WO2022087171A1 - Formulations pour l'amélioration de la perméation des cannabinoïdes - Google Patents

Formulations pour l'amélioration de la perméation des cannabinoïdes Download PDF

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Publication number
WO2022087171A1
WO2022087171A1 PCT/US2021/055905 US2021055905W WO2022087171A1 WO 2022087171 A1 WO2022087171 A1 WO 2022087171A1 US 2021055905 W US2021055905 W US 2021055905W WO 2022087171 A1 WO2022087171 A1 WO 2022087171A1
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active agent
cannabinoid
formulation dose
dose
formulation
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PCT/US2021/055905
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WO2022087171A4 (fr
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Justin Daniel PENTELUTE
Dean D. SMALL
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Tellus Brands, Llc
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Publication of WO2022087171A4 publication Critical patent/WO2022087171A4/fr

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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • 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
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating

Definitions

  • Cannabinoid molecules such as tetrahydrocannabinol (THC), cannabidiol (CBD) cannabigerol (CBG), tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), cannabinchromene (CBC), and cannabigerolic acid (CBGA), are known to cause a variety of therapeutic and psychotropic effects when administered to a subject.
  • Cannabinoids from the plant genus Cannabis could be considered a type of natural health product, but historically they have not been legally available.
  • the laws which have criminalized possession or use of cannabis have been the primary restraint. These laws were put in place apparently to control the use of one specific cannabinoid, delta-9 tetrahydrocannabinol (THC), which causes a mild temporary psychotropic effect in users.
  • THC delta-9 tetrahydrocannabinol
  • the alternate cannabinoids which exert little or no psychoactive effect include, but are not limited to, cannabinol (CBN), cannabidiol (CBD), cannabichromene (CBC), and cannabigerol (CBG).
  • CBD cannabinol
  • CBD cannabidiol
  • CBC cannabichromene
  • CBG cannabigerol
  • Cannabinoids are key players in biological systems and bind to receptors in the body known as cannabinoid receptors (e.g., CB-1 and CB-2) which have been implicated in a variety of physiological functions, including appetite, pain, emotional behavior (mood), memory, and inflammation.
  • cannabinoid molecules have traditionally been administered via inhalation, for example by smoking or heating and inhaling the vapors of cannabis plants or cannabis extracts.
  • the inhalation mode of delivery can be harmful for the mouth, throat, and lungs of the subject, can be inconvenient, and can lack proper dosage control.
  • Oral administration of such molecules can provide improved consistency of dosing, more discreet administration, and increased convenience for users.
  • Oral administration can include formulations such as capsules, tablets, edibles (e.g., food), beverages, tinctures, and liquid drops.
  • known oral formulations are characterized by low bioavailability and slow onset of action.
  • the bioavailability of ingested cannabinoids in known formulations may be less than 20%, indicating that at least 80% of the cannabinoid active agent is metabolized and/or excreted without exerting therapeutic effects. This low bioavailability may be attributable to the chemical composition of cannabinoids.
  • CBD is fat-soluble, which may be more difficult for the body to absorb than water- soluble compounds. Additionally, digestive acids and enzymes may break down a large percentage of the CBD before it can be absorbed. Furthermore, even a portion of the CBD that is absorbed through the intestinal wall into the blood can be metabolized by the liver before reaching the rest of the body.
  • the low bioavailability requires patients to ingest significantly higher doses than would be required by alternative dosing forms (e.g. smoking and vaping). Furthermore, the delayed onset of action presents challenges in clinical uses that require rapid therapeutic effect (e.g., pain relief).
  • a formulation dose for oral delivery in a subject includes a cannabinoid active agent and a permeation enhancer.
  • the cannabinoid active agent includes or represents one or more of cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), or cannabinol (CBN).
  • the permeation enhancer includes or represents a caprate salt. The caprate salt may be present in an amount from about 15 weight percent (wt. %) to about 75 wt. % of a total weight of the formulation dose.
  • a method for producing a formulation dose for oral administration.
  • the method includes providing a cannabinoid active agent that includes one or more of cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), or cannabinol (CBN).
  • CBD cannabidiol
  • CBG cannabigerol
  • CBC cannabichromene
  • CBN cannabinol
  • the method includes mixing the cannabinoid active agent with a permeation enhancer that includes a caprate salt to define an active mixture, and forming the active mixture into a formulation dose for oral administration in a subject.
  • Figure 1 is a cross-sectional view of a formulation dose according to a first embodiment.
  • Figure 2 is a graph illustrating an absorption profile of a first formulation dose according to an embodiment.
  • Figure 3 is a graph illustrating an absorption profile of a second formulation dose according to an embodiment.
  • Figure 4 is a cross-sectional view of a formulation dose according to an embodiment that provides staggered release of a cannabinoid active agent.
  • Figure 5 is a graph illustrating an absorption profile of a third formulation dose according to an embodiment.
  • Figure 6 is a flow chart of a method for producing a formulation dose for oral administration in a subject according to an embodiment.
  • Embodiments disclosed herein provide plant-based cannabinoid oral formulations that include at least one permeation enhancer.
  • the formulations include a cannabinoid as an active ingredient, mixed with the at least one permeation enhancer for oral administration.
  • the oral formulations described herein may provide increased bioavailability, earlier onset of therapeutic effect, faster time to peak concentrations of the cannabinoid agent in the bloodstream, and/or controlled absorption of the cannabinoid agent over a designated time window, relative to an oral formulation that lacks the permeation enhancers described herein.
  • the cannabinoid in one or more embodiments can include or represent one or more de-carboxylated derivatives such as CBD, CBC, CBN, or CBG.
  • the permeation enhancer also referred to herein as an absorption enhancer, can include or represent a salt with a caprate (Cio) anion.
  • the formulation includes a mixture of CBD and sodium caprate, with or without additional excipient substances.
  • the oral formulation lacks THC.
  • bioavailability refers to the fraction (e.g., percentage) or amount of an administered substance that is absorbed by the body’s circulatory system and available for use or storage by a body.
  • bioavailability can refer to the fraction or amount of cannabinoid active agent in an ingested formulation that is absorbed into the bloodstream of the body. Once absorbed into the blood, the active agent can be transported through the body for use in the organs and tissues. Bioavailability may be measured by calculating the concentration of a substance administered to a body over time.
  • Cannabinoid refers to a chemical compound that is capable of acting on cannabinoid receptors, for example in the brain and in the body.
  • Cannabinoids may be produced naturally in the body (endocannabinoids), found in cannabis and some other plants (phytocannabinoids), or manufactured artificially (synthetic cannabinoids).
  • the cannabinoids present in the oral formulations according to one or more embodiments are the natural, plant-based phytocannabinoids that are produced by cannabis during its cultivation and growth, including THC, CBN, CBD, CBC and CBG. More specifically, the oral formulations according to one or more of the embodiments lack THC and other compounds that can product significant psychoactive effect.
  • CBD, CBN, CBC, and CBG may be derived from their respective parent compounds by mild heating typically above 105 °C.
  • CBD cannabidiol
  • CBD cannabidiol (IUPAC: 2-[(lR,6R)-6-isopropenyl-3- methylcyclohex-2-en- 1 -yl]-5-pentylbenzene- 1 ,3 -diol).
