US 20160279073A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0279073 A1 Donsky et al. (43) Pub. Date: Sep. 29, 2016

(54) TERPENE AND CANNABINOID Publication Classification FORMULATIONS (51) Int. Cl. A63L/01 (2006.01) (71) Applicant: FULL SPECTRUM A63L/05 (2006.01) LABORATORIES, LTD., Dublin 2 A636/85 (2006.01) (IE) A63L/352 (2006.01) A63L/05 (2006.01) (72) Inventors: Marc Donsky, Denver, CO (US); A6II 47/36 (2006.01) Robert Winnicki, Denver, CO (US) A 6LX 9/27 (2006.01) A63L/045 (2006.01) (21) Appl. No.: 15/033,023 (52) U.S. Cl. CPC ...... A6 IK3I/01 (2013.01); A61K 9/127 (22) PCT Fed: Oct. 31, 2014 (2013.01); A61 K3I/015 (2013.01); A61 K 31/045 (2013.01); A61K 31/352 (2013.01); (86) PCT No.: PCT/B2O14/OO3156 A61 K3I/05 (2013.01); A61K 47/36 (2013.01); A61K 36/185 (2013.01) S 371 (c)(1), (2) Date: Apr. 28, 2016 (57) ABSTRACT The present invention provides stable, fast-acting liposome and micelle formulations of terpenes, hemp oil, cannabi Related U.S. Application Data noids, or mixtures of a cannabinoid and terpenes or hemp oil and cannabinoids that are Suitable for pharmaceutical and (60) Provisional application No. 61/898,024, filed on Oct. nutraceutical applications. Also provided are methods for 31, 2013. the manufacture of micelle and liposomal formulations. US 2016/0279.073 A1 Sep. 29, 2016

TERPENE AND CANNABINOID medical conditions, including glaucoma, AIDS wasting, FORMULATIONS neuropathic pain, treatment of spasticity associated with multiple Sclerosis, fibromyalgia and chemotherapy-induced PRIORAPPLICATION INFORMATION nausea. Additionally, THC has been reported to exhibit a therapeutic effect in the treatment of allergies, inflammation, 0001. The instant application claims the benefit of U.S. infection, epilepsy, depression, migraine, bipolar disorders, Provisional Patent Application 61/898,024, filed on Oct. 31, anxiety disorder, and drug dependency and withdrawal 2013. syndromes. THC is particularly effective as an anti-emetic FIELD OF THE INVENTION drug and is administered to curb emesis, a common side effect accompanying the use of opioid analgesics and anaes 0002 The present invention relates to liposomal formu thetics, highly active anti-retroviral therapy and cancer che lations of one or more terpenes, as well as a liposomal or a motherapy. micellar formulation of one or more terpenes in combination 0009. Like terpenes, cannabinoids are lipophilic and with one or more cannabinoids or an analog of a cannabi potentially acid-labile compounds. Because of their hydro noid. More specifically, the present invention relates to the phobic nature, cannabinoids are poorly absorbed systemi manufacture and use of Such formulations for medical, cally from oral dosage forms in the aqueous environment of pharmaceutical and nutraceutical applications. the gastrointestinal tract, and oral formulations of cannabi noids, therefore, exhibit low bioavailability. BACKGROUND OF THE INVENTION 0010. The present invention overcomes the drawbacks 0003 Terpenes and terpenoids are natural volatile non described above by providing a stable liposomal composi aromatic compounds found as components of essential oils tion of a terpene as well as stable liposomal and micellar present in many plants and contain a carbon and hydrogen compositions of a terpene-cannabinoid mixture. The inven (terpenes) or a carbon, hydrogen, and oxygen scaffold tive compositions are Suitable for medical, pharmaceutical (terpenoids). Terpenes and terpenoids have been used as and nutraceutical applications. In addition, the present fragrances and flavoring agents, as well as skin penetration invention provides stable liposomal compositions of hemp agents. Terpenes are classified by the number of isoprene oil as well as stable liposomal and micellar compositions repeat units present in their molecular structure. Thus, that contain a mixture of hemp oil and cannabinoid. The hemiterpenes represent a class of compounds which consist formulations according to the present invention are Suitable of a single isoprene unit. Monoterpenes, Such as geraniol, for medical, pharmaceutical and nutraceutical applications. limonene and terpineol, consists of two isoprene units and Also described is the use of such formulations for stimulat conform to a molecular formula CH. Sesquiterpenes ing intellectual activity and mental concentration, and to contain three isoprene units and have a molecular formula procure calming effects (Tambe Yet al., 1996, Planta Med. CH. Illustrative of this class are humulene, farmesene 62(5):469-70; Tembaro and Bartolato 2012, Recent Pat CNS and farnesol. Drug Discovery 7(1) 25-40). 0004 Diterpenes, such as cafestol, kahweol, cembrene and taxadiene (a precursor of taxol), have four isoprene SUMMARY OF THE INVENTION repeat units while sesterterpenes, such as geranylfarnesol, 0011. It is therefore an aspect of the invention to provide contain five isoprene units. solutions to the aforementioned deficiencies in the art. To 0005 Triterpenes containing six isoprene units are the this end the invention provides a stable liposomal formula structural precursors of Steroids. For instance, the triterpene tion of a primary, secondary or tertiary terpene in an aqueous squalene is a major constituent of shark liver oil that is used Solution. Illustrative of the class primary terpene are in the manufacture of lanosterol or cycloartenol. Sesquar C-pinene, C.-bisabolol, B-pinene, guaiene, guaiol, limonene, terpenes. Such as ferrugicadiol and tetraprenylcurcumene, myrcene or Ocimene. The amount of the primary terpene in contain seven isoprene units while tetraterpenes, such as the inventive formulation is 50% (w/w), while the amount of lycopene, monocyclic gamma-carotene, and alpha- and the secondary terpene is from about 30% to about 40% beta-carotenes contain eight isoprene units. Terpenes having (w/w) and the amount of the tertiary terpene is from about more than eight isoprene repeat units are referred to as 8% to about 10% (w/w) of the formulation. polyterpenes. Rubber, for instance, is a polyterpene which 0012. Each unique cultivar of Cannabis sativa may have consists of long chains of repeating isoprene units. a unique cannabinoid and cannabinoid-terpene profile. This 0006 More than 120 different types of terpenes have invention describes Primary, Secondary and Tertiary terpene been identified in extracts obtained from plants belonging to groups. Terpenes can be extracted, collected and encapsu the genus Cannabis. The concentration of each terpene, lated in liposomes or micelles. There is a growing body of however, has been shown to vary between the different plant research on the sedative and stimulatory properties of ter cultivars. penes, and on the organoprotective, anti-cancer and anti 0007 Terpenes have poor solubility in water, but are viral effects of individual and combinations of terpenes and readily soluble in non-aqueous and/or hydrophobic medium. essential oils. Certain terpenes are known to have medicinal Because of their lipophilic nature, terpenes can easily cross properties that have been utilized in aromatherapy, as well as the blood-brain barrier and interact with cell membranes by for sedative, analgesic, anti-inflammatory, antibiotic, anti binding to membrane receptors. fungal and mental stimulation. This invention includes 0008 Cannabinoids are compounds derived from Can unique groupings that have been observed in various culti nabis sativa, an annual plant