropyl cellulose, and alginates.
  • the cannabinoid compounds of the present embodiments are known to those of ordinary skill in the art to have a reduced bioavailability when taken orally by a mammal.
  • Increasing bioavailability is a key issue as it allows a reduction in the total lipophilic agents, while either maintaining the total concentration of the agents within the body or blood stream, or allows for a total increase in the blood plasma concentration levels within the body.
  • Preventing first-pass metabolism, increasing the rate of uptake, or both will increase the bioavailability of the cannabinoids and terpene molecules of the present formulations.
  • Oral administration constitutes the preferred route of administration for a majority of drugs.
  • the less than 10% oral bioavailability of the CBD compound provides a dead end approach toward treatment as the quantity of the CBD necessary to achieve therapeutic levels typically also generates significant GI issues.
  • certain cannabinoids, including CBD have a bitter taste that leads to lack of patient compliance in the case of orally administered dosage forms. In such cases, taste masking is an essential tool to improve patient compliance.
  • compositions also comprise one or more lipophilic active agents which may include but are not limited to dry milk, menthol, sweeteners, sodium bicarbonate, ion-exchange resins, cyclodextrin inclusion compounds, adsorbates, and the like.
  • lipophilic active agents e.g., cannabinoids such as cannabidiol
  • the presently disclosed compositions also comprise one or more lipophilic active agents which may include but are not limited to dry milk, menthol, sweeteners, sodium bicarbonate, ion-exchange resins, cyclodextrin inclusion compounds, adsorbates, and the like.
  • a composition comprises an effective amount of a cannabinoid molecule and a bioavailability enhancing agent wherein the composition is administered orally in order to produce a therapeutic level of CBD within the blood plasma.
  • the blood plasma for therapeutic levels are between 60 and 100 ng/mL.
  • the high dosages resulted in certain GI tract issues and other secondary effects that led to patients reducing the use of the therapeutics.
  • the bioavailability enhancing agent is a long chain fatty acid.
  • the bioavailability enhancing agent is a medium chain fatty acid.
  • the bioavailability enhancing agent is a long chain fatty acid.
  • bioavailability enhancing agent is substantially free of omega-6 fatty acids.
  • the lipophilic active agent infused food product of the present invention is lyophilized.
  • Lyophilization also known as freeze-drying, is a process whereby water is sublimed from a composition after it is frozen. The frozen solution is then typically subjected to a primary drying step in which the temperature is gradually raised under vacuum in a drying chamber to remove most of the water, and then to a secondary drying step typically at a higher temperature than employed in the primary drying step to remove the residual moisture in the lyophilized composition. The lyophilized composition is then appropriately sealed and stored for later use. Tang et al. (2004) Pharmaceutical Research 21 : 191-200 describes the scientific principles pertaining to freeze-drying and guidelines for designing suitable freeze- drying processes. Further description of freeze-drying is found in Remington (2006) The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams, & Wilkins, pp. 828-831.
  • a food material may include one of several different fruits, including but not limited to mango, coconut, and palm fruits, such as date palms.
  • Mango is an attractive food material as it is easily found in large quantities, is high in fiber, and already contains some amounts of terpenes that are important molecules within the various fruits, including but not limited to mango, coconut, and palm fruits, such as date palms.
  • Mango is an attractive food material as it is easily found in large quantities, is high in fiber, and already contains some amounts of terpenes that are important molecules within the various
  • the mango serves as a suitable reservoir for development of a food material, as an oil is absorbed into the fruit, and can be freeze-dried for subsequent use. Once the mango is freeze-dried it can be packaged as freeze-dried pieces or can be encapsulated alone or with one or more additional binding agents and excipients to form an oral dosage pill.
  • the fruit, such as mango, is also useful for masking the bitterness of the CBD, thus improving patient compliance.
  • coconut oil serves as a carrier oil for CBD and terpene compounds, and the coconut oil can be dried with a portion of coconut meat, freeze-dried, and again packaged as with the mango.
