WO2019159174A1 - Administration, dans le côlon, de cannabinoïdes dans des compositions de solution solide - Google Patents

Administration, dans le côlon, de cannabinoïdes dans des compositions de solution solide Download PDF

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Publication number
WO2019159174A1
WO2019159174A1 PCT/IL2019/050184 IL2019050184W WO2019159174A1 WO 2019159174 A1 WO2019159174 A1 WO 2019159174A1 IL 2019050184 W IL2019050184 W IL 2019050184W WO 2019159174 A1 WO2019159174 A1 WO 2019159174A1
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cannabinoid
cannabinoids
poly
composition according
certain embodiments
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PCT/IL2019/050184
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English (en)
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Doron Friedman
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Icdpharma Ltd.
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Publication of WO2019159174A1 publication Critical patent/WO2019159174A1/fr

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    • 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
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to pharmaceutical solid dosage for s and solid solution compositions comprising at least one cannabinoid, essentially solubilized in a mixture of at least one emulsifier and at least one solid matrix forming agent.
  • the composition decomposes by disintegration or erosion or swelling following contact with body fluids and releases a plurality of particles of sub-micron mean size.
  • the cannabinoid is essentially solubilized in the particles and exhibits enhanced oral bioavailability and provides a convenient and efficient method of administration of cannabinoids and cannabis extracts.
  • Cannabinoids have low oral absorption due to low solubility and high first pass effect.
  • Various approaches have been adopted in the prior art in an attempt to solve these problems. For example, to overcome the low solubility, cannabinoids have been dissolved in triglycerides oils, and to overcome the low bioavailability and bypass the first pass effect, cannabinoids have been dissolved in solvents or formulated in muco-adhesive delivery systems and administered in the oral cavity.
  • Solid solutions are preferred physical systems because the components therein readily form liquid solutions when brought into contact with a liquid medium such as gastric juices. This increased propensity for dissolution may be attributed at least in part to the fact that the energy required for dissolving the components from a solid solution is less than that required for dissolving the components from a crystalline or microcrystalline solid phase or solubilizing an oily hydrophobic and insoluble drug.
  • Hot Melt Extrusion is a practical method of formulating poorly soluble bioactive agents in the pharmaceutical field and is attractive for mass production because it is a continuous process, solvent free, easy to clean and can be used for the preparation of different drug delivery systems; including granules, pellets, sustained released tablets, suppositories, stents, ophthalmic inserts, and transdermal and transmucosal delivery systems. Since it is a continuous process, fewer steps are involved resulting in reduced production cost.
  • Type (a) crystalline solid dispersions is a system in which the crystalline of the bioactive agent or drug is dispersed into an amorphous polymer matrix.
  • DSC Differential Scanning calorimetry
  • Type (b) amorphous solid dispersions result when a melt extruded drug-polymer excipient is cooled at a rate that does not allow the drug to recrystallize or processed at temperatures where the drug melts but remains immiscible with the polymer excipient or the drug is non-crystalline and has amorphous nature.
  • the DSC profile for amorphous solid dispersions is characterized by the presence of two Tg values. They can be unstable because the drug can return to the more stable crystalline form.
  • Type (c) is the solid solution, in which the drug molecules are molecularly dispersed in the polymeric matrix and exhibit a single Tg. This system is more stable and has a longer shelf life.
  • Vinylpyrrolidone-vinylacetate copolymer (Kollidon® VA64) and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (Soluplus®) have been applied as polymer excipients for immediate release (IR) profiles.
  • polyvinyl acetate-polyvinylpyrrolidone (Kollidon® SR) has been applied as polymer excipient for sustained release (SR) profiles.
  • Soluplus® has been shown to increase the drug absorption through the intestinal wall when applied as a solid solution.
  • United States Patent Application 20060257463 (Elshoy et al.), teaches a film matrix or a reservoir containing the cannabinoid, and attaching said transmucosal preparation to the mucosa of the subject.
  • United States Patent Application 20170290870 (Schaneville), teaches a fast acting film comprising cannabinoids in a dispersion for oral cavity administration.
  • United States Patent 8,003,672 Mckelvey at al teaches a pharmaceutical formulation comprising a solid dispersion made by hot-melt extrusion comprising a cannabinoid receptor inverse agonist.
  • the present invention supplies a solution for all of the above unmet needs.
  • cannabinoids prepared as a hot melt dissolved in a mixture of emulsifiers and solid matrix forming agents such as polymers and waxes, can form a solid solution that disintegrates or erodes or swells, when in contact with body fluids and release a dispersion of plurality of particle with mean particle size of much below one hundred microns and show significant improved oral bioavailability of at least 50%.
  • the present invention relates to solid solution compositions, formulations and delivery systems, for the administration of combinations of at least one cannabinoid with at least one emulsifier and at least one solid matrix forming agent, to form a solid solution delivery system that disintegrate or erode or swells and forms a fine dispersion of cannabinoid or cannabis extract droplets with a plurality of particles following contact with body fluids in mammals and that this mode of delivery improves oral absorption.
  • the present invention relates to compositions and dosage forms of cannabis or cannabinoids, emulsifiers and solid matrix forming agents that form a solid matrix upon co melting with the cannabinoids and the emulsifiers and cooling, which disintegrates or erodes or swells when in contact with body fluids thereby forming a plurality of particle in the sub-micron range, and displaying improved oral bioavailability through mucus membranes including (but not limited to) the gastrointestinal.
  • these dosage forms and delivery systems have a long shelf life stability.
  • the inventor has unexpectedly discovered that it is possible to prepare a solid solution dosage form of cannabinoids, emulsifiers and solid matrix forming agents, such as polymers or waxes, that has good shelf life stability and improved oral bioavailability. Furthermore, said solid solution dosage form has been used to prepare the pharmaceutical compositions and formulations of the present invention, which are demonstrated herein to possess several therapeutically-beneficial properties.
  • the pharmaceutical, medicinal or veterinary compositions of the present invention comprise mixture of cannabinoids, emulsifiers and solid matrix forming agents such as polymers and waxes, in a stable solid state, that is, a solid solution of cannabinoids, or cannabinoids, which disintegrates or erodes or swells to release fine sub-micron and nano-size droplets comprising the essentially solubilized cannabinoids and may also comprise terpenes that are tailored and assembled for specific pharmacological needs.
  • the compositions of the present invention are stable and anhydrous solids solutions that provide long shelf life stability at ambient room temperature of at least two years.
  • compositions of the present invention are releasing essentially solubilized cannabinoid composition having a fine submicron droplet size, thus improving the oral bioavailability of the cannabinoids by at least 50% and more preferably by at least 100% or by at least 200%.
  • the present invention is primarily directed to a solid solution composition
  • a solid solution composition comprising: a) one or more cannabinoids, b) one or more non-ionic emulsifiers, and c) one or more solid matrix forming agents; wherein said one or more cannabinoids is essentially solubilized in a solid solvent system comprising said one or more emulsifiers and said one or more solid matrix forming agents.
  • the above-disclosed solid solution composition is capable of disintegration after having made contact with liquid. This may occur, for example, when the composition has been formulated for oral administration and has been swallowed by a subject in need of treatment with said composition. Upon disintegration, the solid solution composition releases a plurality of particles, said particles having a mean particle size of about 100 nm to about 100 pm, and wherein said one or more cannabinoids are essentially solubilized in the released particles.
  • the composition comprises about 0.1 % to about 60 % by weight of a cannabinoid or a mixture of cannabinoids. In certain embodiments, the composition comprises about 0.5 % to about 20 % by weight of a cannabinoid or a mixture of cannabinoids. In certain embodiments, the at least one cannabinoid or cannabis extract is essentially solubilized in the solid matrix.
  • the cannabinoid is selected from the group consisting of cannabidiol (CBD), cannabidiolic acid (CBDA), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabielsoin (CBE), iso- tetrahydrocannabimol (iso-THC), cannabicyclol (CBL), cannabicitran (CBT), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), salts thereof, derivatives thereof and mixtures of cannabinoids.
  • CBD cannabidiol
  • CBDA canna
  • the composition comprises about 1 % to about 80 % by weight of a non-ionic emulsifier or a mixture of non-ionic emulsifiers with HLB >10 and HLB of about 10 to about 16. In certain embodiments, the composition comprises about 2 % to about 30 % by weight of an emulsifier or a mixture of emulsifiers.
  • the emulsifier is selected from the group consisting of, sucrose stearate, sucrose ester, sucrose distearate, sucrose laurate, sucrose palmitate, sucrose oleate, polysorbate, polysorbate 80, polyoxyl glycerides, polyoxyl 35 hydrogenated castor oil, tocopherol polyethylene glycol 1000 succinate, lauroyl polyoxyl-32 glycerides, polyglyceryl fatty acid esters, sorbitan fatty acid esters and mixtures of the emulsifiers.
  • the composition comprises a first emulsifier selected from non-ionic surfactants with HLB of about 10 to about 16 and a second emulsifier selected form non ionic hydrophilic or hydrophobic surfactants having an HLB value of about 4 to about 12.
  • the composition comprises from about 10% to about 90% of at least one solid forming matrix agent selected from a polymer or a wax or combinations thereof, In certain embodiments, the composition comprises from about 20% to about 80% of at least one solid matrix forming agent. In certain embodiments, the composition comprises from about 30% to about 70% of at least one solid matrix forming agent, In certain embodiments, the composition comprises from about 40% to about 60% of at least one solid matrix forming agent.
  • the at least one solid matrix forming agent is selected from; Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer), PemuleneTM (crosslinked copolymer of acrylic acid and a hydrophobic C10-30 alkyl acrylate co-monomer), gelatin, Hydroxy propyl methyl cellulose (Methocel), Methyl cellulose , Hydroxy propyl cellulose (Klucel), hydroxyethylcellulose (Natrosol), Sodium carboxy methyl cellulose, acrylates copolymers, Ammonio Methacrylate Copolymer Type A or B, Dimethylaminoethyl Methacrylate - Butyl Methacrylate - Methyl Methacrylate Copolymer (EudragitTM), Methacrylic Acid - Ethyl Acrylate Copolymer, polyvinyl alcohol graft copolymer (Kollicoat
  • the composition of the solid solution of cannabinoid releases upon disintegration or erosion or swelling, a plurality of particles having a mean particle size of 10 microns or less.
