WO2019159174A1

WO2019159174A1 - Colonic delivery of cannabinoids in solid solution compositions

Info

Publication number: WO2019159174A1
Application number: PCT/IL2019/050184
Authority: WO
Inventors: Doron Friedman
Original assignee: Icdpharma Ltd.
Priority date: 2018-02-16
Filing date: 2019-02-15
Publication date: 2019-08-22

Abstract

The present invention is primarily directed to a solid solution composition comprising one or more cannabinoids as active agents, wherein said cannabinoids are dissolved in a solvent system comprising non-ionic emulsifiers and solid matrix-forming agents. After they are administered to a subject in need of such treatment, the solid solution compositions disintegrate, following contact with body fluids, and thereby release sub-micron sized particles containing the cannabinoids.

Description

COLONIC DELIVERY OF CANNABINOIDS IN SOLID SOLUTION

COMPOSITIONS

FIELD OF THE INVENTION

[0001] 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.

BACKGROUND OF THE INVENTION

[0002] 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.

[0003] There have been attempts to improve the bioavailability of drugs of low solubility by preparing solid dosage forms comprising solid dispersions or solid solutions of the drugs. 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.

[0004] Hot Melt Extrusion (HME) 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.

[0005] There are different types of solid dispersions that can be produced by HME: a) crystalline solid dispersions, b) amorphous solid dispersions, and c) solid solutions. The current invention is of type (c), a solid solution of cannabinoids. Type (a) crystalline solid dispersion is a system in which the crystalline of the bioactive agent or drug is dispersed into an amorphous polymer matrix. The Differential Scanning calorimetry (DSC) profile for such a system is characterized by the presence of a melting point (Tm) corresponding to the crystalline Tm of the drug and a characteristic glass transition temperature (Tg) corresponding to the amorphous polymer excipient. 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. Different polymer excipients can be employed to prepare immediate and sustained release profiles via HME. 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. On the other hand, polyvinyl acetate-polyvinylpyrrolidone (Kollidon® SR) has been applied as polymer excipient for sustained release (SR) profiles. Moreover, Soluplus® has been shown to increase the drug absorption through the intestinal wall when applied as a solid solution.

[0006] 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.

[0007] 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.

[0008] There is high need for stable and ready to use and easy to use oral cannabinoid dosage forms, either for buccal, sublingual or for intestinal absorption, whereas the dosage form will comprise the required cannabinoids in a patient friendly dosage form to maximize pharmacological efficacy and will present the insoluble cannabinoid in as small particle as possible and in a solubilized form that will improve the poor oral bioavailability the cannabinoids.

[0009] There remains an unmet need to provide cannabis oral medication with specific pharmacological effects, such as increase alertness, sedative to treat insomnia, antidepressant, anti-fatigue, cancer and pain relief in highly acceptable and convenient dosage form that will contribute to maximal patient compliance and enhanced oral absorption.

[0010] In addition, there is unmet need for cannabis oral medication with specific pharmacological effects such as anti -inflammation and immune-modulating, for systemic administration and for local delivery to the small intestine, large intestine and colon specific and targeted delivery system for the treatment of inflammatory bowel diseases and other intestinal diseases and.

[0011] The present invention supplies a solution for all of the above unmet needs.

SUMMARY OF THE INVENTION

[0012] It has been unexpectedly discovered that 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%.

[0013] 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. More particularly, 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. In addition, these dosage forms and delivery systems have a long shelf life stability.

[0014] 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. For example, 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. Secondly, 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. Moreover, the pharmaceutical 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%.

Thus, the present invention is primarily directed to 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.

[0015] 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.

[0016] In certain embodiments, 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. In certain embodiments, 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.

[0017] In certain embodiments, 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. In certain embodiments, 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. In some embodiments, 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.

[0018] In certain embodiments, 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. In certain embodiments, the at least one solid matrix forming agent is selected from; Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer), Pemulene™ (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 (Eudragit™), Methacrylic Acid - Ethyl Acrylate Copolymer, polyvinyl alcohol graft copolymer (Kollicoat® IR), Poly (vinyl acetate-co-crotonic acid), polymethyl methacrylate and grafted polyethylene oxide, Lignins, Polyvinylpyrrolidone co-vinyl acetate (Kollidone VA64), polyvinyl pyrrolidone (Kollidone K90), cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, carboxymethyl ethylcellulose, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetate phthalate, maltodextrin, dextran, poly(methacrylic acid-co-ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), poly(methacrylic acid-co-ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), polylactic acid (PLA), poly-L-lactide (PLLA), poly-D-lactide (PLDA), poly(lactic-co-glycolic acid) (PLGA), Poloxamer (poly(ethylene oxide)-poly(propylene oxide) block copolymer), Carbowax™ (Polyethylene glycol (PEG1500, PEG4000, PEG6000, PEG8000), and mixtures thereof.

[0019] In certain embodiments, 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. In certain embodiments, 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. In certain embodiments, 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. In certain embodiments, 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.

[0020] In some embodiments, the composition of the invention is formulated as a dosage form suitable for oral administration.