in the Cannabaceae family. The vars of Cannabis sativa that may have medicinal value. plant contains about 60 cannabinoids. The most active 0013. In one embodiment, the stable inventive liposomal naturally occurring cannabinoid is tetrahydrocannabinol Suspensions can further comprise one or more cannabinoids (THC), which is used for the treatment of a wide range of or cannabinoid analogs. The average diameters of liposomes US 2016/0279.073 A1 Sep. 29, 2016 in a formulation according to the invention is in a range consisting of C-pinene, t-carophyllene, terpinolene, between 50 nm to 1000 nm and the final maximum concen ocimene, limonene and linalool and the tertiary terpene is tration of cannabinoids or cannabinoid analogues in the selected from the group consisting of B-pinene, t-carophyl above described formulation is from 0.01 g/liter to 100 lene, limonene, Ocimene, myrcene, C-pinene, bisabolol and g/liter. Any cannabinoids or cannabinoid analogues selected myrcene. The Suspension may further comprise trace from natural compounds, synthetic compounds, semi-syn amounts of one or more terpenes selected from the group thetic compounds, or mixtures thereof can be used in the consisting of C-humulene, C.-bisabolol, guaiene, limonene, claimed Suspension. Exemplary compounds within the class ocimene, 3-carene, B-pinene, C-pinene, myercene, guaiol, cannabinoids or cannabinoid analogues include without C-terpineol, terpinolene and linalool. limitation cannabinol, cannabidiol, A9-tetrahydrocannabi 0023 The invention also provides a stable, aqueous, nol, A-8-tetrahydrocannabinol, 11-hydroxy-tetrahydrocan liposomal Suspension comprising hemp oil and one or more nabinol, 11-hydroxy-A-9-tetrahydrocannabinol, levonant cannabinoids or cannabinoid analogues. Preferably, the can radol, A-11-tetrahydrocannabinol, tetrahydrocannabivarin, nabinoids or cannabinoid analogues in the inventive Suspen dronabinol, amandamide, nabilone, a combination thereof, a sions are natural compounds, synthetic compounds, semi synthetic analogue of a natural cannabinoid, as well as synthetic compounds, or mixtures thereof. Illustrative of compounds having a basic cannabinoid structure and having Such compounds are cannabinol, cannabidiol, A-9-tetrahy physiological properties similar to natural or synthetic can drocannabinol, A-8-tetrahydrocannabinol, 11-hydroxy-tetra nabinoids. hydrocannabinol, 11-hydroxy-A-9-tetrahydrocannabinol, 0014 For certain embodiments, the liposomal suspension levonantradol, A-11-tetrahydrocannabinol, tetrahydrocan can further comprise a stabilizer. The stabilizer may be guar nabivarin, dronabinol, amandamide, nabilone, a combina gum, Xyanthan gum, cellulose, hyaluronic acid, polyvinyl tion two or more such compounds, or a mixture of a natural pyrrolidone (PVP), alginate, chondritin Sulfate, polygamma cannabinoid and a synthetic analogue of a cannabinoid. The glutamic acid, gelatin, chitisin, corn starch or flour and is average size of the micelle or liposome in the aqueous present in an amount from about 0.1% to about 2% (w/v). suspension can range between 50 nm and 1000 nm and the 0015. In one aspect of the invention, the primary terpene final maximum concentration of cannabinoids or cannabi in the Suspension is C-pinene, the secondary terpene is noid analogues in the inventive formulation is from 0.01 myrcene, B-pinene ort-carophyllene, and the tertiary terpene g/liter to 100 g/liter. is B-pinene, t-carophyllene, C.-bisabolol or myrcene. Such a 0024 Suspensions according to the present invention can Suspension may also contain trace amounts of one or more further include one or more stabilizers in an amount from other terpenes selected from the group consisting of C-hu about 0.1% to about 2% (w/v). Exemplary of such stabiliz mulene, C.-bisabolol, guaiene, limonene, ocimene, terpi ing agents include without limitation guar gum, Xyanthan nolene, 3-carene, myercene, guaiol, C-terpineol and linalool. gum, cellulose, hyaluronic acid, polyvinyl pyrrolidone 0016 For certain suspensions, the primary terpene in the (PVP), alginate, chondritin Sulfate, poly gamma glutamic Suspension is C.-bisabolol, the secondary terpene is t-caro acid, gelatin, chitisin, corn starch and/or flour. phyllene, and the tertiary terpene is C-pinene or myrcene and 0025. Also provided is a method for producing a stable, the Suspension can further comprise trace amounts of one or highly concentrated liposomal formulation of one or more more terpenes selected from the group consisting of C-hu terpenes by: (a) dissolving one or more terpenes in ethanol mulene, C-terpineol guaiol, and linalool. to obtain an ethanolic Solution of the terpene; (b) adding a 0017 Alternatively, the invention provides a suspension phospholipid to the ethanolic Solution of terpenes; (c) inject comprising B-pinene as the primary terpene, C-pinene as the ing the ethanolic Solution of phospholipid and terpenes into secondary terpene and t-carophyllene or terpinolene as the distilled water to obtain a liposomal Suspension of terpenes; tertiary terpenes. Such a suspension can further comprise and (d) removing the ethanol from the liposomal Suspension trace amounts of myrcene. of terpenes to obtain a stable liposomal suspension of one or 0018 Illustrative of other liposomal suspensions are the more terpenes. The final maximum concentration of ter following: penes in the liposomal Suspension described above is from 0019 (a) suspension in which the primary terpene is about 0.001 gm/L to about 100 g/liter. guaiene, the secondary terpene is t-carophyllene; and the 0026. In an exemplary composition, the hydrophobic/ tertiary terpenes are myrcene or a humulene with trace lipophilic membrane of the liposome can comprise about amounts of C-pinene, C.-bisabolol, B-pinene, limonene, 40% phosphatidylcholine, about 3.5% phosphatidyletha ocimene and/or terpinolene; nolamine, about 6% phosphonophospholipids, and about 0020 (b) suspension in which the primary terpene is 0.5% of other phospholipids. According to another exem guaiol, the secondary terpene is C.-bisabolol, and the tertiary plary composition the hydrophobic/lipophilic membrane of terpene is t-carophyllene or myrcene with trace amounts of liposomes in the inventive composition can comprise about C-pinene, C-terpineol, C-humulene and terpinolene. 26% phosphatidylcholine, about 10% phosphatidyletha 0021 (c) suspension in which the primary terpene is nolamine, about 13% phosphonophospholipids, and about limonene, the secondary terpenes are myrcene ort-carophyl 1% of other phospholipids. lene; and the tertiary terpenes are selected from the group 0027. In one aspect, the method for producing a lipo consisting of linalool, myrcene, B-pinene and t-carophyl Somal Suspension thus described is qualified in that one or lene, C.