  • Palm oil, or date palms can also be a suitable food carrier. Oils from coconut or palm, or purified MCT oils can also be suitably utilized.
  • oral delivery may by preferred, it is suitable for delivery to the oral mucosa wherein the material is intended to coat the oral mucosa or to remain in the mouth wherein the compounds are exchanged into the bloodstream through the mucosal membranes of the mouth.
  • the nasal membranes provide an advantageous route of delivery.
  • materials may be inhaled through the nasal passages where the compounds are absorbed in the nasal mucosae and in the oral mucosae and the lungs.
  • This can be in the form of an aerosol, which will allow for more material to enter the lungs or can be from gels or liquids that are sprayed or administered into the nasal passages for delivery of the therapeutic compounds.
  • Topical administration is particularly advantageous for delivery of therapeutic compounds to skin cells or for treatment of skin- and dermal-based diseases or infections, for example topical fungal infections on skin surfaces.
  • topical fungal infections for example topical fungal infections on skin surfaces.
  • Such applications are also suitable for delivery of certain cannabinoid molecules into the blood stream.
  • Certain fungal infections are also possible of the oral, nasal, and genital membranes, and application of topical materials is suitable for treatment of said inflictions.
  • the smoke resulting from burning of the material may be suitable to inhale the smoke resulting from burning of the material.
  • burning with or without the presence of oxygen allows some of the compounds to be inhaled, through smoke or vapor, and then pulled into the oral and nasal mucosae, as well as inhaled into the lungs for delivery of the therapeutic materials.
  • a composition comprises an effective amount of CBD, admixed with terpenes selected from the group comprising: Limonene, myrcene, a-pinene, linalool, b-caryophyllene, caryophyllene oxide, nerolidol and phytol, any of the naturally occurring terpenes derived from the cannabis plant or derived from the fruit or skin of the mango plant, and combinations thereof.
  • terpenes selected from the group comprising: Limonene, myrcene, a-pinene, linalool, b-caryophyllene, caryophyllene oxide, nerolidol and phytol, any of the naturally occurring terpenes derived from the cannabis plant or derived from the fruit or skin of the mango plant, and combinations thereof.
  • BORNEOL menthol, camphor, pine, woody. Can be easily converted into menthol.
  • CARYOPHYLLENE ⁇ spicy, sweet, woody, clove, camphor, peppery. Found in black pepper (15-25%), clove (10-20%), and cotton (15-25%). It binds weakly to CB2 receptors. As a topical it is one of the constituents of clove oil, an anti-inflammatory, and an analgesic treatment for toothache. In high amounts, it is a calcium and potassium ion channel blocker. As a result, it impedes the pressure exerted by heart muscles. [0094] CINEOLE/EUCALYPTOL : spicy, camphor, refreshing, minty. Found in rosemary and eucalyptus. It is used to increase circulation and for pain relief, and it easily crosses the blood-brain barrier to trigger fast olfactory reaction. Eucalyptus oil is considered centering, balancing, and stimulating.
  • cypress oil high in A 3 -carene, is used to dry excess fluids, tears, running noses, excess menstrual flow, and perspiration.
  • LIMONENE citrus (orange, tangerine, lemon, and grapefruit), rosemary, juniper, peppermint. Repulsive to predators. Found in the rinds of many fruits and flowers.
  • limonene can be an antibacterial, antifungal, antidepressant, and anticarcinogen. It can synergistically promote the absorption of other terpenes by quickly penetrating cell membranes. The result can be increased systolic blood pressure.
  • LINALOOL floral (spring flowers), lily, citrus, and candied spice. Possesses antianxiety and sedative properties (also in lavender).
  • MYRCENE clove-like, earthy, green vegetative, citrus, fruity with tropical mango and minty nuances. The most prevalent terpene found in most varieties of marijuana, it is also present in high amounts in mangos, hops, lemon grass, East Indian bay tree, verbena, and Mercia. It is a building block for menthol, citronella, and geraniol. It possesses antimicrobial, antiseptic, analgesic, antioxidant, anticarcinogenic, antidepressant, anti-inflammatory, and muscle relaxing effects. Myrcene affects the permeability of the cell membranes, allowing more cannabinoids, including CBD and THC, to reach both the blood stream and also brain cells.