  • the pharmaceutical composition of the solid solution cannabinoid releases upon disintegration or erosion or swelling, a plurality of particles having a mean particle size of 5 microns or less.
  • the pharmaceutical composition of the solid solution cannabinoid releases upon disintegration or erosion or swelling, a plurality of particles having a mean particle size of 2 microns or less.
  • the pharmaceutical composition of the solid solution cannabinoid releases upon disintegration or erosion or swelling, a plurality of particles having a mean particle size of 1 microns or less.
  • composition of the invention is formulated as a dosage form suitable for oral administration.
  • the dosage form is formulated as granules, pellets, micro particles, tablet, hard shell capsules, suspended in a liquid, suspended in a syrup or enema.
  • the dosage form is formulated for oral or mucosal delivery.
  • the dosage form is formulated as or in a lozenge, candy, toffee, chocolate or cookie.
  • the tablet or pellets are an immediate release or slow or controlled release dosage dorms
  • the tablet is enteric coated or is a melt or dissolved in the mouth or is a muco-adhesive dosage form.
  • the unit dosage form which is a unit particle, such as tablet, capsule, granules, pellets, micro-particles and film, are enteric coated or coated with a colonic coat that protect the unit dose from being decomposed at the acidic gastric pH and swells in a time-dependent manner or a pH-controlled manner or both, to release the cannabinoids in the distal portion of the intestinal tract and may also release a portion of the cannabinoids in the intestine for systemic absorption and a portion of the cannabinoids within the colon in order to exert a local colonic pharmacological effect.
  • a colonic coat that protect the unit dose from being decomposed at the acidic gastric pH and swells in a time-dependent manner or a pH-controlled manner or both, to release the cannabinoids in the distal portion of the intestinal tract and may also release a portion of the cannabinoids in the intestine for systemic absorption and a portion of the cannabinoids within
  • the dosage form containing the composition of the invention is capable of disintegrating following contact with fluid in the lower intestine and in the colon, thereby releasing at least about 20% (w/w) of the one or more cannabinoids at the distal jejunum and the colon.
  • the dosage form is acid resistant or has a delayed time release or enzyme release mechanism or combinations thereof, and is capable of disintegrating, decomposing or swelling in the lower or distal intestines and in the colon thereby releasing at least about 50% (w/w) of the one or more cannabinoids in the distal jejunum, and/or the colon.
  • any one of the compositions described above, or any one of the dosage forms described above may be used in a method of treating a cannabinoid- responsive symptom, disease or disorder.
  • the composition or dosage form comprises cannabidiol (CBD).
  • CBD cannabidiol
  • the pharmaceutical composition or dosage form further comprises tetrahydrocannabinoid (THC).
  • THC tetrahydrocannabinoid
  • the CBD:THC weight ratio is about 20:1.
  • the mixture comprises CBD.
  • the mixture comprises THC.
  • the mixture comprises CBD and THC.
  • the mixture comprises CBD and THC in a weight ratio of about 1:1.
  • the mixture comprises CBD and THC in a weight ratio of about 10:1 to about 1:10.
  • the pharmaceutical composition further comprises about 0 % to about 30 % by weight of fatty acid or fatty alcohol, glyceryl or propylene glycol mono or di stearate, fats, lipids, oils other than essential oils, co-solvents or mixtures thereof.
  • the solid solution of the composition further comprises one or more terpenes, one or more essential oils or a mixture thereof.
  • the composition of the invention comprises an oral dosage form selected from the group consisting of a capsule, tablet or sachet filled with granules, wherein said dosage form comprises at least 100 mg of cannabidiol or cannabidiolic acid, at least 50 mg of tocopheryl polyethylene glycol 1000 succinate, at least 50 mg of sucrose distearate or polyglyceryl ester, and at least 100 mg of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer or poly[methacrylic acid, methyl methacrylate] or poly aery late polymer or copolymer or Poloxamer 407.
  • the present invention is directed to a method of treatment of an inflammatory bowel disease in a mammal in need thereof, comprising administering one or more doses of a therapeutically effective amount of a composition of the present invention.
  • the mammalian subject is a human being.
  • each dose administered to the subject comprises between about 10 mg and 2,000 mg of at least one cannabinoid.
  • the present invention is also directed to a method of treating gastrointestinal disease, comprising administering a therapeutically effective amount of one or more doses of a composition according to claim 1 , wherein each of said doses provides a simultaneous dual pharmacological effect comprising a) systemic absorption leading to a measurable cannabinoid blood level and b) local delivery of the cannabinoids to one or more regions of the gastrointestinal tract, selected from the ilium, jejunum, distal jejunum and the colon.
  • each dose comprises: a) particles that are non-pH resistant, and b) particles that are pH resistant and/or have a delayed time release or enzyme release profile.
  • the present invention is directed to a method of manufacturing a composition according to claim 1 by means of hot melt extrusion, comprising the steps of feeding the ingredients into a hot melt extrusion machine, mixing and heating said ingredients until melted and extruded and cooling and shaping, wherein all of these steps together form a single continuous process.
  • the term“cannabinoid” as used herein generally refers to one of a class of diverse chemical compounds that act on a cannabinoid receptor in cells that repress neurotransmitter release in the brain.
  • the term“cannabinoid” as used herein further refers a chemical compound that acts on cannabinoid receptors or has a structure similar the stature of a compound acting on cannabinoid receptor in cells.
  • Ligands for these receptor proteins include the endocannabinoids (produced naturally in the body by humans and animals), the Phyto cannabinoids (found in cannabis and some other plants), and synthetic cannabinoids (manufactured artificially).
  • cannabisbis extract refers to one or more plant extracts from the cannabis plant.
  • a cannabis extract contains, in addition to one or more cannabinoids, one or more non-cannabinoid components which are co-extracted with the cannabinoids from the plant material. Their respective ranges in weight will vary according to the starting plant material and the extraction methodology used.
  • Cannabinoid-containing plant extracts may be obtained by various means of extraction of cannabis plant material. Such means include but are not limited to: supercritical or subcritical extraction with CO2, extraction with hot or cold gas and extraction with solvents.
  • essential oil or“essential oils” as used herein relates to a concentrated hydrophobic liquid oil containing volatile aroma compounds, obtained from plants.
  • Essential oils are also known as volatile oils, ethereal oils, due their distinct typical strong volatility at ambient temperature, or simply as the oil of the plant from which they were extracted, such as“oil of lavender”.
  • An oil is “essential” in the sense that it contains the "essence of” the plant's fragrance, the characteristic fragrance of the plant from which it is derived.
  • Essential oils are generally extracted by distillation, often by using steam. Other processes include expression, solvent extraction, absolute oil extraction, resin tapping, and cold pressing. They are used in perfumes, cosmetics, soaps and other products, for flavoring food and drink, and for adding scents to incense and household cleaning products.
  • the essential oils are comprised mainly of terpenes or terpenoids and the various properties of the different essential oils are derived from their terpenes content.
  • Terpene as used herein also covers terpenoids.
  • Terpenes are lipophilic compounds, volatile and liquid at room temperature and are used herein in this invention as part of the composition that contribute to increased bioavailability as well as cannabinoids solubilizers and as pharmacologically active agents that works in synergy or entourage with the cannabinoids.
  • Terpenes are volatile organic compounds formed by the union of hydrocarbon of 5 carbon atoms, known as isoprene. The smallest and most volatile compounds are monoterpenes, which are biosynthesized by the union of two isoprene molecules. The biggest and least volatile are biosynthesized by the union of three or more isoprene molecules.
  • the sesquiterpenes are next in the chain, which are formed by the union of three isoprene molecules.
  • Terpenes are secondary metabolites, which provide the plant with its organoleptic characteristics (aroma and flavor) and that constitutes most of the essential oil produced by aromatic plants.
  • Terpenes are major secondary metabolites of cannabis and are responsible for the odor and flavor of various cannabis strains. Cannabis strains and hemp strains produce many terpenes as secondary metabolites.
  • Terpenes are synthetized from terpene unit into mono- terpenes, sesqui-terpenes, di-terpenes that are lipophilic, volatile and insoluble in water and are cyclic or bicyclic or not cyclic and may have alcohol, aldehyde or ketone chemical moiety.
  • the term “terpene” further relates to essential oils.
  • the term “terpene” does not include fats and/or lipids.
  • emulsifier as used herein are amphiphilic molecules that are surface active, or surfactants, and that stabilize emulsions by reducing the interfacial tension and by forming a stable layer between the lipophilic and the hydrophilic phases of the emulsion.
  • solid solution defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one component is evenly and homogeneously mixed throughout the other component or components.
  • solid solution of the components is such that the system is chemically and physically uniform or homogeneous throughout or consists of one phase (as defined in thermodynamics)
  • a dispersion is called a "solid solution”.
  • the presence of non solubilized cannabinoid in the solid matrix composition is detected by visual inspection with a light microscope under a magnification of X40 to XI, 000, with or without the use of polarized light and/or by differential scanning calorimetry (DSC).
  • the term“essentially solubilized” cannabinoid in a solid composition or a solid solution is a cannabinoid that is at least 80% solubilized and more preferably 90% and more preferably 95% and more preferably 98% solubilized as detected by its typical differential scanning calorimetry (DSC) signal magnitude.
  • DSC differential scanning calorimetry
  • the term “essentially solubilized” in an emulsion or plurality of particles, can be determined with light microscope visual inspection.
  • solid matrix forming agent is a polymer or a wax that forms“solid matrix” and is a polymer or a wax that is solid at room temperature and co-melts when dissolves in volatile or organic solvents or heated with the emulsifiers and the drugs to form a solid matrix or solid composition upon cooling to room temperature, that may be solid, solid brittle or solid waxy.
  • the solid forming matrix agent produces an essentially real solution that is a solid solution upon cooling and congealing and the polymer or wax or mixtures thereof serving as the solvent for the cannabinoid or cannabis extract or cannabinoids or cannabis extract with the emulsifiers or with emulsifiers and additives such as terpenes, resulting in a solid-state form.
  • a solid-state form is a form of matter that does not flow or deform to fill the space around it or expand to fill the volume around it.
  • pharmaceutical composition as used herein has its conventional meaning and refers to a composition which is pharmaceutically acceptable.