[0021] In certain embodiments, the dosage form is formulated as granules, pellets, micro particles, tablet, hard shell capsules, suspended in a liquid, suspended in a syrup or enema. In certain embodiments, the dosage form is formulated for oral or mucosal delivery. In certain embodiments, the dosage form is formulated as or in a lozenge, candy, toffee, chocolate or cookie. In certain embodiments, the tablet or pellets are an immediate release or slow or controlled release dosage dorms In certain embodiments the tablet is enteric coated or is a melt or dissolved in the mouth or is a muco-adhesive dosage form. [0022] In certain embodiments, 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.

[0023] In some embodiments, 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. In some cases, 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.

[0024] In certain embodiments, 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.

[0025] In certain embodiments, the composition or dosage form comprises cannabidiol (CBD). In certain embodiments, the pharmaceutical composition or dosage form further comprises tetrahydrocannabinoid (THC). In certain embodiments, the CBD:THC weight ratio is about 20:1. In certain embodiments, the mixture comprises CBD. In certain embodiments, the mixture comprises THC. In certain embodiments, the mixture comprises CBD and THC. In certain embodiments, the mixture comprises CBD and THC in a weight ratio of about 1:1. In certain embodiments, the mixture comprises CBD and THC in a weight ratio of about 10:1 to about 1:10.

[0026] In certain embodiments, 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. In some embodiments, the solid solution of the composition further comprises one or more terpenes, one or more essential oils or a mixture thereof.

[0027] In one embodiment, 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.

[0028] The method of production of granules, or pellets, or tablets, compressed tablets, melt in mouth tablet, mucoadhesive tablets, enteric coating, immediate or slow release tablets and capsules and other dosage forms may be obtained from any standard reference work in this field, including, for example: Remington's Pharmaceutical Sciences, Mack Publishing Co, Easton, Pa, USA (1980).

[0029] In another aspect, 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. In one preferred embodiment, the mammalian subject is a human being. In one embodiment of this method, each dose administered to the subject comprises between about 10 mg and 2,000 mg of at least one cannabinoid.

[0030] 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. In one particular embodiment of this aspect of the invention, 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.

[0031] In a further aspect, 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.

DEFINITIONS

[0032] 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).

[0033] The term "cannabis extract" as used herein 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.

[0034] The term“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.

[0035] 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.

[0036] The term "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.

[0037] The term "about" as used herein refers to any value which lies within a range of ± 5% of original value. For example,“about 100” refers to“95 to 105”. [0038] The term "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.

[0039] The term "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. When said 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), such 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).

[0040] 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. The term “essentially solubilized” in an emulsion or plurality of particles, can be determined with light microscope visual inspection.

[0041] The term“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.

[0042] In a preferred embodiment, 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. [0043] The term“pharmaceutical composition” as used herein has its conventional meaning and refers to a composition which is pharmaceutically acceptable. The term “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. The term“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. The term "cosmetic 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. The term“veterinary composition” encompasses the full range of compositions for internal administration and feeds and drinks which can be consumed by animals.

[0044] As used herein, the term“particles” as used herein relates to droplets. The term "particle size" of an emulsion is to be understood also as the "droplet size" of that emulsion. The term "mean particle size" is also to be understood as the term "mean droplet size".

[0045] As used herein, the term "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.

[0046] The methods, uses, materials, and examples that will now be described are illustrative only and are not intended to be limiting; materials, uses and methods similar or equivalent to those described herein can be used in practice or testing of the invention. Other features and advantages of the invention will be apparent from the following figures, detailed description, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1. Light microscope (Nikon Eclipse™ 200) pictures, magnification X100 of pure 99% CBD crystals and formulation 1A at magnifications X100, X200 and X400.

[0048] Figure 2. Light microscope (Nikon Eclipse™ 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.

[0049] Figure 3 : Differential Scanning Calorimetry (DSC) of pure CBD and formulations 1A (401) and II (403).

DETAILED DESCRIPTION OF THE INVENTION

[0050] Provided by the present invention are 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.

[0051] Without being limited to any theory or mechanism, 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. In addition, 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.

[0052] It has been unexpectedly discovered that 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.

[0053] It has been unexpectedly discovered that it is possible to produce an essentially solubilized cannabinoid or cannabinoids or cannabis extract, in a solid matrix which is a solid solution, that is highly stable and homogeneous, and that decompose by disintegration or erosion or swelling into plurality of particles that comprises the cannabinoid in a dispersion whereas the cannabinoid is essentially solubilized in the these dispersion’s particles, that are produced in a specific set of conditions and compositions, whereas the at least one non-ionic emulsifier is selected, having an HLB of 4 to 16 and is selected from sucrose fatty acid esters; such as sucrose stearate, tocopheryl polyethylene glycol 1000 succinate, sorbitan fatty acid esters, polysorbate, polyglyceryl fatty acid ester, polyglyceryl- 3 dioleate and polyoxyl hydrogenated castor oil and the at least one polymer or wax or mixtures thereof that produces solid matrixes and are commonly used in hot melt extrusion and in film casting or spray drying compositions, formulations, dosage forms, technologies and processes as the matrix forming polymer.