  • PlNENE Alpha: pine needles, rosemary; Beta: dill, parsley, rosemary, basil, yarrow, rose, hops, the familiar odor associated with pine trees and their resins. It is the major component in turpentine and is found in many other plant essential oils including rosemary, sage, and eucalyptus. Pinene can increase mental focus and energy, as well as act as an expectorant, bronchodilator (the smoke seems to expand in your lungs), and topical antiseptic. It easily crosses the blood-brain barrier where it inhibits activity of acetylcholinesterase, which destroys acetylcholine, an information transfer molecule, resulting in better memory.
  • PULEGONE mint, camphor, rosemary, candy. It is implicated in liver damage in very high dosages. It is found in tiny quantities in marijuana. Pulegone is an acetylcholinesterase inhibitor. That is, it stops the action of the protein that destroys acetylcholine, which is used by the brain to store memories.
  • SABINENE Found in oak trees, tea tree oil, black pepper and is a major constituent of carrot seed oil.
  • TERPINEOL floral, lilac, citrus, apple/orange blossoms, lime. It is a minor constituent of many plant essential oils. It is used in perfumes and soaps for fragrance.
  • a pharmaceutical composition comprising less than 0.15% THC, greater than 5% CBD, more than 1% b-caryophyllene, and greater than
  • a composition preferably comprises at least 5% CBD, and at least 2% of each of linalool and b-caryophyllene.
  • the composition may comprise a hemp seed oil or hemp extract that comprises within the final formulation at least 0.4% weight percent borneol, and greater than 0.01 weight percent of each of limonene and nerolidol.
  • the compounds In order to create an improved bioavailability of the hemp compounds for oral administrations, the compounds must have a suitable carrier.
  • Applicant tested several different carriers in order to identify and optimize the formulation to improve bioavailability.
  • Applicant tested a food material, an oil carrier of long chain fatty acids, and an oil carrier of medium chain fatty acids and settled upon an emulsion using at least two different emulsifying agents and a medium chain fatty acid to create a composition that dramatically improved bioavailability.
  • the composition in an emulsion comprises three active ingredients: the CBD, the linalool, and the b-caryophyllene. These active ingredients are added to an emulsion comprising about 35% Kolliphor EL, about 30% Tween 80, and about 9% Phosal 50 PG.
  • the emulsion of the composition comprises between 30% and 40% Kolliphor EL, between 25% and 35% Tween 80 and between 5% and 10% Phosal 50 PG (all percentages are by weight percent of the composition).
  • a cosurfactant of propylene glycol is added at about 7%, with a preferred range of 5-10% by weight.
  • a medium chain triglyceride oil is added at about 3% by weight, with a range of between 1 and 10%, and an antioxidant at about 3%, with a range of between 1% and 10% by weight.
  • the active ingredients may be further admixed in a carrier oil of hemp seed oil or provided as pure extracts of the compounds.
  • the emulsion preferably creates particles of less than about 1000 nm, and more preferably less than 750 nm and 500 nm. In certain applications, it may be suitable to add further components to the emulsion; for example, wherein the emulsion comprises a surfactant and active ingredients, an amphiphilic solvent utilized in a composition of the invention is selected from lower alkyl (having between 1 and 8 carbon atoms) esters of lactic acid, lower alkyl (having between 1 and 8 carbon atoms) lactone esters, and A f -M ethyl pyrrol i done.
  • an amphiphilic solvent utilized in a composition of the invention is selected from lower alkyl (having between 1 and 8 carbon atoms) esters of lactic acid, lower alkyl (having between 1 and 8 carbon atoms) lactone esters, and A f -M ethyl pyrrol i done.