  • Oral formulation means a product composition which is conveniently administered orally to a human subject.
  • the formulations described herein can be products in the form of a piece of chewing gum, a chewable capsule or tablet, a non-chewable capsule or tablet, an edible food product, a beverage, liquid drops, or the like.
  • Unit dosage form or “UDF” means a physically fixed unit dose of a formulation which is conveniently consumed by a consumer in unit form (e.g. requires no measuring or adjusting of dosage before consumption).
  • a consumer may consume one or more UDFs at a time to achieve a desired dosage. For example, a consumer may consume two capsules that each have a UDF of CBD of 15 mg to achieve a 30 mg dosage.
  • Enteric coating refers to a barrier applied to an orally-delivered substance that prevents or delays its dissolution or disintegration in the gastric environment.
  • Enteric coatings are a form of time release components that can protect an orally-delivered substance from the acidity of the stomach, protect the stomach from detrimental effects of an orally delivered substance, and/or delay the release of an orally-delivered substance until after the stomach within the intestinal tract.
  • enteric-coated dosage forms include without limitation tablets, minitablets, pellets, granules, capsules, gel capsules, and the like.
  • the permeation enhancer present in the formulation according to one or more embodiments is a salt that includes a caprate ion.
  • Caprate is derived from capric acid, which is an aliphatic saturated 10-carbon medium-chain fatty acid found in saturated fats (cow butter, and plant oils like coconut oil).
  • Capric acid has amphiphilic character and can form micelles and liquid crystalline phases in aqueous solution. Capric acid can be used to elucidate the transport of biologically active molecules.
  • One example salt is sodium caprate, which has the structure (i) shown below:
  • Sodium caprate is a soluble anionic surfactant, sensitive to changes in pH and ionic strength. At pH values 1-3 units below its pKa ( ⁇ 5) in gastric fluid, it exists in the non-ionized, insoluble, and inactive capric acid form. At acidic pH values, the surfactant can reduce surface tension, but does not exhibit detergent action. At pH values 1-3 units above its pKa (i.e., values that typically occur in the small intestine), sodium caprate exists in an ionized soluble form with detergent capacity. Like many other efficient detergents, it does not form micelles efficiently owing to repulsion between the charged hydrophilic head groups.
  • the resulting high concentration of free monomeric surfactant enables epithelial plasma membrane interaction and confers a transcellular element to its mode of action.
  • the critical micellar concentration (CMC) value of sodium caprate varies depending on the medium composition. Micelles form at lower concentrations in higher-ionic-strength buffers because the counter-ions in media interact closely with anionic head groups.
  • varying the ionic strength alters the free monomeric concentration of sodium caprate in the small intestine, sodium caprate at low concentrations is believed to act on tight junctions via intracellular events, and at high concentrations via transcellular perturbation arising from its surfactant effect.
  • Tight junctions are intercellular junctions between cells that form a barrier between the cells. In this way, materials (e.g. small molecules, proteins and drugs) cannot pass between cells but rather must be taken up by the cell and thus enables the cells to regulate what is allowed through. Tight junctions occur in many regions throughout the body including the mouth, small intestine, large intestine and colon and vary in density/tightness within different regions. Within the gastrointestinal (GI) tract, tight junctions refer to the areas between adjacent endothelial cells and act to regulate the uptake of digested materials.
  • GI gastrointestinal
  • Tight junctions are highly regulated and are one of the key elements that form the barrier between the luminal environment of the mouth and/or GI tract and the rest of the body. Tight junctions have three main functions: (1) to hold cells together, (2) to block the movement of integral membrane proteins between the apical and basolateral surfaces of the cell, allowing the specialized functions of each surface (for example receptor-mediated endocytosis at the apical surface and exocytosis at the basolateral surface) to be preserved (this aims to preserve the transcellular transport) and (3) to prevent the passage of molecules and ions through the space between cells and therefore materials must actually enter the cells (by diffusion or active transport) in order to pass through the tissue. This pathway provides control over what substances are allowed through.
  • Sodium caprate may be configured to target tight junction proteins, the signaling pathways regulating junctional function, or tight junction-associated lipid raft microdomains.
  • Sodium caprate may reversibly increase paracellular transport and drug delivery, and may be used as pharmaceutical excipients to improve drug delivery across epithelial barriers and the bloodbrain barrier.
  • the oral formulations described herein are not limited to sodium caprate.
  • the permeation enhancer in one or more embodiments may be a caprate salt including a different cation (e.g., positively charged ion) than sodium.
  • the cation in the caprate salt can be inorganic or organic, and either monatomic or polyatomic.
  • inorganic cations include sodium (as described above), potassium, and lithium.
  • organic cations include alkyl amines R-NH3+ (e.g., primary ammonium), which include most amino acids, and simple carbohydrates (e.g., monosaccharides and disaccharides, commonly known as sugars).
  • SNAC salcaprozate sodium
  • Sodium caprate and SNAC are both weak acids that display amphiphilicity and surface activity. There is a structural difference between the compounds that arises from the greater distribution of hydrophilic functional groups in the salicylamide region of SNAC. Due to the larger size, the hydrophobic region of SNAC may be less efficient at inserting into phospholipid membranes than sodium caprate. This may explain why generally higher concentrations of SNAC are needed than sodium caprate in a formulation to improve permeation. For at least the reason of efficiency and material conservation, caprate salts are preferred as the permeation enhancer over SNAC in the oral formulations disclosed herein.
  • a permeation enhancer that includes or represents a caprate salt is co-formulated with a physiologically acceptable dosage of one or more plant-based cannabinoids which represent an active agent.
  • the caprate salt may be sodium caprate, potassium caprate, lithium caprate, or another salt described above.
  • the one or more plant-based cannabinoids in the active agent include one or more of CBD, CBC, CBG, or CBN.
  • the formulations described herein can be used for treatments known in the art, such as treating symptoms of rheumatoid arthritis and other autoimmune diseases, diabetes, nausea, bowel disorders, inflammation, anxiety, and the like, as well as regulating sleep, appetite, mood, and the like.
  • the cannabinoid active agent may provide neuroprotective effects, anti-cancer effects, and/or reduce many other hard-to-control side effects of other medications.
  • the permeation enhancer (e.g., the caprate compound) is configured to improve the absorption and bioavailability of the cannabinoid active agent through the epithelial tissues of the subject.
  • the permeation enhancer may be present in an amount from about 15 weight percent (wt. %) to about 75 wt. % of the total formulation weight per dose. For example, if the total weight of a single chewable tablet (or gummy) is 200 mg, the weight of the permeation enhancer in the tablet is in the range of 30 mg to 150 mg. In a more specific non-limiting example, the permeation enhancer may be present in an amount from about 25 wt. % to about 65 wt. % of the formulation per dose.
  • the cannabinoid active agent may be present in an amount from about 15 wt. % to 85 wt. % of the total formulation weight per dose. In a more specific non-limiting example, the cannabinoid active agent may be present in an amount from about 25 wt. % to about 75 wt. %. If the cannabinoid active agent includes multiple different cannabinoids, such as CBD and CBG, the weight percentage of the cannabinoid active agent represents the combined weight of all cannabinoids present.
  • the concentrations of the permeation enhancer and the cannabinoid active agent can be described relative to each other in the formulation.