-bisabolol and myrcene. The Suspension may further more cannabinoids or cannabinoid analogues are dissolved comprise trace amounts of one or more terpenes selected in the ethanolic solution of one or more terpenes to obtain from C-humulene, C-pinene, B-pinene, fenchol, guaiene, terpene-cannabinoid liposomes. Preferably, the cannabi linalool, ocimene or C-terpineol. noids or cannabinoid analogs are selected from the group 0022 (d) suspension in which the primary terpene is consisting of cannabinol, cannabidiol, A-9-tetrahydrocan myrcene, the secondary terpene is selected from the group nabinol, A-8-tetrahydrocannabinol, 11-hydroxy-tetrahydro US 2016/0279.073 A1 Sep. 29, 2016 cannabinol, 11-hydroxy-A-9-tetrahydrocannabinol, levo formulations of a terpene/cannabinoid or a hemp oil-can nantradol, A11-tetrahydrocannabinol, nabinoid may further comprise the steps of: (e) adding tetrahydrocannabivarin, dronabinol, amandamide, nabilone, Sodium alginate to the liposomal Suspension in a final and a combination of two or more of these compounds. concentration of 2% to obtain analginate liposomal terpenef Preferably, the average diameter of the liposomes in the cannabinoid Suspension or an alginate liposomal hemp oil suspension is in a range between 50 nm and 1000 nm, and cannabinoid Suspension, (f) adding the alginate liposomal the final maximum concentration of cannabinoids or can terpene/cannabinoid or a hemp oil-cannabinoid Suspension nabinoid analogues in the formulation is from about 0.01 to a calcium chloride solution to obtain a calcium alginate g/liter to about 100 g/liter. encapsulated liposomal terpenef cannabinoid suspension or 0028. In yet another embodiment, the invention provides an alginate-encapsulated liposomal hemp oil-cannabinoid a method of producing a stable, highly concentrated lipo Suspension; (g) cold-pressing, air-drying, spray drying or Somal formulation of hemp oil that comprises the steps of freeze drying the calcium alginate-encapsulated liposomal (a) dissolving hemp oil in ethanol to obtain an ethanol hemp terpene/cannabinoid or hemp oil-cannabinoid Suspensions to oil solution; (b) adding a phospholipid to the ethanol hemp remove the water and obtain a dry terpenefcannabinoid or oil solution to obtain an ethanol-phospholipid hemp oil hemp oil-cannabinoid powder; and (h)re-Suspending the dry Solution; (c) injecting the ethanol-phospholipid hemp oil powder in citrate buffer to obtain an aqueous terpenef solution into distilled water to obtain a liposomal hemp oil cannabinoid or hemp oil-cannabinoid solution. Preferably, Suspension; and (d) removing the ethanol from the liposomal the amount of cannabinoid or cannabinoid analogue in the hemp oil suspension, thereby producing a stable liposomal aqueous terpenefcannabinoid solution or a hemp oil-can suspension of hemp oil. Preferably, the final maximum nabinoid solution is 10% w/w to 80% w/w. The amount of concentration of hemp oil in the liposomal Suspension is hemp oil in the hemp oil-cannabinoid solution is 10% w/w from about 0.01 g/L to about 200 g/L. to 80% w/w, the amount of terpene in the aqueous terpene 0029. In one aspect of the invention, the method further cannabinoid solution is 1% w/w to 10% w/w and the comprises dissolving one or more cannabinoids or cannabi phospholipid content can range from about 20% to about noid analogues in an ethanolic Solution of hemp oil to obtain 99%. an ethanolic hemp oil/cannabinoid solution. To obtain lipo 0032. In an alternative embodiment, the methods of pro Somes, a phospholipid is added to the ethanolic hemp ducing stable, highly concentrated, inventive liposomal for oil/cannabinoid solution followed by injection of the phos mulations of a terpenefcannabinoid or a hemp oil-cannabi pholipid-hemp oil-cannabinoid solution into distilled water noid may further comprise the steps of: (e) adding sodium to obtain a Suspension of hemp oil-cannabinoid liposomes. alginate to the liposomal terpene/cannabinoid or hemp oil Removal of ethanol from this suspension results in a stable cannabinoid suspension in a final concentration of 4% to concentrated Suspension containing hemp oil-cannabinoid obtain an alginate liposomal terpenefcannabinoid or hemp liposomes. Preferably, the cannabinoids or cannabinoidana oil-cannabinoid Suspension, (f) pouring the terpene/cannabi logs are selected from the group consisting of cannabinol, noid or hemp oil-cannabinoid liposomal Suspensions into cannabidiol, A-9-tetrahydrocannabinol, A-8-tetrahydrocan flat trays to a depth of 0.5 cm; (g) further desiccating the nabinol, 11-hydroxy-tetrahydrocannabinol, 11-hydroxy-A- suspensions at 50° C. for 24 hours to yield a 1 mm film; and 9-tetrahydrocannabinol, levonantradol, A-11-tetrahydrocan (h) dissolving the film in distilled water to obtain a terpene/ nabinol, tetrahydrocannabivarin, dronabinol, amandamide, cannabinoid aqueous Solution or a hemp oil-cannabinoid nabilone, a combination thereof, a natural or synthetic Suspension. Preferably, the amount of cannabinoid or can analogue thereof, and a natural or synthetic molecule with a nabinoid analogue in the aqueous terpenefcannabinoid solu basic cannabinoid structure. In a preferred aspect of the tion or a hemp oil-cannabinoid solution is from about 10% invention, the average liposome diameter size in the Sus w/w to about 80% w/w. The amount of hemp oil in the hemp pension is in a range between 50 and 1000 nm, and the final oil-cannabinoid solution is from about 10% w/w to about maximum concentration of cannabinoids or cannabinoid 80% w/w, the amount of terpene in the aqueous terpene analogues in the liposome suspension is from 0.01 g/liter to cannabinoid solution is from about 1% w/w to about 10% 100 g/liter. w/w and the phospholipid content can range from about 20% 0030. In another embodiment, the invention provides a to about 99%. method to produce a stable formulation of hemp oil and 0033. In yet another alternative embodiment, the methods cannabinoids that includes the steps of: (a) dissolving can of producing stable, highly concentrated liposomal formu nabinoid oil in ethanol to obtain an ethanol-cannabinoid lations of a terpenefcannabinoid or a hemp oil-cannabinoid Solution; (b) injecting the ethanol-cannabinoid solution in may further comprise the steps of: (e) adding L-leucine and distilled water to obtain an ethanol-cannabinoid emulsion; a Sugar selected from the group consisting of lactose and (d) adding a carbohydrate. Such as glycerol, to the ethanol Sucrose to the liposomal terpenefcannabinoid or hemp oil cannabinoid emulsion and blending this mixture to obtain cannabinoid Suspension to obtain a Sugar liposomal terpenef ethanol-cannabinoid-carbohydrate solution; (e) adding leci cannabinoid or hemp oil-cannabinoid Suspension, (f) spray thin with terpenes and hemp oil to the above mixture and drying the Sugar liposomal terpene? cannabinoid or hemp blending to obtain a stable cannabinoid-terpene-hemp oil oil-cannabinoid suspension at 55° C. to remove the water so formulation. The concentration range of cannabinoids or as to obtain a dry terpene/cannabinoid or hemp oil-cannabi cannabinoid analogues in the inventive formulation is from noid powder, (g) milling the dry terpenef cannabinoid or 0.01 g/liter to 100 g/liter. The final maximum concentration hemp oil-cannabinoid powder and re-suspending the dry of terpenes in the liposomal Suspension described above is powder in water to obtain an aqueous terpene/cannabinoid from about 0.001 gm/L to about 100 g/liter. Solution or an aqueous hemp oil-cannabinoid solution. The 0031. In an additional embodiment, the methods for amount of cannabinoid or cannabinoid analogue in the producing stable, highly concentrated, inventive liposomal aqueous terpenefcannabinoid solution is from about 10% US 2016/0279.073 A1 Sep. 29, 2016