  • pharmaceutically acceptable as used herein has its conventional meaning and refers to compounds, material, compositions and/or dosage forms, which are, within the scope of sound medical judgment suitable for contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit/risk ratio.
  • excipient as used herein has its conventional meaning and refers to a pharmaceutically acceptable ingredient, which is commonly used in the pharmaceutical technology for preparing a granulate, solid or liquid oral dosage formulation.
  • composition is intended to mean a substance or a preparation intended to be brought into contact with the various superficial parts of the body, in particular the epidermis, the body-hair and head- hair systems, the nails, the lips and the oral mucous membranes.
  • veterinary composition encompasses the full range of compositions for internal administration and feeds and drinks which can be consumed by animals.
  • particle size As used herein, the term“particles” as used herein relates to droplets.
  • particle size of an emulsion is to be understood also as the “droplet size” of that emulsion.
  • mean particle size is also to be understood as the term “mean droplet size”.
  • mean particle size refers to a value which is obtained by measuring the diameters in a specific direction of particles and dividing the sum of respective diameters of particles by the number of measured particles.
  • Figure 1 Light microscope (Nikon EclipseTM 200) pictures, magnification X100 of pure 99% CBD crystals and formulation 1A at magnifications X100, X200 and X400.
  • Figure 2 Light microscope (Nikon EclipseTM 200) pictures magnification X400 of formulation 1A, left picture: a sample that was held for about two minutes in the mouth, and right picture: a sample that was mixed gently with simulated intestinal fluids for five minutes.
  • FIG. 3 Differential Scanning Calorimetry (DSC) of pure CBD and formulations 1A (401) and II (403).
  • compositions of solid solutions of cannabinoids comprising of at least one cannabinoid and at least one emulsifier and at least one solid matrix forming agent, that are essentially a solution of the cannabinoid in a solid state composition and which disintegrates or erodes or swells upon or following contact with mammalians body fluids, releasing a plurality of particles, and having increased oral bioavailability in comparison with the same cannabinoid dissolved in organic solvent or mixture of organic solvents.
  • the present invention is based on the surprising finding that a composition of a: at least one cannabinoid and b: at least one emulsifier, c: at least one solid matrix forming agent, can be formed into a solid matrix, wherein the cannabinoid is essentially solubilized homogeneously in the solid matrix, and are exceptionally proficient, in producing stable solid cannabis product and dosage forms that are releasing essentially solubilized cannabinoids in fine spherical particles of small size, and that are highly convenient to consume and therefore contributes to increased patient compliance and thus the pharmacological effect, and achieving high oral bioavailability which improve the efficacy or enable use of a lower dose.
  • the composition and dosage forms of the present invention enable precise control of the release profile of the cannabinoid and enable targeting the release to specific parts of the gastrointestinal system and enable dual release mechanism that is produced in one step, thereby permitting simultaneous systemic and local drug delivery.
  • a composition of at least one cannabinoid dissolved in a mixture of at least one non-ionic emulsifier, and at least one solid matrix forming agent, all this ingredients or components together are termed the“solid matrix”, can produce a solid composition, whereas the at least one cannabinoid is in a solution state in the solid matrix which is a“solid solution” state, that can be ground, molded and granulated and/or compressed into a tablet, and that produce plurality of particle of below one hundred microns, upon or following with water or with mammals body fluids and increase the at least one cannabinoid oral bioavailability by at least 50% or by at least 100% or by at least 200% in comparison to the same cannabinoid dissolved in a solvent or solvents mixture, such as propylene glycol, ethanol and water.
  • a solvent or solvents mixture such as propylene glycol, ethanol and water.
  • the present invention provides, in one aspect, a cannabinoid solid solution composition, comprising: about 0.1% to about 60% by weight of a cannabinoid or a mixture of cannabinoids, and about 1% to about 80% of an emulsifier or a mixture of emulsifiers, and about 10% to about 90% by weight of a solid matrix-forming polymer or wax or a mixture of polymers or waxes and combinations thereof, wherein upon or following contact and mixing with mammals body fluids, the solid composition is transformed into a dispersion comprising of: a) the solid matrix-forming agent that is water insoluble or water swellable or water dispersed and b) a dispersion comprising the soluble cannabinoid or cannabinoids, that has a plurality of particles having a mean particle size of about 10 nm to about 100 pm, and more preferably from about 50 nm to about 30 pm, or from 80 nm or from 10 pm, and from 90 nm to about 2
  • the present invention provides, in one aspect, a composition comprising a solid solution of cannabinoids, comprising: about 0.1% to about 60% by weight of a cannabinoid or a mixture of cannabinoids, and about 1% to about 80% of an emulsifier or a mixture of emulsifiers, about 10 % to about 90 % by weight of solid matrix forming agent which is a polymer or a wax or mixture thereof, wherein the ratio of the at least one emulsifier to at least one solid matrix forming agent is about 1:10 to about 10:1 and more preferably from about 1:5 to about 5:1 and more preferably from about 1:2 to 2:1, and wherein the composition has a plurality of particles upon disintegration and mixing with mammals body fluids, having a mean particle size of about 10 nm to about 10 pm, and more preferably from 10 nm to 2 pm, and more preferable from about 10 nm to 1,000 nm or from 100 nm to 600 nm or 100
  • the solid composition decomposes by disintegration or erosion or swelling, when in contact with body fluids such as alimentary tract fluids or tears or mucosal discharge, to form a dispersion of the cannabinoids dissolved in a plurality of particular matter, having a droplet shape of fine sub-micron or nano-size range, with a mean particle size of the droplets from about 10 nm to about 10 pm, and from 10 nm to about 1,000 nm and from about 10 nm to about 800 nm and more particularly from about 20 nm to about 600 nm or from about 30 nm to about 400 nm or from about 40 nm to about 300 nm or from about 50 nm to about 200 nm.
  • One type of particle is an oily spherical shape droplet, comprising the cannabinoids and the emulsifiers, whereas the cannabinoids are essentially solubilized in the droplets.
  • the second type of particles have a randomized shape and are the solid matrix forming agents, the polymer or waxes and combinations thereof, that may also solubilize part of the cannabinoids.
  • the random shape particles of polymers and waxes are either insoluble polymers and waxes or polymers in some state of swelling or gelling in the water.
  • solid solution of cannabinoid may be produced by heating the emulsifier and the polymer and or wax to a temperature in the range of about 60°C to about l80°C, depends on the polymer or wax melting point and or transition glass temperature and combined properties of melting in the presence of the emulsifiers and additives, and mix until homogeneous and adding and mixing the cannabinoids to obtain homogeneous mixture and adding other optional ingredients, such as anti-oxidants or colorants or taste masking agents and molding to desired shape and cooling to room temperature or shaping after cooling.
  • the hot melt extrudate may be opaque or clear and if more than one polymer is used the polymers may be solubilized or poorly solubilized.
  • the at least one“matrix forming agent” is an organic or non-organic polymer, selected from; Soluplus® (polyvinyl caprolactam-polyvinyl acetate- polyethylene glycol graft copolymer), PemuleneTM (crosslinked copolymer of acrylic acid and a hydrophobic C10-30 alkyl acrylate co-monomer), gelatin, Hydroxy propyl methyl cellulose (Methocel), Methyl cellulose , Hydroxy propyl cellulose (Klucel), hydroxyethylcellulose (Natrosol), Sodium carboxy methyl cellulose, acrylates copolymers, Ammonio Methacrylate Copolymer Type A or B, Dimethylaminoethyl Methacrylate - Butyl Methacrylate - Methyl Methacrylate Copolymer (EudragitTM), Methacrylic Acid - Ethyl Acrylate Copolymer,
  • the at least one“matrix forming agent” is an organic or non-organic wax, selected from; Beeswax, Carnauba wax, Cetyl palmitate, Glyceryl behenate (Compritol ATOTM), Behenic acid, Behenyl alcohol, Glyceryl monostearate, Glyceryl palmitostearate, Glyceryl stearate, Hydrogenated castor oil, Microcrystalline wax, Paraffin wax, Stearic acid, Stearic alcohol, alkyl silicone, silicone wax, waxy polymethylsiloxane, PEG wax and carbowax.
  • an organic or non-organic wax selected from; Beeswax, Carnauba wax, Cetyl palmitate, Glyceryl behenate (Compritol ATOTM), Behenic acid, Behenyl alcohol, Glyceryl monostearate, Glyceryl palmitostearate, Glyceryl stearate, Hydrogenated castor oil, Microcrystalline wax, Paraffin wax, Stearic
  • the function of the polymer and or wax is to produce a solid matrix, to hold the cannabis or at least one cannabinoid and emulsifier or emulsifiers in a solid solution state, and to provide a workable matrix that can be formed into film, granules, pellets, or free flowing granulation, and prevent the cannabinoids from crystalize or diffuse to form isolate cannabinoids or separate into distinct area.
  • the preferred polymer is thermoplastic, possess high mechanical strength, be physiologically inert, safe and suitable for granulation and tableting processes.
  • solid solution of cannabis compositions may comprise taste masking and taste modifying agents.
  • a taste masking agent may be any sugar, sweetener, for example sucralose, aspartame and liquorice extract, and flavors, for example, a terpene or an essential oil, lemon, orange and mint, MagnasweetTM (Mafco Corp) to mask the unpleasant low to moderately bitter or earthy taste of cannabis extracts.
  • effervescent agents sodium bicarbonate, citric acid
  • Some formulations may include a bitterness blocking agent that masks the bitter taste or the perception of bitter on the tongue.
  • Such bitter blockers may include adenosine monophosphate, lipoproteins, or phospholipids.
  • sodium chloride can be added to a formulation to mask bitterness, as used in the preparation of pioglitazone hydrochloride orally disintegrating tablets.
  • the pharmaceutical composition comprises about 0.1% to about 60% by weight of a cannabinoid or a mixture of cannabinoids. In certain embodiments, the pharmaceutical composition comprises about 1% to about 50% by weight of a cannabinoid or a mixture of cannabinoids. In certain embodiments, the pharmaceutical composition comprises about 1 % to about 40% by weight of a cannabinoid or a mixture of cannabinoids. In certain embodiments, the pharmaceutical composition comprises about 1% to about 30% by weight of a cannabinoid or a mixture of cannabinoids. In certain embodiments, the pharmaceutical composition comprises about 1% to about 20% by weight of a cannabinoid or a mixture of cannabinoids. In certain embodiments, the pharmaceutical composition comprises about 1% to about 10% by weight of a cannabinoid or a mixture of cannabinoids.