  • the amount of the permeation enhancer present in the oral formulation may represent between about 15% and about 300%, by weight, of the amount of the cannabinoid active agent present, for a ratio from 0.15: 1 to 3: 1 enhancer to cannabinoid.
  • the ratio 0.15: 1 indicates 0.15 parts permeation enhancer to every 1 part cannabinoid active agent.
  • the ratio 3 : 1 indicates 3 parts permeation enhancer to every 1 part cannabinoid active agent. If the amount of enhancer is less than 100% of the amount of the cannabinoid active agent, then the formulation includes more of the active agent then the enhancer.
  • the ratio of the enhancer to the active agent is 1 :2. If the amount of the enhancer represents 100% of the amount of the active agent, the ratio is 1 :1 enhancer to active agent. In another example in which the amount of the enhancer is 300% of the amount of the active agent, the ratio is 3: 1 enhancer to active agent.
  • the amount or concentration of the permeation enhancer present in the oral formulations discloser herein may be greater or higher than the typical use of permeation enhancer compounds in oral formulations, which are typically 10 wt. % or less of the formulation per dose.
  • the greater percentage of the enhancer present may provide earlier onset of therapeutic effect and/or increased bioavailability of the cannabinoid active agent, meaning that a greater fraction or total dose of the cannabinoid is absorbed and used by the body than would be absorbed and used at a reduced bioavailability.
  • the cannabinoid active agent may be present in a purity concentration of at least 90% and up to about 100%, with little or no trace of THC.
  • the cannabinoid active agent may exist in the form of an isolate, which is powder like and is light yellow in color.
  • the cannabinoid active agent may also exist in the form of an emulsion without waxes and oils, oil, paste, liquid, resin, crystal, powder, or pulp.
  • a given dosage of the formulation may include from about 2 mg to about 75 mg of cannabinoid, depending on the particular product form and usage-specific types of the product (e.g., regular or extra-strength).
  • a narrower range according to a non-limiting embodiment is from about 3 mg to about 50 mg, and a second, even narrower range is from about 5 mg to about 30 mg.
  • the formulation dose can include between 10 mg and 25 mg of the cannabinoid active agent.
  • a chewable capsule or tablet may have a greater amount of the cannabinoid active agent than a piece of chewing gum.
  • a chewable tablet could have between 15 mg and 25 mg of the cannabinoid active agent, and the slice or piece of chewing gum could have between 5 mg and 10 mg of the active agent.
  • the purified substances, if used in the preparation of the formulation may also be purchased from manufacturers.
  • the commercially available Elixinol 99.4% Hemp extract isolate, EX-513W contains 90- 100% CBD and no THC and it may be suitable for the preparation of the formulation of the present disclosure.
  • a formulation with a higher loading dosage such as about 60 wt. % CBD
  • cannabinoid substances such as a raw extract from cannabis or hemp containing less than 35% CBD
  • the extracted active agent may also be used in a less purified form such that the purity of the cannabinoid is less than about 90%, such as about 70%, about 60%, or about 50%.
  • At least one additional permeation enhancer may be present with the caprate salt (such as sodium caprate).
  • the additional permeation enhancer can include or represent lecithin, phospholipids, octyl sulfate, decyl sulfate, dodecyl sulfate, tetradecyl sulfate, hexadecyl sulfate and octadecyl sulfate, sulfonic acids, taurocholic acid, taurodeoxycholic acid, bile acids and their salts, such as cholic acid, deoxycholic acid and sodium glycocholates, sodium laurate, sodium oleate, sodium lauryl sulphate, sodium cetyl sulphate, sulfated castor oil and sodium dioctylsulfosuccinate, cocamidopropylbetaine and laurylbetaine, fatty alcohols, cholesterols, glyce
  • the oral formulation is designed to control the release of the cannabinoid active agent.
  • the release may be controlled to be at one or more particular locations in the gastrointestinal (GI) tract of the subject, to occur at a designated onset time after ingestion, and/or to extend or sustain the release, absorption, and/or therapeutic effect of the cannabinoid over a designated time window or period.
  • the formulation is designed to delay absorption of the cannabinoid active agent until reaching the intestines.
  • Delaying the release of CBD and/or other cannabinoids can enable more convenient and efficient usage of the cannabinoids to achieve a desired effect, relative to oral administration involving mucosal absorption in the mouth and/or stomach.
  • Mucosal drug administration typically requires larger amounts of the active compound due to mucosal barrier functions and other factors that limit the bioavailability of the active compound.
  • active compounds that are poorly lipid-soluble and/or relatively large, such as larger than 1000 Da may experience poor absorption characteristics across mucosal surfaces.
  • At least a portion of the oral formulation may be designed for immediate release of the cannabinoid active agent, such as to provide early onset therapeutic relief.
  • the formulation or immediate release portion may disintegrate within about 60 seconds upon contacting water, saliva, and/or stomach fluid.
  • the release can be controlled by including at least one time release component in the formulation dose.
  • the time release component can include an outer film, coating, or substance that surrounds the permeation enhancer and the cannabinoid active agent.
  • the time release component may encapsulate the permeation enhancer and the cannabinoid active agent to prevent release until the time release component degrades.
  • the formulation can be a chewable or non-chewable tablet, capsule, or gelcap, a piece of chewing gum, a piece of candy, chocolate, or other food item, or the like.
  • a suspension or solution of the cannabinoid and the permeation enhancer can be filled into a capsule, and the time release component can be applied to the capsule.
  • the time release component is an enteric coating.
  • the enteric coating may also reduce adhesion with the inner surface of the mouth to increase swallow-ability and/or mask a taste of certain ingredients which may be unpleasant (e.g., a hemp taste).
  • the composition of the enteric coating may be polymeric, including fatty acids, waxes, shellac, plastics, and/or plant fibers.
  • Polymeric films that may be used as the enteric coating include vinyl polymers such as polyvinylpyrrolidone, polyvinyl alcohol, and acetate; cellulosics such as methyl and ethyl cellulose, hydroxyethyl cellulose, and hydroxylpropyl methylcellulose; acrylates and methacrylates; copolymers such as the vinyl-maleic acid and styrene-maleic acid types; natural gums and resins such as zein, gelatin, shellac and acacia; cellulose acetate phthalate (EUDRAGIT® S or L), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, polyvinyl acetate phthalate, methacrylic acid copolymers, their salts and derivatives, and any combination thereof.
  • vinyl polymers such as polyvinylpyrrolidone, polyvinyl alcohol, and acetate
  • the presence of the enteric coating may preserve integrity of the dosage, avoiding activation in acidic environments such as the mouth, esophagus, and stomach.
  • the enteric coating is formulated and applied to delay release and absorption of all, or at least a portion, of the cannabinoid active agent and the permeation enhancer until reaching the intestines.
  • the enteric coating may presents a surface that is stable at the intensely acidic pH found in the stomach, but breaks down rapidly at a higher pH (alkaline pH) to allow the cannabinoid active agent and the permeation enhancer to become available for absorption into the bloodstream.
  • the enteric coating may be configured to avoid dissolving in the gastric acids of the stomach (pH ⁇ 3), and to dissolve in the alkaline (pH 7-9) environment present in the small intestine.
  • the enteric coating may also protect gastric mucosa in the stomach from any irritating effects of the substances or compounds within the formulation.