w/w to about 80% w/w. The amount of terpene in the 0039. In one of its aspects, the inventive formulations are aqueous terpene-cannabinoid solution is from about 1% w/w in the form of liposomes that encapsulate one or more to about 10% w/w and the phospholipid content can range terpenes, a mixture of one or more terpenes and a cannabi from about 20% to about 99%. noid or a cannabinoid analog. The inventive formulations in 0034. In a different embodiment, the invention provides another embodiment comprise liposomes containing hemp an aqueous terpenefcannabinoid solution comprising a pri oil, or a mixture of hemp oil and a cannabinoid or a mary terpene, a secondary terpene and a tertiary terpene, and cannabinoid analog. Compositions of cannabinoids or an one or more cannabinoids or cannabinoid analogues. Pref analog of a cannabinoid also can be formulated as a micelle. erably the terpenes and cannabinoids or cannabinoid analogs Within the context of the present technology, the term in the solution are in an amount of 50 g/liter. In a preferred “micelle” refers to an aggregate of Surfactant molecules aspect of the invention, the solution is in the form of a dispersed in a liquid colloid, while “liposome' refers to a fast-acting pharmaceutical composition, a nutraceutical vesicle composed of a lipid monolayer or bilayer. Addition composition, or a food or beverage for administration to a ally, mixtures of one or more terpenes and a cannabinoid or Subject. Even more preferably, the pharmaceutical compo a mixture of one or more terpenes and a cannabinoid analog sition and the nutraceutical composition are fast-acting can be formulated as a micelle. The concentration of the formulations for oral, enteral, parenteral, intravenous, pull terpene in such a micelle is the range from about 0.001 g/L monary, mucosal. Sub-mucosal or topical administration. to about 5 g/L while the concentration of the cannabinoid or 0035. In another embodiment, the invention provides an the cannabinoid analog can range from about 0.01 g/L to aqueous Solution of hemp oil and a cannabinoid comprising about 5 g/L. hemp oil and one or more cannabinoids or cannabinoid 0040. Other drugs as well as pharmaceutically acceptable analogues. Preferably, the concentration of hemp oil and one carriers may also be present in the inventive formulations. or more cannabinoids or cannabinoid analogs in the Solution These additional components, if present in the inventive is about 50 g/liter. In a preferred aspect, the solution is in Suspension, can be associated with the lipophilic membrane form of a fast-acting pharmaceutical composition, a nutra of a liposome or can be entrapped in the aqueous fluid that ceutical composition, or a food or beverage for administra forms the core of the liposome. The entrapped terpenes, tion to a Subject. Even more preferably, the pharmaceutical mixtures of terpenes and cannabinoids, mixtures of terpenes composition and the nutraceutical composition are fast and a cannabinoid analog, hemp oil, mixture of hemp oil and acting formulations for oral, enteral, parenteral, intravenous, cannabinoids or mixture of hemp oil and cannabinoid ana pulmonary, mucosal, Sub-mucosal or topical administration. logs can contribute to the stability of the micelle/liposome 0036. Other advantages, and novel features will be read membranes, permitting the use of Such formulations as ily apparent to those skilled in the art from the following improved, fast-acting, reliable and efficient systems for the detailed description of the invention. oral, enteral, parenteral, intravenous or topical delivery of the above mentioned components. The term “subject” refers DETAILED DESCRIPTION OF THE to a mammal in need of treatment or undergoing treatment PREFERRED EMBODIMENTS using the inventive compositions or desirous of being 0037. The present invention provides stable, fast-acting administered the inventive compositions. Mammalian Sub formulations of terpenes, a mixture of terpenes and cannabi jects include without limitation humans, dogs, cats, horses noids or cannabinoid analogs, hemp oil, or a mixture of or any other animal in need of treatment. Thus, the inventive hemp oil and cannabinoids or cannabinoid analogs. The term compositions can be used for human and Veterinary pur “analog refers to a compound that is structurally related to poses. naturally occurring cannabinoids, but whose chemical and 0041. The inventive Suspensions comprising one or more biological properties may differ from naturally occurring terpenes, a mixture of a terpene and cannabinoid or can cannabinoids. In the present context, analog or analogs refer nabinoid analog, hemp oil, mixture of hemp oil and can to compounds that may not exhibit one or more unwanted nabinoid or mixture of hemp oil and cannabinoid analogs side effects of a naturally occurring cannabinoid. Analog can be manufactured as thermostable unilamellar micelles or also refers to a compound that is derived from a naturally liposomes. Such micelles or liposomes are stable at tem occurring cannabinoid by chemical, biological or a semi peratures greater than 50° C. and are obtained by rapidly synthetic transformation of the naturally occurring cannabi dissolving or injecting through a small orifice under pressure noid. a solution of any of the above mentioned components into 0038 According to one aspect, there are provided aque one of the above described aqueous solvents or an aqueous ous compositions comprising one or more terpenes, a mix Solution of a pharmaceutically active compound or drug. ture of terpenes and cannabinoids or a mixture of terpenes Alternatively, ultrasonic atomization can be used to form the and a cannabinoid analog. The inventive formulations also inventive formulations. encompass formulations of hemp oil, or a mixture of hemp 0042. In one of its aspects, the inventive micellar or oil and cannabinoids or cannabinoid analogs. Because ter liposomal compositions can further comprise a stabilizing penes, hemp oil and cannabinoids are hydrophobic in nature, agent. Illustrative of Such stabilizing agents include poly stable colloidal formulations can be obtained by contacting mers or compounds selected from the group consisting of a solution containing any one of the above mentioned cellulose hyaluronic acid, polyvinyl pyrrolidone (PVP), alg components with a solvent such as water, with or without inate, chondroitin Sulfate, poly gamma glutamic acid, gela pharmaceutically acceptable buffers. Other solvents suitable tin, chitisin, corn starch and flour. for forming colloids include C-C aliphatic alcohols or 0043. The size of micelles in a formulation containing a mixtures of water and C-C aliphatic alcohols, acetone, cannabinoid, a cannabinoid analog, or micelle formulations mixtures of water and acetone, or any water miscible organic containing a mixture of a terpene and a cannabinoid or solvent. cannabinoid analog, is from about 0.01 um to about 2.0 Lum. US 2016/0279.073 A1 Sep. 29, 2016