  • the cannabinoid is a natural cannabinoid. In certain embodiments, the cannabinoid is a natural cannabinoid found in a Cannabis plant. In certain embodiments, the cannabinoid is a synthetic cannabinoid. In certain embodiments, the cannabinoid is a mixture of natural cannabinoids. In certain embodiments, the cannabinoid is a mixture of synthetic cannabinoids. In certain embodiments, the cannabinoid is a mixture of natural and synthetic cannabinoids.
  • natural cannabinoid generally refers to a cannabinoid which can be found in, isolated from and/or extracted from a natural resource, such as plants.
  • synthetic cannabinoids are a class of chemicals that are different from the cannabinoids found e.g. in cannabis but which also bind to cannabinoid receptors.
  • the cannabinoid is selected from the group consisting of cannabidiol (CBD), cannabidiolic acid (CBDA), tetrahydrocannabinol (THC), tetrahydrocannabinol ic acid (THCA), cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabielsoin (CBE), iso-tetrahydrocannabimol (iso-THC), cannabicyclol (CBL), cannabicitran (CBT), cannahivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV) and cannabigerol monomethyl ether (CBGM), salts thereof, derivatives thereof and mixtures of cannabinoids.
  • CBD cannabidiol
  • CBDA
  • “cannabidiol” and“CBD” are interchangeably used herein and refer to a non-psychotropic cannabinoid having structure as described in Formula I below, salt or derivatives thereof, such as A 4 -cannabidiol, A 5 -cannabidiol, D 6 -cannabidiol, D 1 ⁇ 7 - cannabidiol, D 1 -cannabidiol A 2 -cannabidiof D 3 -cannabidiol.
  • the pharmacologically active cannabinoid may be selected from the group consisting of tetrahydrocannabinol, ⁇ 9-tetrahydrocannabinol (TF1C), D8- tetrahydrocannabinol, standardized marijuana extracts, ⁇ 8-tetrahydrocannabinol-DIVIH, D9- tetrahydrocannabinol propyl analogue (TF1CV), 11 -hydroxy-tetrahydrocannabinol, l l-nor- 9-carboxy-tetrahydrocannabinol, S’-azido-. ⁇ 8-tetrahydrocannabinol, AMG-l (CAS
  • the cannabinoid may be included in its free form, or in the form of a salt; an acid addition salt of an ester; an amide; an enantiomer; an isomer; a tautomer; a prodrug; a derivative of an active agent of the present invention; different isomeric forms (for example, enantiomers and diastereoisomers), both in pure form and in admixture, including racemic mixtures; and enol forms.
  • the cannabinoid(s) utilized in the present invention are a lipophilic concentrate of cannabinoid(s). In some embodiments, the cannabinoid(s) utilized in the present invention are a lipophilic concentrate of cannabinoid(s) achieved via CO2, solvents or liquid gas extraction techniques or by oil maceration or oil pressure of partial or whole plant.
  • Extraction of cannabis plant of various plant parts may be done by CO2 extraction or by solvent extraction or solvent-less compression to obtain oily viscous material or waxy material or solid material, depends on plant material, plant parts and extraction methods as skilled in the art. Extraction and processing may result in broad spectrum of cannabis molecules, cannabinoids, terpenes and other families of natural cannabis molecules or in a pure extract of cannabinoids or concentrated cannabinoid terpenes extract. Cannabis or marijuana extract may be further decarboxylated, winterized and/or purified, for example by distillation, as known in the art.
  • the pharmaceutical composition comprises about 1% to about 80% by weight of an emulsifier or mixture thereof. In certain embodiments, the pharmaceutical composition comprises about 2% to about 60% by weight of an emulsifier or a mixture thereof. In certain embodiments, the pharmaceutical composition comprises about 5% to about 40% by weight of an emulsifier or a mixture thereof. In certain embodiments, the pharmaceutical composition comprises about 8% to about 30% by weight of an emulsifier or a mixture thereof. In certain embodiments, the pharmaceutical composition comprises about 10% to about 20% by weight of an emulsifier or a mixture thereof. [0074]
  • the emulsifier ingredients of the composition of this invention improve the cannabinoid solubilization and the emulsifying properties of the formulation.
  • the emulsifiers are selected from the group consisting of polyglycolized glycerides and polyoxyethylene glycerides of medium to long chain mono-, di-, and triglycerides, such as: almond oil PEG-6 esters, almond oil PEG-60 esters, apricot kernel oil PEG-6 esters (Labrafil ® M1944CS), caprylic/capric triglycerides PEG-4 esters (Labrafac® Hydro WL 1219), caprylic/capric triglycerides PEG-4 complex (Labrafac® Hydrophile), caprylic/capric glycerides PEG-6 esters (Softigen® 767), caprylic/capric glycerides PEG-8 esters (Labrasol®), castor oil PEG-50 esters, hydrogenated castor oil PEG-5 esters, hydrogenated castor oil PEG-7 esters, 9 hydrogenated castor oil PEG-9 esters, corn oil PEG-6 esters (
  • Labrafil® Isostearique triolein PEG-6 esters, trioleate PEG-25 esters, polyoxyl 35 castor oil (Cremophor® EL or Kolliphor® EL), polyoxyl 40 hydrogenated castor oil (Cremophor® RH 40 or Kolliphor® RH40), polyoxyl 60 hydrogenated castor oil (Cremophor® RH60), lecithin, phospholipids and mixtures thereof.
  • Sucrose esters surfactants such as sucrose stearate, sucrose distearate, sucrose palmitate, sucrose oleate and polyethylene glycol sorbitan fatty acid esters, which can be used, include PEG-20 sorbitan monolaurate, PEG-20 sorbitan monopalmitate, PEG-20 sorbitan monostearate, and PEG-20 sorbitan monooleate, and TPGS (d-. alpha.
  • a preferred type of an emulsifier is an amphiphilic surface- active molecule, wherein its hydrophobic part comprises at least one moiety of cyclic molecular structure, whereas the cyclic moiety may comprise five to nine atoms, wherein said atoms may be carbon, nitrogen or oxygen.
  • emulsifiers are tocopheryl polyethylene glycol succinate (TPGS), Vit K polyethylene glycol or Coenzyme Q10 polyethylene glycol conjugate, polyethylene glycol or poly glycerol or polysaccharide conjugates of cannabinoids or terpenes, or PEG-Lanoline.
  • Polyoxyethylene -polyoxypropylene block copolymers which can be used as emulsifiers in the compositions of this invention include poloxamers (108, 124, 182, 183, 188, 212, 217, 238, 288, 331, 338, 335, and 407), and mixtures thereof.
  • Sorbitan fatty acid esters which can be used, include sorbitan monolaurate (Span® 80), sorbitan monopalmitate, sorbitan monooleate (Span® 20), sorbitan monostearate, sorbitan tristearate and combinations thereof.
  • a preferred type of emulsifiers is polymeric surfactant, such as Acrylates/C 10-30 Alkyl Acrylate Cross-Polymer. Or alkyl acrylate cross polymer, PemulenTM TR1 or TR2, from Lubrizol.
  • the composition comprises from about 1% w/w to about 80% w/w of at least two emulsifiers. In certain embodiments, the pharmaceutical composition comprises from about 5% w/w to about 50% w/w of at least two emulsifiers. In certain embodiments, the pharmaceutical composition comprise from about 10% w/w to about 40% w/w of at least two emulsifiers.
  • the pharmaceutical composition comprises from about 15% w/w to about 30% w/w of at least two emulsifiers.
  • the two emulsifiers are selected from the group consisting of polysorbate, polysorbate 80, polyoxyl 35 hydrogenated castor oil, sucrose fatty acids esters such as, sucrose stearate and sucrose distearate, tocopherol polyethylene glycol 1000 succinate, polyglyceryl-3 dioleate, sorbitan monooleate, sucrose tatty acid ester, polyglyceryl fatty acid ester and alkyl acrylate cross polymer and salts thereof, derivatives thereof and combinations thereof.
  • a mixture of at least two emulsifiers is more effective in providing stable and low mean particle size of the emulsion that is released from the solid solution and solid cannabinoid composition.
  • at least one of the emulsifiers is a sucrose fatty acid ester selected from sucrose stearate, sucrose distearate, sucrose oleate, sucrose palmitate, sucrose laurate, sucrose tetrastearate and sucrose polystearate.
  • sucrose esters are sucrose stearates for example SurfhopeTM D- 181 IF, SurfhopeTM D-1815, SurfhopeTM D-1615 all from Mitsubishi chemicals, CrodestaTM FI 10 which is a mixture of mono and diesters with a F1LB value of 12, or CrodestaTM F160 which is a monoester with a F1LB value of 14.5.
  • the at least two surfactants or emulsifiers are selected from; sucrose ester, PEG-Castor oil, TPGS, Polysorbate, polyglyceryl fatty acid esters, such as polyglyceryl-3 dioleate, and sorbitan fatty acid esters such as sorbitan laurate.
  • the two emulsifiers are selected from, polysorbate, tocopheryl PEG succinate, polyoxyl castor oil, sucrose esters and sorbitan esters, polyglyceryl fatty acid esters and combinations thereof and a third emulsifier is selected from Acrylates/C 10-30 Alkyl Acrylate Cross-Polymer.
  • the HLB of the at least one emulsifier is about HLB 8 to about HLB 18, In certain embodiments the HLB of the at least one emulsifier is about HLB 8 to about HLB 16, In certain embodiments the HLB of the at least one emulsifier is about HLB 10 to about HLB 16, In certain embodiments the HLB of the at least one emulsifier is about HLB 8 to about HLB 15, In certain embodiments the HLB of the at least one emulsifier is about HLB 11 to about HLB 16, In certain embodiments the HLB of the at least one emulsifier is about HLB 11 to about HLB 15, In certain embodiments the HLB of the at least one emulsifier is about HLB 11 to about HLB 14. Each possibility represents a separate embodiment of the invention.
  • the average HLB calculated on the molar basis HLB of the mixture of the emulsifiers is from about HLB 6 to about HLB 16. In certain embodiments the combined HLB calculated on the molar basis HLB of the mixture of the emulsifiers is from about HLB 8 to about HLB 16. In certain embodiments the combined calculated on the molar basis HLB of the emulsifier mixture is from about HLB 8 to about HLB 15. In certain embodiments the combined HLB calculated on the molar basis HLB of the mixture of the emulsifiers is from about HLB 10 to about HLB 16.