[0054] 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 pm, and from 100 nm to about 1 pm, or from about 100 nm to about 800 nm.

[0055] 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 nm to 400 nm.

[0056] 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. [0057] Upon decomposition or disintegration or erosion or swelling and erosion and swelling and disintegration, a phenomenon that may occur independently or simultaneously, and a process which is a result of specific formulation composition, two types of particles are produced and detected by observation under magnification for example with light microscope. 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.

[0058] In certain embodiment "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.

[0059] In certain embodiments, 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), Pemulene™ (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 (Eudragit™), Methacrylic Acid - Ethyl Acrylate Copolymer, polyvinyl alcohol graft copolymer (Kollicoat® IR), Poly (vinyl acetate-co-crotonic acid), polymethyl methacrylate and grafted polyethylene oxide, Lignins, Polyvinylpyrrolidone co-vinyl acetate (Kollidone VA64), polyvinyl pyrrolidone (Kollidone K90), cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, carboxymethyl ethylcellulose, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetate phthalate, maltodextrin, dextran, poly(methacrylic acid-co-ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), poly(methacrylic acid-co-ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), polylactic acid (PLA), poly-L-lactide (PLLA), poly-D-lactide (PLDA), poly(lactic-co-glycolic acid) (PLGA), Poloxamer (poly(ethylene oxide)-poly(propylene oxide) block copolymer), Carbowax™ (Polyethylene glycol (PEG1500, PEG4000, PEG6000, PEG8000), pectin, zein, and mixtures thereof.

[0060] In certain embodiments, the at least one“matrix forming agent” is an organic or non-organic wax, selected from; Beeswax, Carnauba wax, Cetyl palmitate, Glyceryl behenate (Compritol ATO™), 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.

[0061] 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.

[0062] In certain embodiments, 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, Magnasweet™ (Mafco Corp) to mask the unpleasant low to moderately bitter or earthy taste of cannabis extracts. In addition, effervescent agents (sodium bicarbonate, citric acid) can also be added to improve the mouth feel. 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. These agents compete with the bitter active to bind to the G-protein coupled receptors on the tongue (receptor sites that detect bitter), thus suppressing the bitter taste. It has also been found that sodium chloride can be added to a formulation to mask bitterness, as used in the preparation of pioglitazone hydrochloride orally disintegrating tablets.

[0063] In certain embodiments, 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.

[0064] In certain embodiments, 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.

[0065] The term“natural cannabinoid” as used herein 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.

[0066] In certain embodiments, 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. Each possibility represents a separate embodiment of the invention.

[0067] The terms“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 A⁴-cannabidiol, A⁵-cannabidiol, D⁶ -cannabidiol, D¹·⁷- cannabidiol, D¹ -cannabidiol A²-cannabidiof D³ -cannabidiol.

[0068] Formula I

[0069] In another embodiment, 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

Number 205746-46-9), AMG-3 (CAS Number 205746-46-9), AM-411 (CAS Number 212835-02-4), (-)- 1 1 -hydroxy-7’-isothiocyanato-A8-THC (AM-708), (-)- 11 -hydroxy-7’ - azido-A8-THC (AM-836), AM-855 (CAS Number 249888-50-4), AM-919 (CAS Number 164228-46-0), AM926, AM-938 (CAS Number 303113-08-8), cannabidiol (CBD), cannabidiol propyl analogue (CBDV), cannabinol (CBN), cannabichromene, cannabichromene propyl analogue, cannabigerol, CP 47,497 (CAS Number (lS,3R): 114753-51-4), CP 55,940 (CAS Number 83002-04-4), CP 55,244 (CAS Number 79678-32- 3), CT-3 (ajulemic acid), dimethylheptyl F1F1C, HU-210 ( 1,1 -Dime thy lheptyl- l l-hydroxy- tetrahydrocannabinol), F1U-211 (CAS Number 112924-45-5), F1U-308 (CAS Number 1220887-84-2), WIN 55212-2 (CAS Number 131543-22-1), desacetyl-L-nantradol, dexanabinol, JWH-051 (Formula C25H38O2), levonantradol, L-759633 (Formula C26 l4o02), nabilone, 0-1184, and mixtures thereof.

[0070] 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.

[0071] In some embodiments, 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.

[0072] 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.