  • the enteric material may dissolve quickly once the desired pH is reached.
  • the formulation may have a controlled release at a specific range of pH values, such as above 5 and less than 12, which encompasses the alkaline environment of the small intestines.
  • the enteric coating material typically includes at least 50 wt. % of the enteric coating material relative to the total weight of the formulation for maintaining acid stability. It is therefore quite surprising to observe the acid stability of the dosage even with enteric material as low as about 15-25%.
  • the content of enteric material contained in the formulation ranges from about 5 wt. % to about 50 wt. % of the total formulation.
  • the enteric coating may be present between about 10 wt. % and about 35 wt. % of the formulation dose, and an even narrower non-limiting range is between about 15 wt. % and about 25 wt. %.
  • Figure 1 is a cross-sectional view of a formulation dose 100 according to a first embodiment.
  • the formulation dose 100 includes a time release component in the form of an enteric coating 102 that covers and surrounds an active mixture 104.
  • the active mixture 104 defines a core of the formulation dose 100.
  • the active mixture 104 includes the cannabinoid active agent and the permeation enhancer.
  • the active mixture 104 optionally can include addition materials, such as a probiotic, a bioadhesive material, piperine, a fatty acid, or the like, as described in more detail herein.
  • the cannabinoid active agent may include a single type of plant-based cannabinoid, such as CBD, CBC, CBG, or CBN, or a combination of multiple cannabinoids.
  • the permeation enhancer is a caprate salt such as, but not limited to, sodium caprate.
  • the cannabinoid active agent may be mixed with the permeation enhancer in the active mixture 104, such that the cannabinoid and the enhancer are released from the formulation in a substantially synchronous fashion (e.g., during a common time period).
  • the formulation dose 100 in Figure 1 may provide a delayed release of the active mixture 104 for absorption into the body of the subject at a target location.
  • the enteric coating 102 may have a composition and/or thickness specifically designed to withstand releasing the active mixture 104 until the target location is reached and/or a designated period of time has elapsed since ingesting the formulation dose 100.
  • the target location is the small intestines.
  • the enteric coating 102 can withstand the acidic environment of the stomach and degrade in the presence of the alkaline environment of the intestines.
  • the thickness of the enteric coating 102 can be selected to ensure that such degradation does not cause premature release or late release of the active mixture 104.
  • the amount or thickness of the enteric coating 102 may be selected to provide a few hours, such as about 1-4 hours, of resistance before releasing the active mixture 104 to target the small intestines.
  • the cannabinoid active agent can be gradually released and absorbed, with the assistance of the permeation enhancer, over time.
  • the onset time may refer to the time that the cannabinoid active agent is absorbed into the bloodstream in sufficient concentration to begin providing therapeutic effect.
  • the onset time from ingestion to therapy may be relatively short, such as between 30 minutes and 2 hours.
  • the onset time may be greater, such as between 2 hours and 6 hours.
  • the dose may provide the therapeutic effect over a sustained time window from the onset time.
  • the time window depends on various factors including the amount of cannabinoid active agent that gets absorbed into the bloodstream (e.g., the amount and bioavailability of the active agent), the location and type of receptors that receive the active agent, and the like.
  • the formulation dose may be designed to provide a therapeutic effect that lasts several hours, such as 2 to 8 hours. For example, one formulation dose may be designed to provide long lasting relief for up to 8 hours. Another formulation dose may provide more acute relief for a shorter time period, such as for 2 to 4 hours.
  • the formulation dose may be designed for a desired use and therapeutic effect for the subject.
  • the therapeutic effect can depend on various factors such as the type and amount of cannabinoid(s) present, the type and amount of permeation enhancer(s) present, the type, location, and dimensions (e.g., thickness) of any time release component present, such as a coating, and the like.
  • different cannabinoids can provide different therapeutic effects due to different chemical compositions which may cause the cannabinoids to be absorbed at different parts of the body, at different bioavailability rates, and/or at different time periods. These difference can be attributable at least in part to the type and location of receptor with which the cannabinoids interact.
  • CBD interacts with the CB-2 receptor in the body and immune system. CBD does not interact with CB-1 brain cell receptors in the same way as THC and actually interferes with THC binding to receptors, which explains why THC-containing strains with high CBD content do not produce as intense of a psychoactive high as THC-containing strains with lower concentrations of CBD.
  • CBD is reported to have antidepressant, anti-anxiety and stress, anti-inflammatory, neuroprotective, euphoria (e.g., mood-enhancing), pain-reducing, appetite-promoting, sleeppromoting, and/or creativity-promoting effects on the subject.
  • CBG may be effective at addressing specific health issues, such as glaucoma, cancerous tumor growth, Crohn’s disease, and irritable bowel syndrome (IBS).
  • the cannabinoid CBC may have anti-inflammation properties, and may contribute to neurogenesis and neuroplasticity, which are key functions of brain health and development.
  • the cannabinoid CBN may be effective as a sleep aid and a remedy against arthritis.
  • quick release formulations to provide early onset therapeutic effect may be designed for release and absorption of the active mixture 104, at least in part, within the mouth and/or stomach of the subject.
  • the formulation dose 100 in Figure 1 could be a chewable product.
  • the coating 102 may be thin and may decompose and/or fracture within the mouth when bit to release the active mixture 104 in the mouth.
  • the subject may retain the dose 100 in the mouth, particularly under the tongue, for a period of time, such as up to 1 minute, to enable sublingual absorption of the active mixture 104.
  • the non-absorbed portion of the active mixture 104 may travel to the stomach and then the small intestines.
  • At least some of the active mixture 104 within the stomach and/or the intestines may be absorbed into the bloodstream to increase the bioavailability (e.g., the amount of the cannabinoid active agent in the bloodstream) for increasing the extent of therapeutic effect and/or extending the duration or time window of the therapeutic effect on the subject (relative to the cannabinoid only being absorbed in the mouth).
  • bioavailability e.g., the amount of the cannabinoid active agent in the bloodstream
  • the formulation dose 100 may be specifically designed to provide an anti-anxiety (e.g., stress-relieving) therapeutic effect, particularly when anticipating anxiety-inducing events.
  • the anxiety-inducing events can include trips of the subject, such as aircraft flights, water voyages, car trips, and the like. Other anxiety-inducing events can include, for example, watching a scary movie, attending an uncomfortable social event, riding rollercoasters at an amusement park, and the like.
  • the dose 100 can be formulated based on the anxiety-inducing event, such as the duration of the event.
  • the subject may inject the dose within a designated time period of experiencing the event. In the aircraft example, the subject may ingest the dose prior to or upon entering the aircraft.
  • the dose may have the form of a piece of gum, a chewable tablet or capsule (e.g., gummy), a non-chewable tablet or capsule, a piece of chocolate or other food item, or the like.
  • the chewing gum formulation may have the supplemental benefit of helping to regulate internal air pressure of the subject as the subject chews the dose during takeoff and/or landing.
  • the formulation for the event-based anti-anxiety dose may include at least CBD due to CBD’s reported efficacy for treating anxiety and stress. Because the subject may ingest the dose just prior to or upon entering the cabin of the aircraft, the dose may be formulated to provide quick release of the active mixture 104 for early onset of the therapeutic effect.