For certain embodiments, the size of the spherical micelles terpene in the inventive micelle formulation containing a is about 0.05um, about 0.1 um, about 0.15 um, 0.2 m, 0.25 mixture of terpene and cannabinoid or cannabinoid analog is um, 0.3 um, 0.35um, 0.4 um, 0.45um, 0.5 um, 0.55um, 0.6 about 0.002 g/L, about 0.003 g/L, about 0.004 g/L, about um, 0.7 Lim, 0.75 m, 0.8 um, 0.85 um, 0.9 um, about 0.95 0.005 g/L, about 0.006 g/L, about 0.007 g/L, about 0.008 um, about 1.0 Lum, 1.20 m, 1.40 um, 1.50 um, 1.60 um, 1.70 g/L, about 0.009 g/L, about 0.01 g/L, about 0.02 g/L, about um, 1.80 um, 1.90 um and 2.0 Lum. For certain embodiments, 0.03 g/L, about 0.04 g/L, about 0.05 g/L, about 0.06 g/L, micelles that are about 0.04 um, about 0.05 um, about 0.06 about 0.07 g/L, about 0.08 g/L, about 0.09 g/L, about 0.1 um, about 0.07 um, about 0.08 um, or about 0.09 um are g/L, 0.2 g/L, 0.3 g/L, or about 0.4 g/L. In some embodiments used to formulate the inventive compositions. the ratio of cannabinoid to terpene in the micelle formulation 0044 According to one aspect, the present invention is from about 5:1 to about 10:1. provides a micelle that comprises a terpene, a mixture of a 0048 Typical concentrations of a cannabinoid or a can terpene and a cannabinoid as well as a method for the nabinoid analog in a terpenef cannabinoid liposomal Suspen manufacture of Such a micelle formulation. According to the sion is from about 2 g/L to about 50 g/L, although, maximum inventive methodology, a stable aqueous micelle formula final concentration of cannabinoids or an analog of the tion of a terpene and a cannabinoid or a terpene and a cannabinoid in the liposomal formulation can be in the range cannabinoid analog can be obtained by dissolving the ter from about 0.01 g/L to about 100 g/L. The concentration of pene and the cannabinoids or a cannabinoid analog in terpene in Such a liposomal composition can range from ethanol to obtain an ethanolic solution containing a mixture about 0.001 g/L to about 100 g/L. Illustrative liposome of a terpene and a cannabinoid or a cannabinoid analog. This formulations containing a mixture of a terpene and a can ethanolic solution is then injected into distilled water to nabinoid or a cannabinoid analog can contain from about 0.1 obtain an aqueous-ethanolic Suspension of micelles. To g/L to about 90 g/L, from about 0.1 g/L to about 80 g/L, from obtain the desired final formulation, the aqueous-ethanolic about 0.1 g/L to about 70 g/L, from about 0.1 g/L to about Suspension of micelles is concentrated using rotary evapo 60 g/L, from about 0.1 g/L to about 50 g/L, from about 0.1 ration to remove the ethanol, to produce a stable aqueous g/L to about 40 g/L, from about 0.1 g/L to about 30 g/L, from micelle formulation. The inventive micelle formulations do about 0.1 g/L to about 20 g/L, or from about 0.1 g/L to about not contain phospholipids or cholesterol and shows no 10 g/L, of a cannabinoid or a cannabinoid analog. aqueous core when observed under oil immersion micros 0049. Depending on the amount of cannabinoid or can copy. nabinoid analog present in the liposome formulation, the 0045 Any natural or synthetic cannabinoid can be used amount of terpene in such a formulation can be from about to manufacture the above described micelles. Illustrative of 0.001 g/L (0.001 mg/mL) to 100 g/L (100 mg/mL). For Such compounds include without limitation cannabinoids or certain formulations, the amount of terpene is from about 10 cannabinoid analogues selected from the group consisting of g/L to about 70 g/L. Illustrative of liposome formulations cannabinol, cannabidiol. A9-tetrahydrocannabinol, A8-tetra comprising a mixture of a terpene and a cannabinoid or an hydrocannabinol, 11-hydroxy-tetrahydrocannabinol, 11-hy analog of a cannabinoid are compositions in which the droxy-A9-tetrahydrocannabinol, levonantradol, A11-tetra concentration of terpene is from about 10 g/L to about 60 hydrocannabinol, tetrahydrocannabivarin, dronabinol, g/L, from about 10 g/L to about 50 g/L, from about 10 g/L amandamide, nabilone, and a combination of two or more of to about 40 g/L, from about 10 g/L to about 30 g/L, from these compounds. about 10 g/L to about 20 g/L. 0046. The maximum final concentration of a cannabinoid 0050. The maximum concentration of terpenes and can or a cannabinoid analog in the micelle is in the range from nabinoids in the liposomes according to the present inven about 0.1 g/L (0.1 mg/mL) to about 5 g/L (5 mg/mL). For tion is about 100 g/L. Thus, the inventive liposome formu certain embodiments, the concentration of a cannabinoid or lation can have a cannabinoid:terpene ratio of 0.1 g/L: 99.9 a cannabinoid analog in the micelle of the inventive formu g/L, 1 g/L.99 g/L, 5 g/L.95 g/L, 15 g/L:85 g/L, 25 g/L:75 lation is from about 1 g/L to about 4 g/L, from about 1 g/L g/L, 35 g/L:65g/L, 45 g/L:55g/L, 50 g/L:50 g/L, 55 g/L:45 to about 3 g/L, from about 1 g/L to about 2 g/L, or from g/L, 65 g/L:35g/L, 75 g/L:25g/L, 85 g/L:15g/L, or 95 g/L:5 about 1 g/L to about 1.5 g/L. The concentration of a g/L. The size of the unilamellar spherical liposomes in the cannabinoid or a cannabinoid analog in the inventive micelle inventive composition described above are from about 0.1 formulation can be about 0.2 g/L, about 0.3 g/L, about 0.4 um to about 2.0 um, for example, about 0.2 um, 0.3 um, 0.4 g/L, about 0.5 g/L, about 0.6 g/L, about 0.7 g/L, about 0.8 um, 0.5um, 0.6 um, 0.7 um, 0.8 um, 0.9 um, 1.0 Lim, 1.1 um, g/L, about 0.9 g/L, about 1.0 g/L, about 1.1 g/L, about 1.2 1.2 Lum, 1.3 um, 1.4 um, 1.5um, 1.6 um, 1.7 um, 1.8 um, or g/L, about 1.3 g/L, about 1.4 g/L, about 1.5 g/L, about 1.6 1.9 Lum. g/L, about 1.7 g/L, about 1.8 g/L, about 1.9 g/L, or about 2.0 0051. Formulations pursuant to the present invention are g/L. particularly Suitable for oral, enteral, parenteral, intrave 0047. When the micelle contains a mixture of a terpene nous, pulmonary, mucosal, Sub-mucosal or topical admin and a cannabinoid or a cannabinoid analog the concentration istration. The inventive formulations may be administered to of the terpene is from about 0.001 g/L to about 0.5 g/L. Subjects in need of treatment related to pain, allergies, Illustrative of micelle formulations comprising a mixture of inflammation, infection, epilepsy, depression, migraine, a terpene and a cannabinoid or an analog of a cannabinoid bipolar disorders, anxiety disorder, and drug dependency are compositions in which the concentration of terpene is and withdrawal syndromes (Crowell and Gould, 1994, Crit from about 0.001 g/L to about 0.4 g/L, from about 0.001 g/L Rev. Oncog. 5(1):1-2: Cridge and Rosengren, 2013, Cancer to about 0.3 g/L, from about 0.001 g/L to about 0.2 g/L, from Manag Res. 5:301-13; Salminen et al., 2008, Cellular and about 0.001 g/L to about 0.1 g/L. For certain formulations, Molecular Life Sciences 65, pp. 2979-2999; Nóbrega de the concentration of the terepene can range from about 0.1 Almeida et al., 2001, Molecules 16, 2726-2742: Smith, g/L to about 0.5 g/L. For instance, the concentration of 2005, Curr Opin Investig Drugs 6(7): 680-5: Grotenhermen, US 2016/0279.073 A1 Sep. 29, 2016