[0073] In certain embodiments, 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, also termed surfactants, 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® M 2125 CS), corn oil PEG-8 esters (Labrafil® WL 2609 BS), corn glycerides PEG-60 esters, olive oil PEG-6 esters (Labrafil® M1980 CS), hydrogenated palm/palm kernel oil PEG-6 esters (Labrafil® M 2130 BS), hydrogenated palm/palm kernel oil PEG-6 esters with palm kernel oil, PEG-6, palm oil (Labrafil® M 2130 CS), palm kernel oil PEG-40 esters, peanut oil PEG-6 esters (Labrafil® M 1969 CS), glycerol esters of saturated C8-C18 fatty acids (Gelucire® 33/01), glyceryl esters of saturated C12-C18 fatty acids (Gelucire® 39/01 and 43/01), glyceryl laurate/PEG-32 laurate (Gelucire® 44/14), glyceryl laurate glyceryl/PEG 20 laurate, glyceryl laurate glycery I/PEG 32 laurate, glyceryl, laurate glyceryl/PEG 40 laurate, glyceryl oleate/PEG-20 glyceryl, glyceryl oleate/PEG-30 oleate, glyceryl palmitostearate/PEG-32 palmitostearate (Gelucire® 50/13), glyceryl stearate/PEG stearate, glyceryl stearate/PEG-32 stearate (Gelucire® 53/10), saturated polyglycolized glycerides (Gelucire® 37/02 and Gelucire® 50/02), triisostearin PEG-6 esters (i.e. 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. Polyglycolized derivatives and polyoxyethylene esters or ethers derivatives of medium to long chain fatty acids, commercially named Brij and Myrj variety surfactants, and propylene glycol esters of medium to long chain fatty acids, which can be used including caprylate/caprate diglycerides, glyceryl monooleate, glyceryl ricinoleate, glyceryl laurate, glyceryl dilaurate, glyceryl dioleate, glyceryl mono/dioleate, glyceryl caprylate/caprate, medium chain (C8/C10) mono- and diglycerides (Capmul® MCM, Capmul® MCM (L)), mono-and diacetylated monoglycerides, polyglyceryl oleate, poly glyceryl-2 dioleate, poly glyceryl- 10 trioleate, polyglyceryl- 10 laurate, polyglyceryl- 10 oleate, and polyglyceryl- 10 mono dioleate, propylene glycol caprylate/caprate (Labrafac® PC), propylene glycol dicaprylate/dicaprate (Miglyol® 840), propylene glycol monolaurate, propylene glycol ricinoleate, propylene glycol monooleate, propylene glycol dicaprylate/dicaprate, propylene glycol dioctanoate, 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. -tocopheryl polyethylene glycol 1000 succinate), polysorbate 20 (Tween® 20), polysorbate 80 (Tween® 80), polyethyleneglycol 660 l2-hydroxystearate (Solutol® HS-15 or Kolliphor® HS15), polyglyceryl-3 dioleate ( Plurol ® Oleique CC 497, Gattfosse), Acrylates/C 10-30 Alkyl Acrylate Cross- Polymer(Pemulene™ TR2, Lubrizol). sodium lauryl sulfate and combinations thereof.

[0075] In certain embodiments, 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. Example of such 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.

[0076] 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.

[0077] A preferred type of emulsifiers is polymeric surfactant, such as Acrylates/C 10-30 Alkyl Acrylate Cross-Polymer. Or alkyl acrylate cross polymer, Pemulen™ TR1 or TR2, from Lubrizol. [0078] In certain embodiments, 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. In certain embodiments, the pharmaceutical composition comprises from about 15% w/w to about 30% w/w of at least two emulsifiers. In certain embodiments, 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.

[0079] In certain embodiments, 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. In a preferred embodiment, 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. Preferred sucrose esters are sucrose stearates for example Surfhope™ D- 181 IF, Surfhope™ D-1815, Surfhope™ D-1615 all from Mitsubishi chemicals, Crodesta™ FI 10 which is a mixture of mono and diesters with a F1LB value of 12, or Crodesta™ F160 which is a monoester with a F1LB value of 14.5.

[0080] In certain embodiments 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.

[0081] In certain embodiments of this invention, 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. [0082] In certain embodiments 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.

[0083] In some preferred embodiments 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. In certain embodiments 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.

[0084] In certain embodiments, 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.

[0085] In certain embodiments of the pharmaceutical composition, 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.

[0086] In certain embodiments, the composition comprises an essential oil or a terpenes or combinations thereof. In certain embodiments, the terpene is a natural terpene found in a Cannabis plant. In certain embodiments, the terpene is a synthetic terpene. In certain embodiments, the terpene is a mixture of natural terpenes. In certain embodiments, the terpene is a mixture of synthetic terpenes. In certain embodiments, the terpene is a mixture of natural and synthetic terpenes.

[0087] In certain embodiments, 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.

[0088] In certain embodiment the terpene is a cannabis plant terpene, or a terpene derived from a non-cannabis plant material or a synthetic terpene. In certain embodiment 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.

[0089] About 120 distinct terpenes are produced by the genus Cannabis, with the relative concentrations of the individual terpenes varying greatly among the 700 distinct strains currently in cultivation. Aside from taste and smell differences between varieties, this helps contribute to the broad diversity of potential medical applications of Cannabis. [0090] In certain embodiments of the pharmaceutical composition, the natural cannabinoid is derived or isolated from an extract of a Cannabis plant. In certain embodiments of the composition, the natural terpene is derived or isolated from an extract of a Cannabis plant.

[0091] In certain embodiments, a terpene or the mixture of terpenes solubilized with a cannabinoid or a mixture of cannabinoid. Each possibility represents a separate embodiment of the invention.

[0092] In certain embodiments, 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. Each possibility represents a separate embodiment of the invention.