  • the early onset may be provided by enabling the release of at least some of the CBD and permeation enhancer within the mouth and/or stomach for early absorption into the bloodstream.
  • the early release may be achieved by omitting a barrier coating or providing only a thin coating that readily degrades or fractures in the mouth and/or stomach, as described above.
  • the quick release property of the dose may be more desirable than a delayed release to ensure that the subject receives therapeutic effect while experiencing the anxiety-inducing event.
  • the concentration or amount of the CBD and/or the caprate enhancer may correspond to the duration of the anxiety-inducing event. For example, if a flight has a scheduled duration of about 3 hours, the dose may be formulated to provide quick release of the active mixture 104 and may have sufficient CBD and caprate enhancer to provide extended release and absorption of the CBD such that the CBD is present in the bloodstream for at least the remainder of the scheduled duration of the flight to reduce stress and anxiety of the subject.
  • Figure 2 is a graph 200 illustrating an absorption profile of a first formulation dose according to an embodiment.
  • the vertical axis 202 represents bioavailability of the cannabinoid active agent in the first formulation dose, which is the amount of active agent in the bloodstream of the subject.
  • the horizontal axis 204 represents time starting from the oral ingestion 206 of the first formulation dose.
  • the plot line 208 represents the amount of the cannabinoid active agent of the first formulation dose present in the bloodstream of the subject over time.
  • the first formulation dose depicted in Figure 2 may be an event-based anti-anxiety dose as described above.
  • the dose provides quick release and absorption of the cannabinoid active agent and the permeation enhancer, as reflected in the relatively early presence of the active agent in the bloodstream after ingestion.
  • the cannabinoid agent may include or represent CBD.
  • the cannabinoid active agent may include at least 80 wt. % CBD relative to a total weight of the cannabinoid active agent.
  • the amount of the cannabinoid agent increases and then levels off at a maximum concentration (Cmax) 210, before eventually decreasing as the cannabinoid is filtered from the blood.
  • the dose may manage the controlled release and absorption of the cannabinoid agent over a designated time window 212.
  • the entire time period in which the cannabinoid agent is substantially present in the bloodstream may be referred to as the residence time.
  • the dose may be formulated such that the Cmax 210 and the designated time window 212 are sufficient to provide anti-anxiety therapeutic effect to the subject during most if not all of the duration of an event, such as a flight.
  • the initial onset time 214 e.g., the time elapsed from the ingestion to the initial absorption of the cannabinoid agent into the bloodstream
  • the dose may be in the form of a piece of gum or gummy that can be absorbed sublingually or otherwise within the mouth and stomach.
  • a majority of the cannabinoid agent may be absorbed into the bloodstream over a time window 212 that lasts from about 15 minutes to about 4 hours after ingestion, such as from about 30 minutes to about 3 hours.
  • the dose may have a time release component (e.g., a coating, substrate, or the like), that manages the release of the cannabinoid and the permeation enhancer such that at least 75 wt. % of the total weight of the cannabinoid active agent is released over a time window of 1 hour to 4 hours after ingestion. If the dose includes 10 mg of the cannabinoid active agent, then at least 7.5 mg is released within the first 4 hours after ingestion. In another example, the release window may be shorter and earlier. For example, at least 75 wt. % of the cannabinoid active agent may be released between 15 minutes and 2 hours after ingestion.
  • Figure 2 also shows a sample plot line 216 in phantom representing a formulation that lacks a permeation enhancer with the cannabinoid active agent.
  • the plot line 216 may represent a formulation dose with the same composition as the dose illustrated by the line 208 except for lacking the caprate salt enhancer.
  • the plot line 216 indicates that without the caprate salt enhancer, the bioavailability of the cannabinoid is reduced and the onset is delayed.
  • the bioavailability of the formulation without the caprate salt may be 12% at 3 hours post ingestion, such that only 12% of the cannabinoid active agent is absorbed into the bloodstream.
  • the bioavailability of the first formulation dose may be significantly better, such as at least 20%, at least 25%, or at least 30% at 2 hours post ingestion.
  • the caprate salt enhancer may increase the amount of cannabinoid agent that is absorbed into the bloodstream and the rate at which the agent is absorbed. For these reasons, additional doses of the caprate-less formulation would have to be ingested to achieve similar therapeutic effect as the first formulation dose 208.
  • the first formulation dose depicted in Figure 2 may be designed for pain relief.
  • the dose may be directed for use by subjects experiencing acute pain, such as cramping in the abdomen and/or pelvis.
  • the amount and type of cannabinoids may be selected to provide pain relief.
  • the amount of caprate salt and the type of time release component may be selected to provide immediate release of the caprate salt and the cannabinoid for early absorption onset and quick relief.
  • the cannabinoid may include CBD with or without other cannabinoids, such as CBG.
  • Figure 3 is a graph 220 illustrating an absorption profile of a second formulation dose according to an embodiment.
  • the graph 220 is similar to the graph 200 shown in Figure 2, except that the plot line 222 represents the amount of the cannabinoid active agent of the second formulation dose present in the bloodstream of the subject over time.
  • the second formulation dose may be specifically formulated as a delayed and extended release of the cannabinoid active agent over time.
  • the second formulation dose may be a dose that is taken at regular intervals, such as once or twice daily, by the subject to provide sustained or extended therapeutic effect.
  • the dose may have a time release component, such as an enteric coating, that resists releasing a substantial amount of the cannabinoid and enhancer until reaching the basic environment of the small intestines.
  • a time release component such as an enteric coating
  • the time to onset 214 may be longer than the quick-release embodiment shown in Figure 2.
  • the onset 214 may correspond to the amount of time it takes for the dose to travel to the intestines, which may be between 1 and 5 hours, depending on the subject, the presence of food, and/or other variables.
  • the enteric coating may gradually release the cannabinoid agent and the permeation enhancer. For example, at least 75 wt.
  • % of the cannabinoid active agent may be released over a time window of 2 hours to 8 hours after ingestion.
  • the bioavailability of the cannabinoid agent in the bloodstream is extended for a longer period of time (e.g., longer residence time) than the cannabinoid agent of Figure 2, at the sacrifice of a delayed onset relative to the formulation in Figure 2.
  • the bioavailability of the cannabinoid agent in the second formulation dose may be at least 20%, at least 25%, or at least 30% at 4 hours or 5 hours post ingestion.
  • the second formulation dose depicted in Figure 3 may be used to treat chronic, continuing conditions.
  • the cannabinoid active agent may be CBD to treat general anxiety, boost and/or regulate mood, help cope with stress, balance cortisol levels, increase appetite, improve sleep, and/or the like on a daily basis.
  • the second formulation dose may be used to treat chronic pain, such arthritis.
  • at least 80 wt. % of the cannabinoid agent may be CBN due to the benefits of CBN treating arthritis.
  • the chronic pain may be cramping attributable to a digestive condition, such as irritable bowel syndrome (IBS).
  • IBS irritable bowel syndrome
  • at least 80 wt. % of the cannabinoid agent may be CBG due to the benefits of CBG treating IBS and other gastrointestinal issues.
  • the subject may decide to ingest two different products.
  • the subject may take the first formulation dose shown in Figure 2 for immediate pain relief and the second formulation dose shown in Figure 3 for extended relief.