2004, Neuroendocrinology Letters Nos. 1/2, February–April extracting cannabinoids, and alcohol-water mixtures, for Vol. 25; Jin et al., 2011, Archives of Pharmacal Research 34, instance water-ethanol or water-butanol mixtures. pp 223-228; Cabral, 2001, Journal of Cannabis Therapeutics 0055. In addition to natural cannabinoids, the present 1, pp 61-85; Blaas, 2008, Cannabinoids 3(2):8-10; Ashton et technology encompasses synthetic cannabinoid compounds al., 2005, J Psycopharmacol. 19(3):293-300; Scavone et al., as well as cannabinoids that can be obtained using semi 2013, Neuroscience 248:637-54). synthetic protocols. The manufacture of cannabinoid com 0052 Any terpene may be used in the formulations of the pounds or an analog of a cannabinoid using a semi-synthetic invention. Preferred terpenes include, but are not limited to, protocol involves contacting an appropriate Substrate with C-pinene, myrcene, B-pinene, t-carophylene, 3-pinene, one of the cannabinoid synthase enzymes. For instance, C.-bisabolol, C.-humulene, guaiene, limonene, ocimene, ter tetrahydrocannabinolic acid (THCA) or its analogs can be pinolene, 3-carene, guaiol, C-terpineol, linalool, fenchol. manufactured semi-synthetically by contacting cannab Preferably, the formulations comprise a primary terpene, a igerolic acid (CBGA) or an appropriately substituted deriva secondary terpene, and a tertiary terpene, and may comprise tive of CBGA with THC synthase to obtain the correspond trace amounts of additional terpenes. According to one ing THCA or THCA analog respectively. embodiment, the amount of the primary terpene in the 0056 Pursuant to the semi-synthetic strategy, a Formula formulations is 50% (w/w), the amount of the secondary I compound can be brought in contact with a cannabinoid terpene is up to 40% (w/w) and the amount of the tertiary synthase, for example, cannabidiolic acid synthase, a tetra pinene is up to 10% (w/w) of the formulation. The terpenes hydrocannabinoilic acid synthase or a cannabichromene may be isolated from any plant, including the Cannabis acid synthase to promote the enzyme catalyzed conversion sativa plant. Many of the formulations according to the of the Formula I compound to a cannabinoid or cannabinoid present invention can comprise hemp oil. analog. 0053 For inventive formulations comprising a cannabi noid and terpenes, the cannabinoid is selected from the group consisting of cannabinol, cannabidiol. A9-tetrahydro Formula I cannabinol, A8-tetrahydrocannabinol, 11-hydroxy-tetrahy drocannabinol, 11-hydroxy-A9-tetrahydrocannabinol, levo nantradol, A-11-tetrahydrocannabinol, tetrahydrocannabivarin, dronabinol, amandamide, and nabilone. Moreover, any combination of two or more of the above mentioned cannabinoids can be present in the inven tive formulations. The inventive formulations can also con tain cannabimimetic agents. The phrase “cannabimimetic agent” refers to any Substance that is a cannabinoid receptor agonist as demonstrated by binding studies and functional 0057 The structure and biochemical properties of prod assays. For instance, a cannabimimetic agent can be a ucts obtained via Such a synthetic strategy will depend on (a) compound having: (i) 2-(3-hydroxycyclohexyl)phenol core the cannabinoid synthase used and (b) the chemical identi that can be further substituted at the 5-position of the ties of Substituent groups R. R. R. and R in the Formula I phenolic ring by alkyl or alkenyl group; (ii) 3-(1-naphthoyl) compound used. indole or 3-(1-naphthylmethane)indole core further substi 0.058 Thus for Formula I compounds, R can be selected tuted at the nitrogen atom of the indole ring, whether or not from —OH, halogen, —SH, or a NRR group. Substituents Substituted on the naphthoyl or naphthyl ring to any extent; R and R are each independently selected from the group (iii) 3-(1-naphthoyl)pyrrole core further substituted at the consisting of H. —C(O)R —OR, an optionally Substituted nitrogen atom of the pyrrole ring, whether or not substituted C-C linear or branched alkylene, an optionally substituted on the naphthoyl ring to any extent; (iv) 1-(1-naphthylm C-Co linear or branched alkenylene, an optionally Substi ethylene)indene core further substituted at the 3-position of tuted C-Co linear or branched alkynylene, an optionally the indene ring, whether or not substituted on the naphthyl Substituted C-C aryl, an optionally Substituted C-Co ring to any extent; and (V) 3-phenylacetylindole or 3-ben cycloalkyl, (C-Co)aryl-(C-Co.)alkylene, (C-Co)aryl Zoylindole core further substituted at the nitrogen atom of (C-C)alkenylene, and (C-C)aryl-(C-C)alkynylene. the indole ring, whether or not substituted on the phenyl ring 0059 For certain Formula I compounds, R and R to any extent. together with the carbon atoms to which they are bonded 0054 Naturally occurring cannabinoids are compounds form a Cs-Co cyclic ring. In one aspect, the Cs-Co cyclic obtained from plant tissue, for example, the trichomes of the ring comprises one or more heteroatoms selected from Cannabis sativa plant. The cannabinoids can be extracted oxygen, sulfur or nitrogen. R. in Formula I can be selected from plant tissue by Suspending the latter in an appropriate from the group consisting of H. —C(O)R and C-Co linear solvent to obtain a crude extract followed by analytical or or branched alkyl, with groups R and R, each indepen preparative purification of Such an extract to provide phar dently being H. —OH, -SH, -NH. (C-C) linear or maceutical grade cannabinoid compounds. Alternatively, branched alkyl, or a C-Co cycloalkyl. cannabinoid compounds will be extracted from plant tissue 0060. The inventive compositions have unexpected under supercritical conditions. Solvents that can be used for advantageous properties. For instance, liposomal composi Supercritical extraction of cannabinoids include without tions according to the present invention are stable at high limitation carbon dioxide or other gases in isolation or temperatures exceeding 50° C. and also are stable to soni combination with or without solvent modifiers, selected cation. Further, the liposomal compositions according to the from ethanol, propanol, butanol, hexane, chloroform, present invention are capable of carrying large payloads of dichloromethane, acetone, or any organic solvent capable of terpenes, hemp oil, mixtures ofterpenes and cannabinoids or US 2016/0279.073 A1 Sep. 29, 2016

mixtures of hemp oil and cannabinoids. The payload of the When formulated as a suspension, the inventive formula inventive liposome formulations can range from about 0.01 tions may contain Suspending agents, for example, ethoxy g/L to about 100 g/L. Exemplary liposome formulations can lated isostearyl alcohols, polyoxyethylene sorbitol, sorbitan have payloads in the range from about 0.01 g/L to about 0.1 esters, microcrystalline cellulose, aluminum metahydroxide, g/L, from about 0.01 g/L to about 0.5 g/L, from about 0.01 bentonite, agar-agar, tragacanth, and mixtures thereof. g/L to about 1 g/L, from about 0.01 g/L to about 5g/L, from According to one embodiment, micelles containing a mix about 0.01 g/L to about 10 g/L, from about 0.01 g/L to about ture of terpene and cannabinoids or a liposome formulation 20 g/L, from about 0.01 g/L to about 30 g/L, from about 0.01 containing a terpene, a hemp oil, a mixture of a cannabinoid g/L to about 40 g/L, from about 0.01 g/L to about 50 g/L, and a terpene, or a mixture of hemp oil and a terpene can be from about 0.01 g/L to about 60 g/L, from about 0.01 g/L to formulated as a nutraceutical composition, such as a bever about 70 g/L, from about 0.01 g/L to about 80 g/L, or from age, drink, or soup that is suitable for oral administration. about 0.01 g/L to about 90 g/L. In addition to the above 0064. The inventive liposomes can be encapsulated by a mentioned components, the inventive micelle or liposomal calcium alginate matrix. A therapeutically effective amount formulations can include other drug(s) suitable for use in of Such an encapsulated liposome formulation of a terpene, combination therapy. The inventive compositions also can hemp oil, mixture of a cannabinoid and a terpene, or a be stored for extended periods of time, for example, greater mixture of hemp oil and a cannabinoid can be combined than 20 weeks at 25°C. and are believed to exhibit superior with food or baked goods to obtain a solid nutraceutical systemic delivery and biorelease of their payloads. composition. Other pharmaceutically acceptable Solid dos 0061. As stated above, compositions of the invention