  • the combined calculated on the molar basis HLB of the mixture of the emulsifiers is from about HLB 10 to about HLB 15. In certain embodiments the combined HLB calculated on the molar basis HLB of the mixture of the emulsifiers is from about HLB 10 to about HLB 14. In certain embodiments the calculated combined HLB, on the molar basis, of the mixture of the emulsifiers is from about HLB 10 to about HLB 14. In certain embodiments the combined HLB calculated on the molar basis HLB of the mixture of the emulsifiers is from about HLB 8 to about HLB 13. In certain embodiments the combined HLB calculated on the molar basis HLB of the mixture of the emulsifiers is from about HLB 10 to about HLB 12.
  • the pharmaceutical composition comprises also about 0.01% to about 10% by weight of a terpene or terpenes or an essential oil or mixtures. In certain embodiments, the pharmaceutical composition comprises about 0.02% to about 5% by weight of a terpene or terpenes or an essential oil or mixtures. In certain embodiments, the pharmaceutical composition comprises about 0.05% to about 2% by weight of a terpene or terpenes or an essential oil or mixtures. In certain embodiments, the pharmaceutical composition comprises about 0.1% to about 1% by weight of a terpene or terpenes or an essential oil or mixtures.
  • the weight ratio between the cannabinoid and the emulsifier is about 10:1 to about 1:20 In certain embodiments of the pharmaceutical composition, the weight ratio between the cannabinoid and the emulsifier is about 5:1 to about 1:10. In certain embodiments of the pharmaceutical composition, the weight ratio between the cannabinoid and the emulsifier is about 2:1 to about 1:5. In certain embodiments of the pharmaceutical composition, the weight ratio between the cannabinoid and the emulsifier is about 1:1 to about 1:2.
  • the composition comprises an essential oil or a terpenes or combinations thereof.
  • the terpene is a natural terpene found in a Cannabis plant.
  • the terpene is a synthetic terpene.
  • the terpene is a mixture of natural terpenes.
  • the terpene is a mixture of synthetic terpenes.
  • the terpene is a mixture of natural and synthetic terpenes.
  • the terpene is selected from the group consisting of bisabolol, borneol, caryophyllene, carene, camphene, cineol, citronella, eucalyptol, geraniol, guaiol, humulene, isopropyltoluene, isopulegol, linalool, limonene, methyl salicylate, menthol, myrcene, nerolidol, ocimene, pinene, phytol, pulegone, terpinene, terpinolene, thymol, salts thereof, derivatives thereof and mixtures thereof.
  • Each possibility represents a separate embodiment of the invention.
  • the terpene is a cannabis plant terpene, or a terpene derived from a non-cannabis plant material or a synthetic terpene.
  • the terpene is a taste modifier or smell modifier agent, a food grade or pharmaceutical grade, a solubilizer or solvent and an excipient in the formulation.
  • the natural cannabinoid is derived or isolated from an extract of a Cannabis plant.
  • the natural terpene is derived or isolated from an extract of a Cannabis plant.
  • a terpene or the mixture of terpenes solubilized with a cannabinoid or a mixture of cannabinoid are also possible.
  • the pharmaceutical composition comprises (i) about 1 % to about 60 %, preferably about 2% to about 20%, more preferably about 2% to about 10% by weight of a cannabinoid or a mixture of cannabinoids; (ii) about 1% to about 80% or about 2 % to about 30% by weight of an emulsifier or a mixture of emulsifiers: and (iii) about 20% to about 90% by weight of a solid matrix forming agent, and more preferably about 30% to about 80% by weight of a solid matrix forming agent, and more preferably from about 40% to about 70% of a solid matrix forming agent or a mixture of solid matrix forming agents.
  • a solid matrix forming agent preferably about 30% to about 80% by weight of a solid matrix forming agent, and more preferably from about 40% to about 70% of a solid matrix forming agent or a mixture of solid matrix forming agents.
  • the at least one cannabinoid is essentially solubilized in the solid solution matrix.
  • the cannabinoid solubility in the solid matrix is measured by differential scanning calorimetry (DSC) and by comparing non solubilized and crystalline cannabinoids signal alone and in its combination and in the specific compositions.
  • DSC differential scanning calorimetry
  • at least about 80% of the at least one cannabinoid is solubilized in the solid matrix as can be measured by differential scanning calorimetry (DSC).
  • DSC differential scanning calorimetry
  • at least about 90% of the at least one cannabinoid is solubilized in the solid matrix as can be measured by DSC.
  • At least about 95% of the at least one cannabinoid is solubilized in the solid matrix as can be measured by DSC. In certain embodiments at least about 98% of the at least one cannabinoid is solubilized in the solid matrix as can be measured by DSC.
  • the composition is formed into granules or pellets or microparticles and in certain embodiment the granules or pellets or micro particles are coated for taste masking or for improving chemical stability or enteric-coated.
  • the solid matrix acts as a solvent for the cannabinoids molecules and the cannabinoids are molecularly dissolved in the solid matrix. In certain embodiments, at least 80% of the cannabinoids are molecularly dissolved in the solid matrix. In certain embodiments, at least 90% of the cannabinoids are molecularly dissolved in the solid matrix. In certain embodiments, at least 95% of the cannabinoids are molecularly dissolved in the solid matrix. In certain embodiments, at least 98% of the cannabinoids are molecularly dissolved in the solid matrix.
  • Hot melt extrusion has an advantage of being a process that avoids explosive solvents, however solid solutions can be produced by methods of dissolving the polymers, waxes and the emulsifiers and the cannabinoids in a suitable solvent and obtaining a homogeneous mixture and evaporating the solvents under vacuum or vacuum and heating to obtain the desired solid solution.
  • Another option to produce solid solution of cannabinoids is spray drying, however this process also requires explosive solvents.
  • the HME may be further combined with mold injection, or granulation process.
  • the composition is formed into a tablet, mixing with tablet forming materials, such as, fillers, glidants, lubricants, hydration regulators can be selected according to desired tablet properties and loading level.
  • tablet forming materials such as, fillers, glidants, lubricants, hydration regulators can be selected according to desired tablet properties and loading level.
  • the tablet possesses desired physical characteristics such as hardness, friability, dissolution behavior and can be manufactured using standard equipment such as granulators, ovens, dryers, mixers, tablet press, drum coater, and the like as known in the art of pharmaceutical sciences.
  • the tablet Upon or following contact with water or simulated intestinal fluids or mammals body fluid the tablet releases a plurality of particles comprising the cannabinoid essentially dissolved in the particles, and having plurality of particles of mean particle size below ten microns or below one micron.
  • the solid solution composition comprises a release controlling agent to produce an immediate or contrary a slow or prolonged or control or targeted or colonic release of the at least one cannabinoid.
  • a release controlling agent may be part of the solid solution composition or added in the final dosage form production and is selected from a polymer that control the dissolution rate of the solid dosage form, tablet or granule or pellet.
  • Preferred polymers are water swellable or water soluble cellulose derivatives, for example, Hydroxypropyl methylcellulose (MethocelTM, types A, E, K, F, Dow Chemical), Hydroxyethyl cellulose (NatrosolTM, Hercules), Hydroxypropyl cellulose (KlucelTM, Aqualon), Carboxymethylcellulose (cellulose gum).
  • Hydroxypropyl methylcellulose MetalolTM, types A, E, K, F, Dow Chemical
  • Hydroxyethyl cellulose NonatrosolTM, Hercules
  • Hydroxypropyl cellulose KerelTM, Aqualon
  • Carboxymethylcellulose cellulose gum
  • Another type of synthetic polymers includes polyacrylic acid (CarbopolTM, BFGoodrich), Polyethylene oxide (PolyoxTM, Union Carbide), Polyvinyl pyrrolidone (KollidonTM, PVP and PVP-VA, BASF), natural gums and polysaccharides— X an than gum (XanturalTM, Kelco), carrageenan, locust bean gum, acacia gum, chitosan, alginic acid, hyaluronic acid, pectin, Zein, etc.
  • a release enhancing agent is selected from soluble small or polymeric molecules such as sucrose, maltose, xylose, and disintegrating agents such as cross carmelose of pre gelatinized starch.
  • the release controlling agent is mixed with the polymer or is part of the polymer mixture that is solid solution forming agent.
  • a possible mechanism of slow release is the hydration and gelling of the polymers, in parallel with emulsification process. Release of the formed emulsion from the gel is by dissolution and partial diffusion of the droplets from gelled matrix to surrounded media by mechanism of solid dosage form erosion, biodegradation, disintegration, swelling, or some combination of all.
  • the solid solution cannabinoid composition releases, upon or following hydration, a plurality of particles, wherein at least 90 % of the particles by numbers, have a size of 10 microns or less. In certain embodiments, the solid solution cannabinoid composition releases upon hydration a plurality of particles, wherein at least 90 % of the particles have a size of 1 microns or less.
  • the solid solution cannabinoid composition releases upon or following hydration a plurality of particles, wherein at least 95 % of the particles have a size of 1 microns or less the solid solution cannabinoid composition releases upon or following hydration a plurality of particles, wherein at least 98 % of the particles have a size of 1 microns or less. In certain embodiments, the solid solution cannabinoid composition releases upon or following hydration a plurality of particles, wherein at least 99 % of the particles have a size of 1 microns or less.
  • the solid solution cannabinoid composition releases upon or following hydration a plurality of particles, wherein at least 99 % of the particles have a size of 0.8 microns or less or 0.6 microns or less, or 0.4 microns or less.
  • the solid matrix forming polymer is selected from the pharmaceutical acceptable polymers and excipients, consisting of: poly (acrylic acid), poly (ethylene oxide), poly (ethylene glycol), poly (vinyl pyrrolidone), poly (vinyl alcohol), polyacrylamide, poly (isopropyl acrylamide), poly (cyclopropyl methacrylamide), ethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate phthalate, alginic acid, carrageenan, chitosan, hyaluronic acid, pectinic acid, (lactide-co-glycolide) polymers, starch, sodium starch glycolate, polyurethane, silicones, polycarbonate, polychloroprene, polyisobutylene, polycyanoacrylate, poly (vinyl acetate), polystyrene), poly(vinyl acetate), polys
  • the solid solution composition may have meltable mixture of a polymer and a wax or mixtures thereof. Because numerous drugs are heat-sensitive, HME requires the selection of polymers and or waxes or mixtures thereof that can be processed at low temperatures.