[0093] In certain embodiments, 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. In certain embodiments 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). In certain embodiments at least about 90% of the at least one cannabinoid is solubilized in the solid matrix as can be measured by DSC. In certain embodiment 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.

[0094] In certain embodiments, 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. [0095] In certain embodiments, 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.

[0096] Hot melt extrusion (HME) 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.

[0097] In certain embodiment 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. 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. 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.

[0098] In certain embodiments 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 (Methocel™, types A, E, K, F, Dow Chemical), Hydroxyethyl cellulose (Natrosol™, Hercules), Hydroxypropyl cellulose (Klucel™, Aqualon), Carboxymethylcellulose (cellulose gum). Another type of synthetic polymers includes polyacrylic acid (Carbopol™, BFGoodrich), Polyethylene oxide (Polyox™, Union Carbide), Polyvinyl pyrrolidone (Kollidon™, PVP and PVP-VA, BASF), natural gums and polysaccharides— X an than gum (Xantural™, 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.

[0099] In certain embodiments the release controlling agent is mixed with the polymer or is part of the polymer mixture that is solid solution forming agent.

[00100] Without limiting the invention, 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.

[00101] In certain embodiments, 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. In certain embodiments, 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. 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 0.8 microns or less or 0.6 microns or less, or 0.4 microns or less.

[00102] In a certain embodiments of the invention, 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, polypropylene, poly (vinyl chloride), polyethylene, poly (methyl methacrylate), poly (hydroxyethyl methacrylate), acrylic acid, butyl acrylate copolymer, 2-ethylhexyl acrylate and butyl acrylate copolymer, vinyl acetate and methyl acrylate copolymer, ethylene vinyl acetate and polyethylene terephthalate, ethylene vinyl acetate and polyethylene, polyethylene terephthalate, cellulose, methyl cellulose, hypromellose acetate succinate nf, hypromellose acetate succinate jp, hypromellose acetate succinate, hypromellose phthalate nf, hypromellose phthalate, low-substituted hydroxypropyl cellulose nf, low-substituted hydroxypropyl cellulose jp, low-substituted hydroxypropyl cellulose nf-low-substituted hydroxypropyl cellulose jp copolymer, hypromellose usp, hypromellose ep, hypromellose jp, hypromellose phthalate jp, hypromellose phthalate ep, hypromellose, hypromellose phthalate nf, hypromellose phthalate, low-substituted hydroxypropyl cellulose, methacrylates, cellulose acetate butyrate, polylactide-polyglycolide copolymers, polycaprolactone, polylactide, polyglycolide, polyvinylpyrrolidone-co-vinyl acetate, polyrethanes, polyvinyl caprolactam-polyvinyl acetate-polyethylene glicol graft copolymer, polyvinyl caprolactam, polyvinyl acetate, vinylpyrrolidone-vinyl acetate copolymer, vinylpyrrolidone, vinyl acetate, polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene, polyoxypropylene, polyoxirane, povidone, polyethylene oxide, cellulose acetate, copovidone, povidone kl2, povidone kl7, povidone k25, povidone k30, povidone k90, hypromellose e5, hypromellose e4m, hypromellose k3, hypromellose klOO, hypromellose k4m, hypromellose klOOm, hypromellose phthalate hp-55, hypromellose phthalate hp-50, hypromellose acetate succinate 1 grade, hypromellose acetate succinate m grade, hypromellose acetate succinate h grade, cellulose acetate phthalate, cationic methacrylate, methacrylic acid copolymer type a, methacrylic acid copolymer type b, methacrylic acid copolymer type c, polymethylacrylates, polyvinyl alcohol, hydroxypropylmethylcellulose acetate succinate, ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate, ethyl acrylate-methyl methacrylate copolymer, butyl/methyl methacrylate-dimethylaminoethyl methacrylate copolymer, butyl/methyl methacrylate, dimethylaminoethyl methacrylate, methacrylic acid-ethyl acrylate copolymer, methacrylic acid, methacrylic acid-methyl methacrylate copolymer, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, methyl acrylate, methyl methacrylate and diethylaminoethyl methacrylate copolymer, methyl methacrylate, diethylaminoethyl methacrylate, succinate, d-a-tocopheryl polyethylene glycol 100 succinate, d-a-tocopheryl polyethylene glycol, ethylene oxide, polypropylene oxide, polyvinyl alcohol-polyethylene glycol graft copolymer, methacrylic acid-ethyl acrylate copolymer, poloxamer, micronized poloxamer, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, ethylene glycol-vinyl alcohol graft copolymer, polydextrose nf, hydrogenated polydextrose nf, methacrylic acid copolymer, methacrylic acid and methyl methacrylate copolymer, methacrylic acid and ethyl acrylate copolymer, carbomer homopolymer, carbomer copolymer, carbomer interpolymer and others.

[00103] In certain embodiment of the invention, 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.

[00104] Polymer that is matrix forming or solid matrix forming material can be either biodegradable or nonbiodegradable. To be extrudable, the polymer must exhibit thermoplastic characteristics next to its thermal stability in the required extrusion temperature range. 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. Commonly used 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.