can age forms include without limitation capsules, tablets, pills, be administered independently or in combination with other powders, and granules of the inventive calcium alginate therapeutic agents. When used in combination therapy, the encompassed liposome formulations of terpene, hemp oil, inventive compositions can be administered simultaneously mixture of cannabinoid and terpene, or a mixture of hemp oil with another drug using a single or a separate dosage form and a cannabinoid. or the inventive composition is administered as a separate 0065. Pharmaceutically acceptable excipients or a carrier dosage form within hours or days of the administration of Such as Sodium citrate or dicalcium phosphate and/or fillers the other therapeutic agent. Examples of compounds/drugs or extenders. Such as starches, lactose, Sucrose, glucose, used in Such combination therapies include without limita mannitol, and silicic acid can also be present in the Solid tion, chemotherapeutic agents, immunosuppressive agents, composition. Binders such as carboxymethylcellulose, alg immunostimulatory, antipyretic, cytokines, opioids, cytok inates, gelatin, polyvinylpyrrolidone, Sucrose, and acacia; ines, cytotoxic agents, nucleolytic compounds, radioactive humectants such as glycerol and disintegrating agents such isotopes, receptors, pro-drug activating enzymes, which may as agar-agar, calcium carbonate, potato or tapioca starch, be naturally occurring or produced by recombinant methods, alginic acid, certain silicates, and sodium carbonate may be anti-inflammatory agents, antibiotics, protease inhibitors, present. Solid dosage forms of the calcium alginate encom growth factors, osteo-inductive factors and the like. passed liposome formulation of a terpene, hemp oil, mixture 0062. The inventive formulations can optionally com of cannabinoid and terpene, or a mixture of hemp oil and prise one or more pharmaceutically acceptable excipients, cannabinoid may further contain Solution retarding agents diluents, adjuvants, stabilizers, emulsifiers, preservatives, Such as paraffin; absorption accelerators such as quaternary colorants, buffers, and/or flavor imparting agents, and may ammonium compounds; wetting agents such as acetyl alco be consumed directly or formulated into a nutraceutical or a hol and glycerol monostearate; absorbents such as kaolin pharmaceutically acceptable composition Suitable for oral, and bentonite clay; and lubricants such as talc, calcium enteral, parenteral, intravenous or topical administration. Stearate, magnesium Stearate, Solid polyethylene glycols, The inventive formulations can be formulated as a single or Sodium lauryl Sulfate, or mixtures thereof. For capsules, a multiple dosage form that is Suitable for oral administra tablets and pills, the dosage form can also comprise buffer tion. Liquid dosage forms can include, but are not limited to, ing agents. pharmaceutically acceptable micelles, liposomes, emul 0066. The inventive liposome formulations can be encap sions, Solutions, Suspensions, syrups and elixirs. The liquid Sulated with a variety of polymers, Sugars, and chelating dosage forms may contain inert diluents commonly used in agents to yield a stable solid liposomal cannabinoid prepa the art. For instance, liquid formulations may contain water, ration. Encapsulation of the liposomes can take place by alcohol, polyethylene glycol ethers, glycerol, flavorings, cross linking of polymers used as the encapsulating agent. preservatives, essential oils, vitamins or any other pharma Alternatively, the liposomes can be trapped within a non ceutically acceptable diluents and/or solvents. Agents used crosslinked polymer network, or by dispersing the liposome to stabilize emulsions are well known in the pharmaceutical within the crystalline structure of macromolecules such as art and Such agents can be added to formulations in accor Sugars, starches or protein molecules. The granules of pro dance with the present invention. tein, polymer, Sugar or starch encapsulated liposomes can be 0063 For certain formulations an emulsifier such as ethyl further processed to yield Sublingual films, Suppositories, alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, dispersable powder, tablets, or gel capsules. benzyl alcohol, benzyl benzoate, propylene glycol, 1.3- 0067 Solid dosage forms described above may further be butylene glycol, dimethyl formamide, oils (in particular, coated using compounds that accelerate or decrease the cottonseed, groundnut, corn, germ, olive, castor, and sesame release of the active agents. For instance, the invention oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene gly encompasses solid dosage forms having enteric coatings, cols and fatty acid esters of sorbitan, and mixtures thereof extended-release coatings, Sustained-release coatings, may optionally be present. Additionally, oral compositions delayed release coatings and immediate-release coatings. can include adjuvants such as wetting agents, Suspending Methods used to coat solid dosage forms as well as the agents, Sweetening, flavoring, and odor imparting agents. materials used to manufacture such coatings are well known US 2016/0279.073 A1 Sep. 29, 2016 in the pharmaceutical art. The Solid dosage forms may solubilizers, skin permeation enhancers, preservatives (e.g., optionally contain opacity enhancing agents. anti-oxidants), moisturizers, gelling agents, buffering 0068 A dietary composition according to the present agents, Surfactants, emulsifiers, emollients, thickening invention is any ingestible preparation that contains the agents, stabilizers, humectants, dispersing agents and phar suspensions of the invention mixed with a food product. The maceutical carriers. Examples of moisturizers include jojoba food product can be dried, cooked, boiled, lyophilized or oil and evening primrose oil. Suitable skin permeation baked. Breads, teas, Soups, cereals, salads, sandwiches, enhancers are well known in the art and include lower sprouts, vegetables, animal feed, pills and tablets are among alkanols, such as methanol, ethanol and 2-propanol; alkyl the vast number of different food products contemplated in methyl sulfoxides such as dimethylsulfoxide (DMSO), the present invention. decylmethylsulfoxide (C10 MSO) and tetradecylmethyl sul 0069. The inventive micelles or liposomes can be formu foxide:pyrrollidones, urea; N,N-diethyl-m-toluamide: C-C, lated as Subcutaneous injections, intravenous injections, alkanediols; dimethyl formamide (DMF), N,N-dimethylac intramuscular injections, intrasternal injections or infusions etamide (DMA) and tetrahydrofurfuryl alcohol. Examples of for parenteral delivery. Excipients used in the manufacture solubilizers include, but are not limited to, hydrophilic of parenteral formulations are well known in the art and are ethers such as diethylene glycol monoethyl ether (ethoxy non-toxic compounds that do not degrade the active agent or diglycol, available commercially as TranscutolR) and dieth other components of the formulations. Compositions for ylene glycol monoethyl ether oleate (available commercially parenteral injection comprise pharmaceutically acceptable as SoftcutolR); polyoxy 35 castor oil, polyoxy 40 hydroge sterile aqueous or non-aqueous solutions, dispersions, Sus nated castor oil, polyethylene glycol (PEG), particularly low pensions or emulsions as well as sterile powders for recon molecular weight PEGs, such as PEG 300 