  • the first formulation dose may have at least 80 wt. % CBD (relative to the total amount of cannabinoid active agent) for the acute pain
  • the second formulation dose may have at least 80 wt. % CBG (relative to the total active agent amount) for extended treatment of the IBS.
  • the formulation dose may be designed to target and treat connective tissues in the body.
  • the connective tissue surround the muscles, bones, nerves, and blood vessels.
  • the anti-inflammatory effects of CBD may work with the CB-2 receptors to strengthen the connective tissues and/or protect against cartilage degradation or inflammation in the joints.
  • the cannabinoid active agent may include at least 80 wt. % CBD.
  • the cannabinoid active agent optionally may include CBC as well, which also has anti-inflammation properties.
  • the formulation dose may be designed to promote relaxation and sleep.
  • the cannabinoid active agent may include CBN and/or CBD, which both have sleep-promoting properties.
  • CBN at least 80 wt. % of the cannabinoid active agent may be CBN, and 20 wt. % or less may be CBD.
  • at least 80 wt. % of the cannabinoid active agent may be CBD, and 20 wt. % or less may be CBN.
  • the formulation may also include one or more sleep-promoting additives, such as magnesium, 1-theanine, and/or the like.
  • the cannabinoid active agent in the formulation dose may include multiple plant-based, non-THC cannabinoids depending on the specific desired therapeutic effects on the subject ingesting the dose.
  • the subject may take a dose that is specifically formulated to include CBG for treating the IBS and one or more of CBD, CBC, or CBN for treating the arthritis and associated pain and inflammation.
  • the formulation dose may be configured to provide a staggered release sequence of the cannabinoid active agent.
  • Figure 4 is a cross-sectional view of a formulation dose 110 according to another embodiment.
  • the formulation dose 110 includes a first coating 112 that covers and surrounds a first active mixture 114.
  • the first active mixture 114 covers and surrounds a second coating 116 (e.g., an enteric coating), which covers and surrounds a second active mixture 118.
  • Both the first and second active mixtures 114, 118 include a cannabinoid active agent.
  • the arrangement shown in Figure 4 is configured to release the cannabinoids at different times, at different locations, and/or for different lengths of time within the subject.
  • the coatings 112, 116 are time release components that control the timing and rate of release of the active mixtures 114, 118.
  • the two active mixtures 114, 118 represent different release phases or tracks in the staggered release sequence.
  • the first active mixture 114 is released prior to the second active mixture 118.
  • the first active mixture 114 is an initial release phase.
  • the initial release phase may be designed for immediate or quick absorption to provide early therapeutic effect.
  • the first active mixture 114 may include one or more cannabinoids specifically selected for providing pain or stress relief, such as CBD.
  • the first active mixture 114 also includes the caprate salt permeation enhancer mixed with the cannabinoid active agent to increase the absorption rate of the cannabinoid active agent.
  • the first coating 112 may readily degrade in the mouth to release the first active mixture 114.
  • the coating 112 optionally may be a flavored sugar coating.
  • the formulation dose 110 may lack the first coating 112, such that the first active mixture 114 defines the outer perimeter of the dose 110.
  • the first active mixture 114 may be configured to degrade for absorption of the cannabinoid agent into the mucosal tissue of the mouth and/or the lining of the stomach.
  • the first active mixture 114 may provide a certain amount of cannabinoid agent, such as between 10 wt. % and 40 wt. % of the total cannabinoid active agent in the dose, for immediate availability and use by the body.
  • the cannabinoid agent in the initial phase may provide therapeutic effect at an initial onset between 30 seconds and 30 minutes after oral ingestion, such as between 1 and 10 minutes.
  • the initial phase may provide therapeutic effect over a first time window that lasts from about 15 minutes to about 4 hours post ingestion, such as from about 30 minutes to about 3 hours.
  • the second active mixture 118 represents a secondary release phase.
  • the secondary release phase may be designed for relatively uniform cannabinoid absorption and concentration in the bloodstream to provide therapeutic effect over an extended period of time.
  • the therapy provided by the secondary release phase may be longer than the therapy provided by the initial phase, but may have a delayed onset relative to the initial release phase.
  • the second coating 116 is a barrier between the first and second active mixtures 114, 118.
  • the second coating 116 is a time release component that manages the controlled release of the second active mixture 118.
  • the second coating 116 is an enteric coating that is the same or similar to the enteric coating 102 described in Figure 1.
  • the enteric coating 116 may be configured to delay releasing the second active mixture 118 until reaching a designated target location in the body based on pH or the like.
  • the designated target location may be the intestines, such as the small intestines or the large intestines.
  • the presence of the enteric coating 116 may delay the initial release of the second active mixture 118 for a period of time, such as between 1 and 5 hours. As such, the initial onset of absorption of the cannabinoid into the bloodstream may not occur until 1 to 5 hours after ingestion.
  • the cannabinoid in the first active mixture 114 provides initial therapeutic effect to the subject.
  • the second active mixture 118 may be released at a relatively constant rate for an extended period of time.
  • the second active mixture 118 may release a certain amount of the total cannabinoid agent in the dose, such as between 60 wt. % and 90 wt. % over a delayed time window.
  • the delayed time window may be, for example, from 1 hours post ingestion to 8 hours post ingestion, such as from 2 hours to 6 hours.
  • the cannabinoid may be absorbed into epithelial tissue in the intestines over an extended absorption period, such as from 2 hours to 10 hours post ingestion.
  • the first active mixture 114 may release about 25 wt. % of the cannabinoid agent in the formulation dose, and the second active mixture 118 may release the remainder (e.g., about 75 wt. %) of the cannabinoid agent.
  • Figure 5 is a graph 240 illustrating an absorption profile of a third formulation dose according to an embodiment.
  • the graph 240 plots bioavailability over time, similar to the graphs 200 and 220 shown in Figures 2 and 3, respectively.
  • the third formulation dose may be the formulation dose 110 shown in Figure 4, including the first and second active mixtures 114, 118 separated by the enteric coating 116.
  • the plot line 242 represents the amount of the cannabinoid active agent of the first active mixture 114 present in the bloodstream of the subject over time.
  • the plot line 244 represents the amount of the cannabinoid active agent of the second active mixture 118 present in the bloodstream of the subject over time.
  • the absorption profile of the first active mixture 114 may be similar to the quick release absorption profile shown in Figure 2.
  • the absorption profile of the second active mixture 118 may be similar to the extended release absorption profile shown in Figure 3.
  • the cannabinoid active agent (of the active mixtures 114, 118) may be present in the bloodstream for a longer time period.
  • the residence time shown in Figure 5 is greater than each of the residence times shown in Figures 2 and 3.
  • the formulation dose 110 may provide therapy over a greater time period.
  • the formulation dose 110 shown in Figure 4 has 50 mg of cannabinoid active agent in total, a first portion such as 40 wt, % (e.g., 20 mg) may be present in the first active mixture 114 and a second portion such as 60 wt. % (e.g., 30 mg) may be present in the second active mixture 118.
  • a first portion such as 40 wt, % (e.g., 20 mg) may be present in the first active mixture 114 and a second portion such as 60 wt. % (e.g., 30 mg) may be present in the second active mixture 118.
  • the formulation dose 110 can alleviate the reduced bioavailability by including the caprate salt enhancer in one or both of the first and second active mixtures 114, 118.