[00105] Other 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.

[00106] 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.

[00107] The terms "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. In particular cases, 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.

[00108] Suitable apparatus for producing hot melt extrusion are 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.

[00109] 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. Alternatively, the extrudate is cut into pieces, either before (hot-cut) or after solidification (cold-cut).

[00110] 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.

[00111] 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.

[00112] 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.

[00113] 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.

[00114] Exemplary ionizable cellulosic polymers that are at least partially ionized at physiologically relevant pHs that may be used as the dispersion polymer 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 cellulose acetate succinate phthalate, hydroxypropyl methyl cellulose succinate phthalate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic acid cellulose acetate, ethyl picolinic acid cellulose acetate, carboxymethyl cellulose, carboxymethyl cellulose acetate, and ionizable salts of all the foregoing.

[00115] The addition of 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.

[00116] 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. [00117] 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.

[00118] 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.

[00119] Furthermore, 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.

[00120] 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.

[00121] These optional components can be used either alone or in combination with other ingredients to improve the chemical and physical properties of the cannabinoid solid solution drug delivery systems and the cannabinoids or the terpenes chemical stability and shelf life.

[00122] The present invention further provides, in an aspect, a dosage form, comprising or consisting of any one of the compositions described above.

[00123] The term "dosage 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.

[00124] In certain embodiments, 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.

[00125] 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.

[00126] In certain embodiments, 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. Each possibility represents a separate embodiment of the invention. In certain embodiments, the dosage form is formulated for mucosal delivery. The term "mucosal delivery" refers to the delivery to a mucosal surface, including nasal, vaginal, rectal, urethral, sublingual and buccal delivery. In certain embodiments, the dosage form is formulated in a candy, toffee, dragee, chocolate, cookie or lozenge.

[00127] In certain embodiments, 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. In such manner a controlled release is obtained, when partial of the cannabinoids dose is release in the jejunum and are intended for systemic absorption and part of the dose is released in the colon or at end of jejunum to be targeted for the colon and have essentially local effect in the colon. [00128] 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 Eudragit™. 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.

[00129] According to the principles of the present invention, 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. 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.

[00130] In an embodiment, 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.

[00131] In some embodiments, 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.

[00132] 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. [00133] The phrase“cannabinoid-responsive symptom, disease or disorder” as used herein 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.

[00134] Using marijuana is beneficial for patients living with different forms of inflammatory bowel disease, including Crohn’s disease and ulcerative colitis. Observational studies indicate that using marijuana can result in an improvement in symptoms, as well as a reduction in the use of standard medications. In a 2014 study, researchers found that IBD patients who used marijuana showed greater improvements in symptoms than those who received a placebo. The study found that of the 11 participants given marijuana, 5 were able to achieve complete remission of the disease. Inflammation: Tambe Y, Tsujiuchi H, Honda G, et al. 1996. Gastric cytoprotection of the non-steroidal anti-inflammatory sesquiterpene, beta-caryophyllene. Planta Med, 62:469-70.

[00135] In some additional embodiments there is provided 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.

[00136] According to some embodiments, there is provided the above method of treatment, whereas 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.

[00137] In certain embodiments, 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.

[00138] In certain embodiment 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. In certain embodiment 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. In certain embodiments the solid solution releases the cannabinoids only in presence of pectinases. In certain embodiments the solid solution dosage form releases the cannabinoids only at neutral pH and presence of pectinases, a condition prevailing in the colon. In certain embodiment 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.

[00139] In certain embodiments, 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. In certain embodiments, 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.

[00140] In certain embodiments, 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. In certain embodiments, 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.

[00141] In certain embodiments, 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. In certain embodiments, 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.

[00142] It is of high need to provide a 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. [00143] In certain embodiments, 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. Such 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. Such dual active compositions are administered as a complementary kit of a day IBD treatment composition and a night IBD treatment composition.

[00144] In some embodiments, there is provided 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.

[00145] In some embodiments, there is provided above 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.

[00146] In some other embodiments, there is provided 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.

[00147] In some other embodiments, there is provided the above composition of this invention, wherein the at least one solid matrix forming agent is selected from the group consisting of, Soluplus® (polyvinyl caprolactam-polyvinyl acetate -polyethylene glycol graft copolymer), Pemulene™ (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 (Eudragit™), Methacrylic Acid - Ethyl Acrylate Copolymer, polyvinyl alcohol graft copolymer (Kollicoat® IR), Poly(vinyl acetate-co-crotonic acid), polymethyl methacrylate and grafted polyethylene oxide, Lignins, Polyvinylpyrrolidone co- vinyl acetate (Kollidone VA64), polyvinyl pyrrolidone (Kollidone K90), cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, carboxymethyl ethylcellulose, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetate phthalate, maltodextrin, dextran, poly(methacrylic acid-co-ethyl acrylate), poly (methacrylic acid-co-methyl methacrylate), poly (methacrylic acid-co-ethyl acrylate), poly (methacrylic acid-co-methyl methacrylate), polylactic acid (PLA), poly-L-lactide (PLLA), poly-D-lactide (PLDA), poly(lactic-co-gly colic acid) (PLGA), Poloxamer (poly(ethylene oxide)-poly(propylene oxide) block copolymer), Carbowax™ (Polyethylene glycol (PEG1500, PEG4000, PEG6000, PEG8000), and mixtures thereof, in a concentration of from about 1% w/w to about 80% w/w, and more preferably from about 20% to about 60%, and more preferably from about 30% w/w to about 50% w/w.