  • lower alkyl esters include methyl, ethyl, propyl, isopropyl, butyl, hexyl, pentyl, and octyl esters, and at least one piperine compound (E,E)l-[5-(l,3-benzodioxyl-5-yl)-l- oxo-2, 4-pentadenyl]piperi dine (for example, as derived from Piper longum or Piper nigrum ) or an analog of the same.
  • piperine compound (E,E)l-[5-(l,3-benzodioxyl-5-yl)-l- oxo-2, 4-pentadenyl]piperi dine for example, as derived from Piper longum or Piper nigrum ) or an analog of the same.
  • protective colloids include polypeptides (such as gelatin, casein, and caseinate), polysaccharides (such as starch, dextrin, dextran, pectin, and gum arabic), as well as whole milk, skimmed milk, milk powder, or mixtures of these.
  • polyvinyl alcohol, vinyl polymers for example polyvinylpyrrolidone, (meth)acrylic acid polymers and copolymers, methylcellulose, carboxymethylcellulose, hydroxypropyl cellulose and, alginates. See R. A. Morton,“Fat-Soluble Vitamins,” Intern. Encyclopedia of Food and Nutrition, Vol. 9, Pergamon Press 1970, pages 128-131.
  • the CBD and terpene combinations are absorbed into a food material and freeze-dried.
  • Mango serves as a specifically advantageous material, as mango extract is naturally high in certain terpenes of the formulations. Accordingly, the CBD and terpene mixture can be admixed with fresh or freeze-dried mango, with the compounds being absorbed into the fruit. The combination of the fruit enables a dramatic increase in the bioavailability of the freeze-dried fruit.
  • Table 1 provides a summary of certain formulations, each of which are admixed into a carrier.
  • formulations 1-5 utilized an MCT oil carrier
  • formulations 6-13 utilized a hemp-based extract comprising CBD, extracted linalool, and extracted b-caryophyllene as the primary active ingredients in an emulsion.
  • Inclusion of THC utilized extracts comprising THC concentrations.
  • Kolliphor EL Tween 20, Tween 80, Pluronic F68, Phosal, Agar, Albumin, Alginates, Casein, Cetyl alcohol, Cholic acid, Deoxycholic acid, Glycerol, Carrageenan, Lecithin, mono- and diglycerides, monosodium phosphate, monostearate, and combinations thereof.
  • Pluronic F68 Pluronic F68, Phosal, Agar, Albumin, Alginates, Casein, Cetyl alcohol, Cholic acid, Deoxycholic acid, Glycerol, Carrageenan, Lecithin, mono- and diglycerides, monosodium phosphate, monostearate, and combinations thereof.
  • a cosurfactant is advantageously used with the emulsifying agent, for example, propylene glycol, polysorbate 80, benzalkonium chloride, butanol, glycerol, sorbitol, diethylene glycol monoethyl ether, sorbitan monostearate, and ethanol, that may be utilized in the formulation.
  • the emulsifying agent for example, propylene glycol, polysorbate 80, benzalkonium chloride, butanol, glycerol, sorbitol, diethylene glycol monoethyl ether, sorbitan monostearate, and ethanol, that may be utilized in the formulation.
  • An antioxidant may be utilized to prevent oxidation of the formulation.
  • vitamin E Ascorbic acid, alpha tocopherol, propyl gallate, cysteine, hydroxyanisole, butylated hydroxytoluene, and sodium metabi sulfite, as a nonlimiting example of antioxidants.
  • Hemp seed oil refers to a pressed hemp seed oil, which includes additional terpene molecules as well as other medium and long chain fatty acids.
  • the piperine is a purified pipeline or derivative of the piperine.
  • a particular embodiment is as follows: CBD 50 mg, linalool 20 mg, b-caryophyllene 20 mg, Kolliphor EL 371 mg, Tween 80 308 mg, Phosal 50 PG 87 mg, propylene glycol 77 mg, MCT oil 32 mg, and vitamin E 600 ppm.
  • This can be formulated with a binder, glidant, or other excipient as known to those of ordinary skill in the art, as well as a coating material for oral administration.
  • This provides for a“50 mg” dose with regard to CBD.