  • the caprate salt enhancer may be present at relatively substantial concentrations, such as between 15 wt. % and 300 wt. % of the amount of the respective cannabinoid active agent.
  • the bioavailability of the cannabinoid agent in the illustrated formulation dose 110 may be at least 20%, at least 25%, or at least 30% at both 2 hours and 4 hours, for example, post ingestion.
  • the first and second active mixture 114, 118 may have the same composition.
  • the composition can refer to the type of the cannabinoid active agent present, the type of the permeation enhancer present, and/or the (weight) ratio of the cannabinoid active agent to the permeation enhancer.
  • the staggered release sequence extends the time that the single active mixture composition can provide therapeutic effect.
  • the compositions may be the same even though one of the active mixtures is present at a greater amount than the other active mixture.
  • the amount of the second active mixture 118 may exceed the amount of the first active mixture 114.
  • the second active mixture 118 may include between 55 wt. % and 95 wt.
  • the first active mixture 114 includes the remaining 5 wt. % to 45 wt. %. More specifically, the second active mixture 118 may be present at an amount of 60 wt. % to 90 wt. %, with the balance contained in the first active mixture 114. In a nonlimiting example, if the first active mixture 114 is 25 wt. % of the total cannabinoid content in the dose, the second active mixture 118 may define the remaining 75 wt. %. In an alternative embodiment, the first active mixture 114 exceeds the amount of the second active mixture 118.
  • the second active mixture 118 differs in composition from the first active mixture 114.
  • the permeation enhancer such as sodium caprate or another caprate salt, may be present in both the first and second active mixtures 114, 118.
  • the compositions may differ in the type of the cannabinoid(s) present.
  • the cannabinoid active agent in the first active mixture 114 differs from the cannabinoid active agent in the second active mixture 118.
  • the first cannabinoid active agent may include only CBD to provide pain relief.
  • the second cannabinoid active agent in the second active mixture 118 may include a combination of CBD with one or more other cannabinoids, such as CBG, CBD, and/or CBN.
  • composition of cannabinoids may be based in part on the desired therapeutic effect.
  • the CBD in the first active mixture 114 can provide quick pain relief, and a combination of CBD, CBC, and CBN in the second active mixture 118 to provide anti-inflammation over an extended period of time.
  • a formulation dose 110 specifically formulated as a sleep aid may include CBD in the first active mixture 114 to provide relaxation before bed, and a combination of CBD and CBN in the second active mixture 118 to provide a restful, extended night of sleep.
  • the caprate permeation enhancer may be present in both the first and second active mixtures 114, 118, but at different amounts and/or concentrations relative to the cannabinoid active agent.
  • the first active mixture 114 may have less total caprate enhancer than the second active mixture 118, but a greater concentration relative to the local amount of the cannabinoid active agent.
  • the greater concentration of the enhancer in the first active mixture 114 may provide a greater absorption rate of the cannabinoid during the initial phase than during the extended phase for accelerating the onset of the therapeutic effect.
  • the illustrated embodiment in Figure 4 includes two active mixtures 114, 118 separated by an enteric coating 116 for a staggered release sequence.
  • Both active mixtures include at least one cannabinoid and a caprate permeation enhancer.
  • the staggered release sequence may include additional coatings, additional active mixtures, and/or a different arrangement of layers per formulation dose.
  • the formulation dose may include multiple enteric coatings of different composition and/or thickness for staggered release in additional locations throughout the body.
  • a first enteric coating of hydroxypropyl methylcellulose phthalate (trade name “HPMCP (Hypromellose Phthalate), manufactured by Shinetsu Chemical Industry Co., Ltd.) may dissolve at the pH of the upper small intestine
  • a second enteric coating of methacrylate copolymer (trade name “Eudragit LI 00], Evonik Rohm GmbH Co., Ltd., Higuchi Shokai Co., Ltd.) may dissolve at the pH of a middle part of the small intestine
  • a third enteric coating of methacrylate copolymer (trade name “Eudragit S100”, manufactured by Evonik Rohm GmbH Co., Ltd., Higuchi Shokai sales) may dissolve at the pH of the lower small intestine.
  • the thicknesses of the coatings may be intentionally varied such that thinner coatings dissolve prior to thicker coatings to release associated active mixtures earlier than active mixtures surrounded by thicker coatings.
  • the formulation dose may include a lipid compound, such as a fatty acid, a wax, a sterol, a triglyceride, or the like. Due to the fat-soluble nature of CBD, including a lipid source with the CBD can enhance the absorption of the cannabinoid, in terms of rate of absorption and/or amount absorbed.
  • the lipid compound may be an omega-3 fatty acid.
  • the oral formulation dose also includes piperine, which can represent another permeation enhancer.
  • Piperine is a compound found in black pepper, and it works on several levels to provide powerful absorption-boosting effects. For example, piperine may stimulate transporter molecules in the intestinal lining that are responsible for bringing the cannabinoid agent across the intestinal membrane and into the bloodstream. Once the cannabinoid agent is absorbed, piperine may inhibit enzymes that degrade the cannabinoid agent, providing more time to reach its target tissues where it can be taken up and utilized.
  • the piperine may be co-formulated (e.g., mixed) with the caprate salt to define the permeation enhancer.
  • One or more other embodiments described herein lack piperine.
  • a pH modifier compound may be added to the formulation to alter the pH in the environment.
  • the pH modifier may alter the pH in the intestinal environment to be within a designated range to improve the absorption or uptake of the cannabinoid active agent.
  • the pH modifier may be a base to increase the pH in the intestinal environment for increasing the solubility and absorption of the cannabinoid active agent and/or sodium caprate into the epithelial intestinal tissue.
  • the pH modifier may include or represent sodium carbonate, magnesium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, ascorbic acid, citric acid, succinic acid, fumaric acid, derivatives thereof, and combinations thereof. More specifically, the pH modifier may represent Acetic acid, Adipic acid, Citric acid, Fumaric acid, Glucono-5-lactone, Gluconic acid, Lactic acid, Malic acid, Maleic acid, Tartaric acid, Succinic acid, Propionic acid, Ascorbic acid, Phosphoric acid, Sodium orthophosphate, Potassium orthophosphate, Calcium orthophosphate, Sodium diphosphate, Potassium diphosphate, Calcium diphosphate, Pentasodium triphosphate, Pentapotassium triphosphate, Sodium polyphosphate, Potassium polyphosphate, Carbonic acid, Sodium carbonate, Sodium bicarbonate, Potassium carbonate, Calcium carbonate, Magnesium carbonate, Magnesium oxide, or any combination thereof.
  • the formulation dose may include a bioadhesive layer that increases the bioactivity of the cannabinoid active agent at a given amount of caprate enhancer.
  • the bioadhesive layer may increase the activity of the caprate enhancer, allowing for a reduction in the amount of caprate enhancer utilized per dose and/or an improvement in the absorption rate and/or bioavailability of the cannabinoid relative to formulation doses with the same amount of caprate enhancer but without the bioadhesive layer.
  • the bioadhesive layer may include hydroxypropyl methylcellulose (HPMC), polycarbophil AA1, or the like.
  • HPMC hydroxypropyl methylcellulose
  • the bioadhesive layer is a composite of multiple materials, such as a bioadhesive polymer, a plasticizer, and/or other materials to modify the release rate.