[00148] In some other embodiments, there is provided 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. [00149] In some other embodiments, there is provided the above 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.

[00150] In some other embodiments, there is provided 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.

[00151] In some other embodiments, there is provided 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.

[00152] In some other embodiments, there is provided 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.

[00153] In some other embodiments, there is provided the above composition of this invention, whereas 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, or 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, or the dosage form is an oral or mucosal or external or rectal or vaginal, or 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.

[00154] In some other embodiments, there is provided the above 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.

[00155] In some other embodiments, there is provided the above 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. In some embodiments of tis invention there is provided 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.

[00156] In some embodiment of this invention, there is provided 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.

[00157] In some other embodiments, there is provided the above composition of this invention, whereas 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. [00158] In some other embodiments, there is provided 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. 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. And (ii) 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.

[00159] In some other embodiments, there is provided 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. 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. at least about 1 mg to about 10 mg of a psychoactive sedating cannabis extract or a cannabinoid or derivatives thereof and c. at least about 0.5 mg to about 5.0 mg of at least one sedative terpene. In certain embodiments, 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.

[00160] According to the principles of the present invention, and without being limited to any theory or mechanism, in certain embodiments, 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. In certain embodiments, 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. EXAMPLES

[00161] Example 1.

Table 1A. Immediate release solid solution compositions of Cannabidiol (CBD) and various matrix forming polymers

Table IB. Ingredients chemical and trade names or pharmacopoeia names

[00162] Example 2.

Table 2. Immediate release solid solution compositions of Cannabidiol with various emulsifiers

[00163] Example 3.

Table 3. Solid solution compositions of various cannabinoids and cannabis extract

[00164] Example 4.

Table 4. Solid solution composition of cannabis extract and with terpenes

[00165] Example 5.

Table 5. Slow release solid solution composition of cannabinoids or cannabis extracts

[00166] Example 6.

Table 6. Distal jejunum and colonic targeted and slow release solid solution composition of anti-inflammatory cannabinoids, CBD and CBDA

[00167] 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. [00168] 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.

[00169] For determining the mean particle size or“maximal particle size” or the “Largest detected size”, 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. [00170] 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. Accurate mean particle size of particles below 1 pm cannot be examined in light microscope since the particle size is below the visible wavelength and using laser light diffraction for example with Malvern™ nanosizer is not possible since the polymers and waxes are insoluble or partially soluble or swellable and hampering the detection of smaller particles by the diffracting laser beam and obtaining such data.

In figure 1, a light microscope picture of composition 1A (Nikon, Eclipse™ E200) magnification X400 the matrix is homogeneous and glassy, and no crystals are observed.

In figure 2, the solid solution of 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.

In figure 3, 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.

[00171] Example 7.

Tablet was pressed with the following composition: formulation 7A

Solid solution composition 3A 60%

Microcrystalline cellulose

(A vied PH 102) 29%

Killidon CL 10%

Magnezium stearate 0.5%

Aerosil 200 0.5%

[00172] Example 8.

Hard shell gelatin matrix was filled with the following composition: formulation 8A Solid solution composition 1A 70%

Killidon CL 15%

Microcrystalline cellulose 15%

[00173] Example 9.

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 Eudragit™ 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.

[00174] Example 10.

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.

[00175] Example 11.

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 (Xantural™ 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.

[00176] Example 12.

Coating of the granules shaped from 2 A, formulation 12 A, was produced by coating and drying with a solution of Eudragit™ 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. Disintegration test:

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. 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.

[00177] Example 13.

Pharmacokinetic oral bioavailability study in rats. The grinded pulverized solid solution of formulation 1A was suspended in saline and administered in gavage to the stomachs of five Sprague drawly rats weighing 220-250 grams at 12 mg/kg. Blood samples were obtained at various time points after oral administration and the plasma was separated. The CBD concentration in the plasma was tested by LC-MS and the area under the curve was calculated. Comparative group of five rats received 12 mg/kg of CBD dissolved in propylene glycokethanol: water 1:1:1 (a Sativex™-like formulation)

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.

Claims

1. 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.

2. The composition according to claim 1, wherein the solid solution composition is capable of disintegration following contact with liquid, thereby releasing 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.

3. The composition according to claim 1, wherein the concentration of the one or more cannabinoids is in the range of about 0.1 to about 60% (w/w), the concentration of the at least one non-ionic emulsifier is in the range of about 1 to about 80% (w/w) and the concentration of the at least one solid matric forming agent is in the range of about 10 to about 90% (w/w).