  • a preferred polymer and wax mixture is for example a water-insoluble polymers and waxes such as ethyl cellulose or carnauba wax from which the rate of drug release is diffusion controlled.
  • Polymer that is matrix forming or solid matrix forming material can be either biodegradable or nonbiodegradable.
  • the polymer To be extrudable, the polymer must exhibit thermoplastic characteristics next to its thermal stability in the required extrusion temperature range.
  • plasticizers To improve the processing conditions (e.g. lowering the extrusion temperature) during the manufacturing of the solid solution, often plasticizers need to be incorporated. These are typically low molecular weight compounds able to improve processing conditions by increasing the free volume between polymer chains, thus lowering the melt viscosity or the Tg (the temperature of transition into a glassy state) of the polymer. Consequently, they can soften the polymer and improve the flexibility and properties of the final product.
  • plasticizers include triethyl citrate, tributyl citrate, triacetin, poly(ethylene glycol) (PEG) and poly(propylene glycol).
  • Other functional excipients such as diluents, release and pH modifiers, antioxidants, processing aids, surfactants and stabilizers can also be incorporated into the solid solution composition during the HME process to improve its efficiency.
  • agents such as anti-oxidants, vitamin E, ascorbyl palmitate, fatty acids or fatty alcohols such as hydrogenated castor oil, capric/caprylic triglyceride, sesame oil, glyceryl monostearate, behenic acid, olive oil NF and others may be added.
  • the cannabinoid solid solution composition is produced by methods known to skilled in the art of pharmaceutical compounding, such methods may include melting, hot melt extrusion, film casting, spray drying, spray congealing and the like.
  • melt and “melting” should be interpreted broadly. For our purposes, these terms not only mean the alteration from a solid state to a liquid state, but can also refer to a transition to a glassy state or a rubbery state, and in which it is possible for one component of the mixture to get embedded more or less homogeneously or solubilize into the other.
  • the polymer or polymer and the wax and the emulsifier component will melt and the other component, the cannabinoid will dissolve in the melt, thus forming a solution, which, upon cooling, will form a solid solution having advantageous properties.
  • extruders include single screw extruders, intermeshing screw extruders or else multiscrew extruders, preferably twin screw extruders, which can be corotating or counterrotating and are optionally equipped with kneading disks and heating.
  • the melt ranges from pasty to viscous. Before allowing the melt to solidify, the melt may be molded into virtually any desired shape.
  • the shaping of the extrudate is conveniently carried out by a calender with two counter-rotating rollers with mutually matching depressions on their surface.
  • a broad range of tablet forms can be produced by using rollers with different forms of depressions.
  • the extrudate is cut into pieces, either before (hot-cut) or after solidification (cold-cut).
  • a preferred class of polymers comprises polymers that are“amphiphilic” in nature, meaning that the polymer has hydrophobic and hydrophilic portions.
  • Hydrophobic groups may comprise groups such as aliphatic or aromatic hydrocarbon groups.
  • Hydrophilic groups may comprise either ionizable or non-ionizable groups that are capable of hydrogen bonding such as hydroxyls, carboxylic acids, esters, amines or amides.
  • One class of polymers suitable for use in the present invention is cellulosic polymers
  • Polymers suitable for use with the present invention may be cellulosic or non- cellulosic.
  • the polymers may be neutral or ionizable in aqueous solution.
  • Another class of polymers suitable for use with the present invention comprises ionizable non-cellulosic polymers.
  • Exemplary polymers include: vinyl polymers and copolymers having substituents of hydroxyl, alkylacyloxy, and cyclicamido, carboxylic acid-functionalized polymethacrylates and carboxylic acid functionalized polyacrylates such as the EUDRAGITS®, amine-functionalized polyacrylates and polymethacrylates, proteins, and carboxylic acid functionalized starches such as starch glycolate.
  • Non- cellulosic polymers that are amphiphilic are copolymers of a relatively hydrophilic and a relatively hydrophobic monomer. Examples include acrylate and methacrylate copolymers.
  • Exemplary commercial grades of such copolymers include the EUDRAGITS®, which are copolymers of methacrylates and acrylates.
  • Exemplary non-ionizable cellulosic polymers that may be used as the polymer include: hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl methyl cellulose, hydroxy ethyl cellulose acetate, and hydroxyethyl ethyl cellulose.
  • a preferred polymers are those that are amphiphilic, such as: hydroxypropyl methyl cellulose and hydroxypropyl cellulose acetate.
  • Exemplary ionizable cellulosic polymers that are at least partially ionized at physiologically relevant pHs include: hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate (CAP), methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl
  • hydrophilic polymers helps to avoid incomplete drug release due to encapsulated drug clusters in the insoluble matrix.
  • Various functional excipients such as croscarmellose sodium (Ac-Di-Sol®) and sodium starch glycolate (Explotab®), into the solid matrix compositions enhance the drug release rate. Incorporation of swelling agents successfully reduced the initial burst release from the matrix.
  • Cytochrome P450/P-gp (PGP) inhibitors include any agent incorporated into the formulation matrix that inhibits pre-systemic hepatic first pass metabolism (i.e. first pass metabolism), such as d-. alpha. -tocopheryl polyethylene glycol 1000 succinate, anise oil, cinnamon oil, coriander oil, grapefruit oil, lemon oil, orange oil, peppermint oil, ascorbyl palmitate, propyl gallate, piperin, curcumin, resveratrol, terpenes (essential oils) and various combinations thereof.
  • Intestinal PGP efflux inhibitors include any agent incorporated into the formulation matrix that inhibits PGP induced cellular efflux mechanisms (i.e.
  • MDR such as polyethoxylated castor oil derivatives, polyoxyethylene sorbitan monooleate, polyoxyethylene glycerides, herbal extracts such as, for example; piperin, ginger licorice, berberin, terpenes (essential oils) and various combinations thereof.
  • Absorption enhancers are selected from herbal extracts such as piperin, ginger extract, berberin, liquorish, quercetin, resveratrol, terpenes and vitamin E PEG 1000 succinate (d-. alpha. -tocopheryl polyethylene glycol 1000 succinate or TPGS) and mixtures thereof.
  • herbal extracts such as piperin, ginger extract, berberin, liquorish, quercetin, resveratrol, terpenes and vitamin E PEG 1000 succinate (d-. alpha. -tocopheryl polyethylene glycol 1000 succinate or TPGS) and mixtures thereof.
  • the dosage form may include viscosity modifying agents, stabilizing agents, fillers, glidants disintegration agent, coating and enteric-coating, microbial preserving agents, buffers, taste masking agents, as skilled in the art to produce desired dosage form and manufacturability.
  • Antioxidants include ascorbyl palmitate, butylated hydroxy anisole, butylated hydroxy toluene, propyl gallate, a-tocopherol, and g-tocopherol, etc.
  • the antioxidants that can be chosen include combinations of two or more agents described above, whereby ascorbyl palmitate and tocopherol provide optimal synergistic effects.
  • the present invention further provides, in an aspect, a dosage form, comprising or consisting of any one of the compositions described above.
  • drug form denotes any form of the solid formulation that contains an amount of a cannabinoid or of a mixture of cannabinoids sufficient to achieve at least a partial therapeutic effect with a single administration.
  • the dosage form is an oral dosage form. In certain embodiments, the dosage form is a rectal dosage form. In certain embodiments, the dosage form is a nasal dosage form. In certain embodiment, the dosage form is mucosal dosage form. In certain embodiments, the dosage form is a rectal or vaginal dosage form. In certain embodiments, the dosage form is a topical dosage form.
  • the solid solution composition of the cannabinoid or cannabinoids may be a dosage from as is in form of films, granules, pellets, micro particles or any shape or be used in the production of a specific dosage form such as tablet or capsule with functional additives that serves to form the specific dosage form.
  • the dosage form is formulated as a tablet, enteric coated tablet, enteric coated capsule, dissolve in mouth tablet, dissolve in mouth strip, or capsule, enteric coated granules, granules or pellets.
  • the dosage form is formulated for mucosal delivery.
  • mucosal delivery refers to the delivery to a mucosal surface, including nasal, vaginal, rectal, urethral, sublingual and buccal delivery.
  • the dosage form is formulated in a candy, toffee, dragee, chocolate, cookie or lozenge.
  • the solid solution dosage form of the cannabinoid, or cannabinoids is targeted to be released at distal (lower) intestine or upon entering the colon.
  • the solid solution comprises polymer that is not decomposes in low pH of the stomach and slightly acidic pH of the upper jejunum.
  • the acid resistant polymer starts to hydrate and enable decomposition of the dosage form only upon entering neutral pH and above pH 6.5 or 7.0 and at a delayed manner.
  • Such solid solutions are designed to release the cannabinoids essentially at the colon or at the end of jejunum and in the colon or partly in the jejunum and partly at the colon.
  • Such partial release may be designed by mixing solid solution particles with different release and pH-controlled release properties.
  • Preferred cannabinoids for colon delivery are anti-inflammatory cannabinoids such as CBDA and THCA, which are not psychotropic.
  • Preferred polymers for producing solid solution of cannabinoids for IBD are pH responsive polymers are poly acrylates EudragitTM.
  • Preferred polymer forming matrix for IBD targeting are polymers that do not degrade by stomach and jejunal enzymes such as dietary fibers, such as pectin and zein.
  • the solid solution cannabinoid compositions dosage form comprises a“cannabis active ingredient” (i.e. Cannabis-extracted and purified cannabinoid or synthetic cannabinoid or cannabis extract), and optionally a terpene, an emulsifier or emulsifiers, and a solid matrix forming agent or agents, and optionally inactive ingredients.