  • the bioadhesive layer can be present in an amount from about 0.5 wt. % to about 10 wt. % of the formulation, such as from about 1 wt. % to about 5 wt. %.
  • the thickness of the bioadhesive layer can be modulated to achieve desirable release kinetics and absorption.
  • the bioadhesive layer may be incorporated into a coating, such as the enteric coatings described herein.
  • Formulations with the bioadhesive layer incorporated into the enteric coating may allow an increased absorption window in the intestines and can achieve earlier clinical responses, which is generally more desirable.
  • the formulations with the bioadhesive layer incorporated into the enteric coating may reduce the coating requirements and simplify the manufacturing process, thereby reducing the production time and subsequently the cost to produce the desired formulation doses.
  • a probiotic may be added to the formulation dose for stomach and gut health.
  • Probiotics contain different types of micro-organisms such as yeast (saccharomyces boulardii) and bacteria (such as lactobacillus, bifidobacterium). Probiotics are used to improve digestion and restore normal flora in the microbiome. Probiotics provide beneficial microbes that have the potential to influence and balance systems such as the microbiomes in your gut and throughout your body. Probiotics have been used to treat bowel problems (such as diarrhea, lactose intolerance, and irritable bowel). Cannabinoids such as CBD may also affect the gut by helping to maintain a healthy intestinal tract, helping to support gut flora and pH, and supporting proper digestion.
  • yeast sacharomyces boulardii
  • bacteria such as lactobacillus, bifidobacterium
  • Probiotics are used to improve digestion and restore normal flora in the microbiome.
  • Probiotics provide beneficial microbes that have the potential to influence and balance systems such as the microbiomes in your gut
  • Including a probiotic into the formulation dose to change the bacterial composition of the GI tract could affect how the body reacts to the cannabinoid active agent in the dose.
  • the probiotic may be included in the first active mixture 114, such that the micro-organisms in the probiotic can be released into the mouth, esophagus, and/or stomach.
  • no probiotic is present in the second active mixture 114 which may be released in the intestines.
  • Figure 6 is a flow chart 300 of a method for producing a formulation dose for oral administration in a subject according to an embodiment.
  • the formulation dose that is formed by the method is the formulation dose according to the embodiments described herein, such as with reference to Figures 1 through 5.
  • a cannabinoid active agent including cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), and/or cannabinol (CBN) is provided.
  • CBD cannabidiol
  • CBD cannabigerol
  • CBC cannabichromene
  • CBN cannabinol
  • the cannabinoid active agent may be provided in the form of an oil or extract.
  • THC is not present in the cannabinoid active agent.
  • the cannabinoid active agent is mixed with a permeation enhancer that includes a caprate salt to define an active mixture.
  • the caprate salt may be sodium caprate in a non-limiting example.
  • the cannabinoid active agent is mixed with the permeation enhancer in a lab environment with diligent control over the conditions and amounts of the substances.
  • mixing the cannabinoid active agent with the permeation enhancer may include controlling relative amounts of the cannabinoid active agent and the permeation enhancer such that the amount of caprate salt represents between about 15% and about 300% of the amount of the cannabinoid active agent present in the active mixture.
  • the active mixture is formed into a formulation dose for oral administration in a subject.
  • the forming process may include shaping into a tablet, capsule, piece of gum, gummy, and/or the like.
  • a time release coating may be applied on the active mixture to manage controlled release of the active mixture in the subject after ingestion of the formulation dose.
  • the formulation dose has a staggered release profile.
  • the active mixture is a first active mixture that includes a first portion of the cannabinoid active agent.
  • a second portion of the cannabinoid active agent is mixed with the permeation enhancer to define a second active mixture.
  • a coating may be applied to surround the second active mixture.
  • the first active mixture may be applied to surround the coating such that the coating defines a barrier between the first and second active mixtures.
  • the first active mixture Due to the relative positions and the barrier, the first active mixture has an earlier initial onset of release into the subject than the second active mixture.
  • the first active mixture can provide initial, relatively immediate therapeutic effect, and the second active mixture can provide delayed but sustained or extended therapeutic effect.
  • the coating may be an enteric coating configured to delay release of the second portion of the cannabinoid active agent until the formulation dose reaches an intestinal environment of the subject.
  • the method may also include orally administering the formulation dose to the subject.
  • value modifiers such as “about,” “substantially,” and “approximately” inserted before a numerical value indicate that the value can represent other values within a tolerance range above and/or below the specified value, such as values within 5%, 10%, or 15% of the specified value.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Une dose de formulation pour administration orale chez un sujet comprend un agent actif cannabinoïde et un activateur de perméation. L'agent actif cannabinoïde comprend ou représente un ou plusieurs éléments parmi le cannabidiol (CBD), le cannabigérol (CBG), le cannabichromène (CBC), ou le cannabinol (CBN). L'activateur de perméation comprend ou représente un sel de caprate.
PCT/US2021/055905 2020-10-20 2021-10-20 Formulations pour l'amélioration de la perméation des cannabinoïdes WO2022087171A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170290870A1 (en) * 2016-04-12 2017-10-12 Scott Schaneville Ingestible films having substances from hemp or cannabis
WO2018011808A1 (fr) * 2016-07-14 2018-01-18 Icdpharma Ltd Compositions auto-émulsifiantes de cannabinoïdes
WO2019159174A1 (fr) * 2018-02-16 2019-08-22 Icdpharma Ltd. Administration, dans le côlon, de cannabinoïdes dans des compositions de solution solide
WO2020014776A1 (fr) * 2018-07-15 2020-01-23 Rapid Dose Therapeutics Corp. Bande de film cannabinoïde dispersible par voie orale
WO2020037403A1 (fr) * 2018-08-20 2020-02-27 Hexo Operations Inc. Produits, récipients, systèmes, et procédés contenant un cannabinoïde
WO2020054702A1 (fr) * 2018-09-12 2020-03-19 京セラ株式会社 Insert de coupe, outil rotatif et procédé de production d'une pièce ouvrée coupée
US20200138772A1 (en) * 2018-07-09 2020-05-07 Volker Berl Stabilized formulations of cannabinoid compositions

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170290870A1 (en) * 2016-04-12 2017-10-12 Scott Schaneville Ingestible films having substances from hemp or cannabis
WO2018011808A1 (fr) * 2016-07-14 2018-01-18 Icdpharma Ltd Compositions auto-émulsifiantes de cannabinoïdes
WO2019159174A1 (fr) * 2018-02-16 2019-08-22 Icdpharma Ltd. Administration, dans le côlon, de cannabinoïdes dans des compositions de solution solide
US20200138772A1 (en) * 2018-07-09 2020-05-07 Volker Berl Stabilized formulations of cannabinoid compositions
WO2020014776A1 (fr) * 2018-07-15 2020-01-23 Rapid Dose Therapeutics Corp. Bande de film cannabinoïde dispersible par voie orale
WO2020037403A1 (fr) * 2018-08-20 2020-02-27 Hexo Operations Inc. Produits, récipients, systèmes, et procédés contenant un cannabinoïde
WO2020054702A1 (fr) * 2018-09-12 2020-03-19 京セラ株式会社 Insert de coupe, outil rotatif et procédé de production d'une pièce ouvrée coupée

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