4. The composition according to claim 1, wherein the at least one cannabinoid is selected from the group consisting of a cannabis plant extract or purified natural or synthetic cannabinoid: 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), cannahivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), salts thereof, derivatives thereof and mixtures of cannabinoids and combinations thereof.

5. The composition according to claim 1, wherein the 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, poly glyceryl fatty acid esters, polyoxylglycerides, salts thereof, derivatives thereof, and combinations thereof.

6. The composition according to claim 1, whereas the at least one emulsifier 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.

7. The composition according to claim 1, wherein the at least one solid matrix forming agent is selected from the group consisting of, Soluplus® (polyvinyl caprolactam- polyvinyl acetate -polyethylene glycol graft copolymer), Pemulene™ (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 (Eudragit™), Methacrylic Acid - Ethyl Acrylate Copolymer, polyvinyl alcohol graft copolymer (Kollicoat® IR), Poly(vinyl acetate-co-crotonic acid), polymethyl methacrylate and grafted polyethylene oxide, Lignins, Polyvinylpyrrolidone co-vinyl acetate (Kollidone VA64), polyvinyl pyrrolidone (Kollidone K90), cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, carboxymethyl ethylcellulose, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetate phthalate, maltodextrin, dextran, poly(methacrylic acid-co-ethyl acrylate), poly(methacrylic acid-co- methyl methacrylate), poly(methacrylic acid-co-ethyl acrylate), poly(methacrylic acid-co- methyl methacrylate), polylactic acid (PLA), poly-L-lactide (PLLA), poly-D-lactide (PLDA), poly(lactic-co-glycolic acid) (PLGA), Poloxamer (poly(ethylene oxide)- poly(propylene oxide) block copolymer), Carbowax™ (Polyethylene glycol (PEG1500, PEG4000, PEG6000, PEG8000), and mixtures thereof.

8. The composition according to claim 7, comprising a second solid matrix forming agents, wherein the second solid matrix forming agent 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.

9. The composition according to any one of the above claims, wherein at least 80%, of the at least one cannabinoid is fully solubilized in the solid composition, as measured by differential scanning calorimetry.

10. The composition according to claim 1, wherein the solid solution of the cannabinoids composition further comprises one or more terpenes, one or more essential oils or a mixture thereof.

11. The composition according to claim 1, wherein the ratio of the at least one cannabinoid to the at least one emulsifier, is from about 5: 1 to about 1:20.

12. The composition according to claim 1, wherein the ratio of a) the at least one cannabinoid to b) the mixture of the at least one emulsifier and the at least one solid matrix forming agent is from about 2:1 to about 1:20.

13. The composition according to any one of the preceding claims, wherein said composition is provided in a dosage form suitable for oral delivery, selected from the group consisting of a tablet, capsule, particles, granules, lozenge, candy, toffee, chocolate, cookie, in a sachet or a unit dose package or suspended in a liquid or gel.

14. The composition according to claim 13, wherein the dosage form 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.

15. The composition according to claim 13, whereas 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.

16. The composition according to claim 1, comprising 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 poly glyceryl ester, and at least 100 mg of poly vinylcaprolactam-poly vinyl acetate- polyethylene glycol graft co-polymer or poly[methacrylic acid, methyl methacrylate] or poly acrylate polymer or copolymer or Poloxamer 407.

17. A method of treatment of inflammatory bowel disease in a mammal in need thereof, comprising administering one or more doses of a therapeutically effective amount of the composition according to claim 1.

18. The method according to claim 17, wherein each dose comprises about 10 mg to about 2,000 mg of least one cannabinoid

19. 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.

20. The method according to claim 19, whereas 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.

21. 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.

22. A kit for the treatment of inflammatory bowel diseases and intestinal diseases improving the general wellbeing and alertness of patients, comprising:

(i) A day time dosage form comprising a composition according to claim 1, comprising:

a. at least about 10 mg of an anti-inflammatory cannabis extract or a cannabinoid or derivatives thereof, wherein said extract, cannabinoid and/or derivatives are devoid of any substantial psychoactive activity; and b. at least about 0.5 mg of at least one alerting terpene; and

(ii) A night time dosage form comprising a composition according to claim 1, comprising:

a. about 1 mg to about 10 mg of a psychoactive sedating cannabis extract or a cannabinoid or derivatives thereof and

b. about 0.5 mg to about 5.0 mg of at least one sedative terpene.

23. A kit for the treatment of inflammatory bowel diseases and intestinal diseases and improving the general wellbeing and alertness of patients, comprising:

a. at least about 10 mg of anti-inflammatory cannabis extract or a cannabinoid or derivatives thereof, wherein said extract, cannabinoid and/or derivatives are devoid of any substantial psychoactive activity; and

b. at least about 0.5 mg of at least one alerting terpene.

a. at least about 10 mg of anti-inflammatory and not psychoactive cannabis extract or a cannabinoid or derivatives thereof;

b. about 1 mg to about 10 mg of a psychoactive sedating cannabis extract or a cannabinoid or derivatives thereof and

c. about 0.5 mg to about 5.0 mg of at least one sedative terpene.