  • a“cannabis active ingredient” i.e. Cannabis-extracted and purified cannabinoid or synthetic cannabinoid or cannabis extract
  • a terpene i.e. Cannabis-extracted and purified cannabinoid or synthetic cannabinoid or cannabis extract
  • an emulsifier or emulsifiers i.e. Cannabis-extracted and purified cannabinoid or synthetic cannabinoid or cannabis extract
  • a terpene i.e. Cannabis-extracted and purified cannabinoid or synthetic cannabinoid or cannabis extract
  • the advantages of the pharmaceutical composition over known cannabis compositions are manifold and include: (a) high oral bioavailability (b) stable solid solution releasing particles of droplet shape upon disintegration or erosion or swelling, produced by common production methods and machinery (c) high dose of cannabinoid in a concise size dosage form and (d) a ready to use and easy to swallow and administer to all segments of population including infants, toddlers and elderly, for successful patient compliance and effective medication.
  • optional components of the formulation can include absorption enhancers, such as cytochrome P450 metabolic inhibitors, P- glycoprotein efflux inhibitors and intestinal epithelial cells tight junction temporal openers.
  • absorption enhancers such as cytochrome P450 metabolic inhibitors, P- glycoprotein efflux inhibitors and intestinal epithelial cells tight junction temporal openers.
  • a functional inactive ingredient maybe optionally added, such as colorant or antioxidants or chelating agent or microbial preservative or viscosity modifier, pH modifying agents, buffer, or melting point modifier or anti microbial agent or suspending agent.
  • the present invention further provides, in another aspect, a composition as described above, or a dosage form as described above, for use in a method of treating a cannabinoid-responsive symptom, disease or disorder.
  • a cannabinoid-responsive symptom, disease or disorder refers to any symptom, disease or disorder which is associated with therapeutic benefit by a cannabinoid, by a mixture of cannabinoids, or by extracts of Cannabis.
  • a method of treatment for inducing an alerting response wherein the at least one alerting terpene is selected from limonene, alfa and beta pinene, orange terpenes, thymol, isoborneol, and isoeugenol or citronella or orange essential oils or lavender essential oil, caryophyllene, rosmarinus oil, citrus oil and combinations thereof.
  • the at least one sedating terpene is selected from myrcene, linalool, linalyl acetate, alfa terpineol, terpinolene and citronellal, sandalwood, lavender, valerian, neroli oils and combination thereof and the at least one sedating cannabinoid is selected from Tetrahydrocannabinol (THC) and Cannabinol (CBN) and combinations thereof.
  • THC Tetrahydrocannabinol
  • CBN Cannabinol
  • the cannabinoid responsive disease is selected from inflammatory bowel disease (IBD) such as Crohn's disease, ulcerative colitis, irritated bowels, and intestinal and colon cancers or auto-immune diseases.
  • IBD inflammatory bowel disease
  • the cannabinoid or cannabinoids are anti inflammatory cannabinoid and in certain embodiment the solid solution dosage form is resistant to low pH and disintegrate or decomposes and release the cannabinoid only upon contact with neutral pH intestinal or colon fluids.
  • the solid solution decomposes is acid resistant and do not and release the cannabinoids in low pH environment, and the cannabinoids are released upon a pH of greater than 6.5 or greater than 7.0.
  • the solid solution releases the cannabinoids only in presence of pectinases.
  • the solid solution dosage form releases the cannabinoids only at neutral pH and presence of pectinases, a condition prevailing in the colon.
  • the solid solution is acid resistant and release the at least one cannabinoid upon crossing the stomach and entering a pH of greater than 6.5 and over at least four hours and more preferably over at least six hours.
  • At least 20% of the cannabinoids dose on a weight basis is released from the solid solution matrix in the colon. In certain embodiments, at least 30% of the cannabinoids dose on a weight basis is released from the solid solution matrix in the colon. In certain embodiments, at least 40% of the cannabinoids dose on a weight basis is released from the solid solution matrix in the colon. In certain embodiments, at least 50% of the cannabinoids dose on a weight basis is released from the solid solution matrix in the colon. In certain embodiments, at least 60% of the cannabinoids dose on a weight basis is released from the solid solution matrix in the colon.
  • At least 70% of the cannabinoids dose on a weight basis is released from the solid solution matrix in the colon. In certain embodiments, at least 80% of the cannabinoids dose on a weight basis is released from the solid solution matrix in the colon. In certain embodiments, at least 90% of the cannabinoids dose on a weight basis is released from the solid solution matrix in the colon. In certain embodiments, at least 95% of the cannabinoids dose on a weight basis is released from the solid solution matrix in the colon. In certain embodiments, the cannabinoids are essentially released from the solid solution matrix in the colon.
  • At least 20% of the cannabinoids dose on a weight basis is not released from the solid solution matrix before entering the distal jejunum. In certain embodiments, at least 30% of the cannabinoids dose on a weight basis is not released from the solid solution matrix before entering the distal jejunum. In certain embodiments, at least 40% of the cannabinoids dose on a weight basis is not released from the solid solution matrix before entering the distal jejunum. In certain embodiments, at least 50% of the cannabinoids dose on a weight basis is not released from the solid solution matrix before entering the distal jejunum.
  • At least 60% of the cannabinoids dose on a weight basis is not released from the solid solution matrix before entering the distal jejunum. In certain embodiments, at least 70% of the cannabinoids dose on a weight basis is not released from the solid solution matrix before entering the distal jejunum. In certain embodiments, at least 80% of the cannabinoids dose on a weight basis is not released from the solid solution matrix before entering the distal jejunum. In certain embodiments, at least 90% of the cannabinoids dose on a weight basis is not released from the solid solution matrix before entering the distal jejunum.
  • not more than 10% of the cannabinoids dose on a weight basis is released before reaching the distal jejunum. In certain embodiments, not more than 20% of the cannabinoids dose on a weight basis is released before reaching the distal jejunum. In certain embodiments, not more than 30% of the cannabinoids dose on a weight basis is released before reaching the distal jejunum. In certain embodiments, not more than 40% of the cannabinoids dose on a weight basis is released before reaching the distal jejunum. In certain embodiments, not more than 50% of the cannabinoids dose on a weight basis is released before reaching the distal jejunum.
  • not more than 60% of the cannabinoids dose on a weight basis is released before reaching the distal jejunum. In certain embodiments, not more than 70% of the cannabinoids dose on a weight basis is released before reaching the distal jejunum. In certain embodiments, not more than 80% of the cannabinoids dose on a weight basis is released before reaching the distal jejunum. In certain embodiments, not more than 90% of the cannabinoids dose on a weight basis is released before reaching the distal jejunum.
  • Cannabis anti-inflammatory and immune- modulating and pain control composition that will provide the cannabis effects without reducing the IBD patient alertness during the day time and a different and matching cannabis composition for the night time that will be anti-inflammatory and pain control and provide good sleep and alleviate insomnia.
  • Cannabis is effective in alleviating the IBD by its anti-inflammatory effect treating the pain associated with IBD, by reducing the inflammation and by its intrinsic pain control pharmacological activity. Cannabis is also immune-modulating thus alleviating inflammation, reducing pain by reducing the local inflammation at the IBD site, the colon, and improving sleep by reducing pain.
  • the solid solution of cannabinoid for treating intestinal and IBD diseases is composed of high dose of CBDA (Cannabidiolic acid) and or THCA (Tetrahydrocannbinolic acid) the non-decarboxylated cannabinoids, which are effective anti-inflammatory agents, without psychoactivity, with the terpene caryophyllene and other terpenes that are working as anti-inflammatory by themselves and in entourage with cannabinoids, and are also alerting and are designated to be used throughout the day time and with sedating terpenes at night time to promote sleep.
  • CBDA CBDA
  • THCA Tetrahydrocannbinolic acid
  • compositions may provide effective treatment for IBD without sedating during day time when alertness is needed for daily life activities, and a sedating composition for night time to treat the IBD pain and aid the sleep during night.
  • dual active compositions are administered as a complementary kit of a day IBD treatment composition and a night IBD treatment composition.
  • a solid solution of cannabinoids in a solid matrix comprising about 0.1 % to about 60% by weight of a cannabinoid or a mixture of cannabinoids, and about 1 % to about to about 80% of at least one non-ionic emulsifier, and about 10% to about 90% of at least one solid matrix forming agent, whereas the at least one cannabinoid is essentially solubilized in the solid matrix of the at least one emulsifier, and the at least one solid matrix forming agent, and whereas the solid matrix composition disintegrates or erode or swell upon contact with body or intestinal fluids, and release a dispersion of plurality of particles having a mean particle size of about 10 nm to about 100 pm, whereas the cannabinoid is essentially solubilized in the particles.
  • composition of this invention wherein one of the at least at least one non-ionic emulsifier is selected from the group consisting of polysorbates, polysorbate 80, polyoxyl hydrogenated castor oil, sucrose ester, sucrose distearate, tocopheryl polyethylene glycol 1000 succinate, sorbitan fatty acid ester, sorbitan monooleate, polyglyceryl fatty acid esters, Polyoxylglycerides, salts thereof, derivatives thereof, and combinations thereof, in a concentration of from about 1 % w/w to about 80% w/w, preferably from about 10% w/w to about 30% w/w.
  • one of the at least at least one non-ionic emulsifier is selected from the group consisting of polysorbates, polysorbate 80, polyoxyl hydrogenated castor oil, sucrose ester, sucrose distearate, tocopheryl polyethylene glycol 1000 succinate, sorbitan fatty acid ester, sorbitan monooleate, polygly
  • the above composition of this invention wherein the at least one emulsifier is selected from non-ionic surfactants with HLB of about 10 to about 16 and a second emulsifier selected form non-ionic hydrophilic or hydrophobic surfactants having a HLB value of about 4 to about 12.
  • the at least one solid matrix forming agent is selected from the group consisting of, Soluplus® (polyvinyl caprolactam-polyvinyl acetate -polyethylene glycol graft copolymer), PemuleneTM (crosslinked copolymer of acrylic acid and a hydrophobic Cl 0-30 alkyl acrylate co-monomer), gelatin, Hydroxy propyl methyl cellulose (Methocel), Methyl cellulose, Hydroxy propyl cellulose (Klucel), hydroxyethylcellulose (Natrosol), Sodium carboxy methyl cellulose, acrylates copolymers, Ammonio Methacrylate Copolymer Type A or B, Dimethylaminoethyl Methacrylate - Butyl Methacrylate - Methyl Methacrylate Copolymer (EudragitTM), Methacrylic Acid - Ethyl Ac
  • a second solid matrix forming agent that is selected from the group consisting of, Beeswax, Carnauba wax, Cetyl palmitate, Glyceryl behenate, Behenic acid, Behenyl alcohol, Glyceryl monostearate, Glyceryl palmitostearate, Glyceryl stearate, Hydrogenated castor oil, Microcrystalline wax, Paraffin wax, Stearic acid, Stearic alcohol, alkyl silicone, silicone wax, waxy polymethylsiloxane, PEG wax and carbowax.