  • For a dose of 100 mg the amounts would be doubled for the other components.
  • multiple oral dosage forms can be consumed, i.e. 2, 3, or 4 pills or gel caps, to reach the necessary dosage.
  • the CBD and terpenes with a microencapsulated formulation wherein the microcapsules enable the CBD and terpene molecules to pass through the upper GI tract before being attacked by stomach acids, which allows for an increase in the total dose of the compounds and thus increases the amount of material able to be absorbed by the body.
  • each of these combinations may be admixed together, thus a colloid may be used with a food material in certain embodiments.
  • a colloid may be used with a microcapsule formulation, and finally the use of a colloid with a food material and a microcapsule.
  • Microencapsulation may comprise the addition of an encapsulating polymer within an emulsion wherein the CBD and terpenes are encapsulated within the polymer.
  • extracts from Cannabis sativa were combined with those of Cannabis indica in a ratio of between 100: 1 and 1 : 100 wherein the strains and ratio are selected to maintain the THC concentration at less than 0.3% and preferably at less than 0.15% for those compositions that are intentionally low in THC.
  • Mango extract is also high in several terpenes that are found in the Cannabis sativa plant, and in some cases, these can be more easily extracted and extracted at a reduced amount.
  • a preferred embodiment comprises any one of formulations 1-5, provided as 1000 mg, and admixed into 25 mL of long chain fatty acid oil instead of the MCT oil. The oil is then combined with excipients and a binding agent and an optional flowing agent to form an oral dosage form.
  • a further preferred embodiment comprises any one of formulations 1-5, provided as 1000 mg, and admixed with a colloidal compound, which is then admixed with an excipient and a binding agent and formed as an oral dosage form.
  • Formulations 1-5 utilized an oil or colloidal carrier, whereas formulations 6-13 utilized an emulsifying agent and surfactant, with a lower amount of an MCT oil, as well as an antioxidant. Data showed that the use of the emulsion increased bioavailability of the formulation with regard to the CBD, linalool, and b-caryophyllene, as compared to
  • a further preferred embodiment comprises an extract of Cannabis sativa, comprising less than 0.15% THC but more than 0.01% THC, and comprising at least 5% CBD; a second extract comprising about 2% b-caryophyllene, about 2% linalool, an antioxidant (vitamin E), and suspended in an emulsion of Tween 80, Kolliphor EL, and Phosal 50 PG with an MCT oil.
  • a further embodiment also admixed 1, 2, 3, 4, 5, and 10% of a full spectrum hemp extract comprising additional cannabinoids and terpenes wherein the composition comprises greater than 0.4% borneol, and greater than 0.01 percent of each of limonene and nerolidol; wherein said composition is formed as an oral dosage form.
  • the second extract comprises an extract of Cannabis sativa , which combined generate at least the above composition of terpene compounds.
  • a further preferred embodiment takes any of the above formulations admixed with a long chain fatty acid oil or with a colloidal compound and adds it to a portion of fresh or freeze- dried fruit.
  • the fruit serves as a solid form carrier for the composition and the material.
  • the material can then be cut into servings or can be ground and packaged in an oral dosage form.
  • an extract of Cannabis sativa is combined with an extract of Cannabis indica at a ratio of 10: 1 wherein the combined extracts have a concentration of less than 0.3% THC and wherein the extracts are combined into a carrier for oral administration.
  • the C. sativa and C. indica combination is further admixed with a third extract comprising additional concentrations of terpenes wherein the terpenes are combined into the composition having a concentration of 1-3% b-caryophyllene and 1-3% linalool.
  • any composition as described herein comprising at least 1% myrcene.
  • compositions of formulations 6-13 were further admixed with curcumin at 1, 2, 5, and 10% weight% of the composition.

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Abstract

Une composition comprenant une composition active constituée d'au moins 5 % de CBD, d'au moins 2 % de bêta-caryophyllène et d'au moins 2 % de linalool; ladite composition comprenant un support et des excipients pour augmenter la biodisponibilité orale pour une consommation de mammifère.
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