  • composition of this invention wherein at least 80% or at least 90% or at least 95% or at least 98% of the plurality of spherical particles released upon or following solid solution matrix decomposition are below about 100 pm preferably below about 30 pm, below about 10 pm, below about 5 pm or below about 2 pm or below about 1 pm, or below 800 nm or below 600 nm or below 400 nm.
  • the above composition of this invention wherein the solid solution of the cannabinoids composition comprises a terpene or terpenes, or essential oil or essential oils and mixture thereof, wherein the terpene or essential oil and mixtures and combinations thereof comprising from 0.01% to about 10%, and more preferably from 0.1% to 1%, or 0.2 to about 0.5% by weight.
  • the above composition of this invention wherein the ratio of the at least one cannabinoid or cannabinoids to the at least one emulsifier or mixture of emulsifiers, is from about 5:1 to about 1:20, and more preferably from about 2:1 to about 1:10, more preferably from about 1:1 to about 1:2 on weight basis.
  • the above composition of this invention wherein the ratio of a: the at least one cannabinoid or cannabinoids to b: the mixture of the at least one emulsifier or mixture of emulsifiers, and the at least one solid matrix forming agent or mixture of solid matrix forming agents is from about 10:1 to about 1:20, and more preferably from about 2:1 to about 1:20, more preferably from about 2:1 to about 1:10 and more preferably from about 1:1 to about 1:5 on weight basis.
  • the dosage form is a tablet, granules, capsule, hard shell capsule, soft shell capsule, a powder for reconstitution, granules to be administered by a spoon or by a volume measuring device or mixed with nutrients or foods
  • the dosage form is a powder or granules or pellets or micro-particles, in a sachet or a unit dose package or suspended in a liquid, suppository or suspended in a syrup or enema
  • the dosage form is an oral or mucosal or external or rectal or vaginal
  • the dosage form is a tablet or a capsule, lozenge, candy, toffee, chocolate or cookie, having an immediate release or slow or controlled release or dissolve in mouth or muco adhesive or enteric coated.
  • composition of this invention wherein the dosage form is acid resistant and decomposes at the lower intestines and in the colon and releases at least about 20% on a weight basis, or at least 40%, or at least 60% of the cannabinoid or cannabinoids at the colon.
  • composition of this invention wherein the dosage form is acid resistant and decomposes at the lower or distal intestines and in the colon and releases at least about 50% on a weight basis, or about 70% or about 90%, of the cannabinoid or cannabinoids at the colon.
  • a treatment of inflammatory bowel diseases in a mammal in need thereof by administration therapeutically effective amount of the composition of claim 1, wherein comprising from about 10 mg to about 2,000 mg of at least one anti inflammatory cannabinoid per unit serving, and providing dual pharmacological effect simultaneously; a) systemic cannabinoid blood level and b) local delivery of the cannabinoids to various parts of the gastro intestinal system, selected from the ilium, jejunum, the distal jejunum or the colon or combinations thereof.
  • a hot melt extrusion method of production of the composition which is free from volatile solvent and make use of melt extrusion machine, whereas the ingredients are fed into the machine and mixed and heated until melted and extruded and finally cooled and shaped in one continuous process.
  • a unit dose of plurality of particles of solid solution of cannabinoid or cannabinoids for the treatment of inflammatory bowel disease comprises of: a) particles that are non-pH resistant, and b) particles that are pH resistant, providing simultaneously, a systemic cannabinoid blood levels and a locally active distal jejunum and colonic cannabinoids.
  • a kit for the treatment of inflammatory bowel diseases and intestinal diseases improving the general wellbeing and alertness of the patients comprising a day composition and a night composition according to claim 1, comprising: (i) A day time composition comprising a.
  • a night time dosage form comprising a. at least about 1 mg to about 10 mg of a psychoactive sedating cannabis extract or a cannabinoid or derivatives thereof and b. at least about 0.5 mg to about 5.0 mg of at least one sedative terpene.
  • kits for the treatment of inflammatory bowel diseases and intestinal diseases improving the general wellbeing and alertness of the patients comprising a day composition and a night composition according to claim 1, comprising: (i) A day time composition comprising a. at least about 10 mg of anti-inflammatory and not psychoactive cannabis extract or a cannabinoid or derivatives thereof b. at least about 0.5 mg of at least one alerting terpene. (ii) A night time dosage form comprising a. at least about 10 mg of anti-inflammatory and not psychoactive cannabis extract or a cannabinoid or derivatives thereof b.
  • the pharmaceutical composition comprises or consists of a formulation presented in Table 1 to Table 6. Each table represents a separate embodiment of the invention.
  • the Cannabinoid, oil, Emulsifier and polymer, in each formulation can be substituted with other Cannabinoid, oil, Emulsifier and polymer in the same or substantially the same % by weight.
  • the pharmaceutical composition comprises or consists of a formulation having a Cannabinoid/oil/Emulsifier/polymer ratio as a formulation in Tables 1 to 6. Each possibility represents a separate embodiment of the invention.
  • Table IB Ingredients chemical and trade names or pharmacopoeia names
  • the cannabis pure extract in Table 3 to 5 were produced by an ethanol extraction of decarboxylated plant material and comprises about 80% by weight of THC and CBD, and about 2 % by weight terpenes.
  • the solid solutions of examples 1 to 6 were prepared by combining the emulsifiers and the polymers and heating to about l20°C to about l80°C and mixing until homogeneity obtained, adding and mixing the cannabinoids to obtain uniform and homogeneous mixture and cooling to room temperature.
  • the tested formulation is mixed 1 :10 with distilled water at room temperature and slightly rotated until the solid matrix decomposes or partially decomposes and releases the particles. A drop of the sample is then placed on bearing glass and covered with top glass, and the sample is immediately examined with light microscope magnification X200 or X400 with calibrated scale.
  • All solid solution cannabinoids composition of table 1 to 6 where tested with light microscope for particle size and had max particle size below 50 pm to below 10 mhi and mean particle size below 5 pm to below 1 pm.
  • composition 1A is decomposed into two types of particles that are detected: a) the polymer particles of irregular shapes, and b) a fine cannabinoids oily particles which are having spherical shape.
  • the differintial scanning calorimetry (DSC) histogram of examples 1A (401) and II (403) and pure CBD, show that no CBD crystals are seen for formulation 1A and about 18% of the CBD is in crystals state in formulation II. It can be seen that in formulation of example II, over 80% of the CBD is solubilized and in a solid solution form, and in formulation of example 1A essentially all or 100% of the cannabidiol is not ceystalline and is in a solid solution state.
  • Hard shell gelatin matrix was filled with the following composition: formulation 8A Solid solution composition 1A 70%
  • Enteric coating of the tablets 7A, and of hard vegetable capsules filled with granules, formulation 8A was produced by coating and drying with a solution of EudragitTM L100- 55 6%, PEG6000 1.2%, Talk 2%, water 6% and isopropyl alcohol (IP A) 84.8%.
  • Enteric coating of solid solution of cannabinoids in the shape of granules was produced by spraying the enteric coating solution in a fluidized bed apparatus.
  • Melt in the mouth tablet 10A is produced from 100 grams of one formulation of tables 1 to 4, mixed with 50 grams lactose and 50 grams micro crystalline cellulose (MCC) and 10 grams of Croscarmellose Sodium (Solutab®) and pressed in a tablet press under moderate pressure.
  • MCC micro crystalline cellulose
  • Solutab® Croscarmellose Sodium
  • Muco adhesive tablets 11A is produced by mixing 100 grams of one formulation of tables 1, 2, 3, and 4, with 50 grams of xanthan gum (XanturalTM 3000) and 50 grams of Hydroxypropyl methylcellulose (HPMC) K4M, and 1 gram magnesium stearate with high speed planetary mixer and pressed in a tablet press.
  • XanturalTM 3000 xanthan gum
  • HPMC Hydroxypropyl methylcellulose
  • Coating of the granules shaped from 2 A, formulation 12 A was produced by coating and drying with a solution of EudragitTM S 100 6%, PEG6000 1.2%, Talk 2%, water 6% and isopropyl alcohol (IP A) 84.8% and water to 100% with granules coater drum instrument or with fluidized bed coating apparatus.
  • Enteric coating of solid solution of cannabinoids in the shape of granules was produced by spraying the enteric coating solution in a fluidized bed apparatus.
  • Formulations of table 6 in the shape of granules were suspended in three consecutive compartment solutions.
  • Compartment A 200 ml of simulated gastric fluids (SGF) (pFl 1.5) at 37oC for two hours and transferred to compartment B) 200 ml of simulated intestinal fluid (SIF) (pFl 6.4) at 37oC for four hours and then transferred to compartment C) simulated intestinal fluids adjusted to pH of 7.0 at 37oC.
  • SGF gastric fluids
  • SIF simulated intestinal fluid
  • compartment C simulated intestinal fluids adjusted to pH of 7.0 at 37oC.
  • the granules did not decompose or disintegrated in the SGF or SIF and decomposed in compartment (C) of high pH within less than four hours.
  • Formulation comprising pectin, passed same test while compartment (C) contained pectinases.
  • the oral absorption calculated as AUC (Area Under the Curve) of formulation 1A was 220 ng/ml/hour and that of the control group was 104 ng/ml/hour. An increase of oral absorption of about 100% was demonstrated.

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Abstract

La présente invention concerne principalement une composition de solution solide comprenant un ou plusieurs cannabinoïdes en tant que principes actifs, lesdits cannabinoïdes étant dissous dans un système de solvant comprenant des émulsifiants non ioniques et des agents de formation de matrice solide. Après leur administration à un sujet ayant besoin d'un tel traitement, les compositions de solution solide se désintègrent, après contact avec des fluides corporels, et libèrent ainsi des particules de taille submicronique contenant les cannabinoïdes.
PCT/IL2019/050184 2018-02-16 2019-02-15 Administration, dans le côlon, de cannabinoïdes dans des compositions de solution solide WO2019159174A1 (fr)

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