and PEG 400, and stitution into sterile injectable solutions or dispersions prior polyethylene glycol derivatives such as PEG-8 caprylic/ to use. Examples of Suitable aqueous and non-aqueous capric glycerides (available commercially as Labrasol (R): carriers, diluents, solvents or vehicles will include without alkyl methyl sulfoxides, such as DMSO; pyrrolidones, limitation, water, ethanol, polyols (such as glycerol, propyl DMA, and mixtures thereof. ene glycol, polyethylene glycol, and the like), carboxym 0072. One of ordinary skill will appreciate that effective ethylcellulose and suitable mixtures thereof, vegetable oils amounts of one or more terpenes, hemp oil, or mixtures of (such as olive oil), and injectable organic esters such as ethyl terpene and cannabinoid as well as mixtures of hemp oil and oleate. Proper fluidity will be maintained, for example, by cannabinoid in the compositions can be determined using the use of coating materials such as lecithin, by the main assays and methodologies known in the art. It is also to be tenance of the required particle size in the case of disper understood that, when administered to a human patient, the sions, and by the use of Surfactants. The compositions of the total daily usage of the composition of the present invention present invention may also contain adjuvants such as, but will be decided by the attending physician within the scope not limited to, preservatives, wetting agents, emulsifying of Sound medical judgment. The specific therapeutically agents, and dispersing agents. Compositions for parenteral effective dose level for any particular patient will depend delivery also can include isotonic agents such as Sugars, upon a variety of factors, such as the type and degree of the sodium chloride, and the like. Prolonged absorption of the response to be achieved; the activity of the specific compo injectable pharmaceutical formulation can be obtained by sition employed; the age, body weight, general health, sex the inclusion of agents which delay absorption Such as and diet of the patient; the duration of the treatment; drugs aluminum monostearate and gelatin. used in combination or coincidental with the method of the 0070 Injectable depot forms can be made by microen invention; and like factors well known in the medical arts. capsulating the micelle or liposome in a biodegradable 0073. The compositions of the invention ca be adminis polymer Such as polylactide-polyglycolide or a polymer of tered by a variety of other routes, including mucosal, nasal alginic acid. Depending upon the ratio of liposome to and using transdermal patches. The present invention thus polymer or micelle to polymer and the biochemical nature of generally described, will be understood more readily by the polymer employed, the rate of release of a terpene, hemp reference to the following examples, which are provided by oil, mixture of cannabinoid and terpene, or a mixture of way of illustration only, and are not intended to be limiting hemp oil and cannabinoid from the encapsulated micelle or the present invention. liposome can be controlled. Examples of other biodegrad able polymers include poly(orthoesters) and poly(anhy EXAMPLES drides). The injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter, or A. General Protocol for the Manufacture of by incorporating sterilizing agents in the form of sterile Solid Emulsions compositions which can be dissolved or dispersed in sterile 0074 The manufacture of an emulsion composition com water or other sterile injectable medium just prior to use. prising a cannabinoid, or a mixture of cannabinoids, hemp 0071 Dosage forms for topical administration include, oil and one or more terpenes, is prepared by adding an but are not limited to, ointments, creams, lotions, gels and amphipathic molecule such as a phospholipid, including Sunscreens comprising a micelle of a terpene and cannabi lecithin, Sterols, fatty acids to an ethanolic Solution, as noid or a liposome containing a terpene, hemp oil, mixture discussed herein. The ethanolic cannabinoid solution is of cannabinoid and terpene, or a mixture of hemp oil and rapidly injected into distilled water using a Luer Lok Syringe cannabinoid. Such topical formulations can contain agents or ultrasonic atomizer nozzle. The Suspension obtained is that promote penetration of the inventive micelles or lipo then blended with glycerol. A solution of hemp oil, terpenes Somes through the epidermis. Various other additives known and a phospholipid are blended into the cannabinoid/etha in the art may be included in the topical formulations. nol/water/glycerol solution. This gives a homogenous can Examples of such additives include, but are not limited to, nabinoid terpene Supplement emulsion. The physical prop US 2016/0279.073 A1 Sep. 29, 2016

erties such as size, composition and concentration of prepared as described above. A Suitable cross linking agent reagents with the emulsion can be controlled by the chemi can then be added to the polymer-liposome reaction mixture cal properties of the terpenes, hemp oil and cannabiniods to initiate cross-linking. After cross-linking the polymer or and by the physical properties of the ethanol/acqueous/ encapsulating matrix, the reaction will be dehydrated by glycerol environment used to manufacture the inventive rotary evaporation, freeze drying, or spray drying to obtain cannabinoid/terpene emulsion Supplement. the encapsulated liposome compositions. The dehydrated encapsulated compositions can be milled to obtain a powder B. General Protocol for the Manufacture of having a desired average particle size. Micelles 007.9 The present invention uses micelles of a terpene 0075. A micelle composition comprising a cannabinoid, and a cannabinoid or liposomes as vehicles for the delivery or a mixture of a cannabinoid or its analog and a terpene is of formulations containing a terpene, hemp oil, cannabinoid prepared by dissolving these components in a water miscible or a cannabinoid analog, a mixture of terpenes and a organic solvent followed by the rapid injection of the cannabinoids or a cannabinoid analog, or a mixture of hemp organic Solution into distilled water using a Luer Lock oil and a cannabinoid or a cannabinoid analog to a subject Syringe equipped with a 22 gauge needle or an ultrasonic in need thereof. The micelles and liposomes of the invention atomizer nozzle. The Suspension thus obtained can be con are dispersed in a pharmaceutically acceptable solvent that centrated by rotary evaporation to form micro or nano is suitable for a specific route of delivery to a subject in need micellar particles containing cannabinoids or a mixture of a of treatment. cannabinoid or its analog and a terpene. The size, compo sition and concentration of the micelles are controlled by the I. Emulsion Formulation chemical properties of the terpenes and cannabinoids, and by the physical properties of the aqueous-organic solvent 0080. The formulations of the present invention may used to manufacture the inventive formulations. comprise hemp oil, cannabinoids and terpenes or any mix ture thereof. This emulsion is prepared by first dissolving C. General Protocol for the Manufacture of cannabinoids into ethanol. Using a 60 mL sterile Syringe Liposomes with a 16 gauge needle, 33 ml of the cannabinoid-ethanol solution is injected into 90 mL sterile distilled water, con 0076. The inventive liposome formulations are manufac tained in a 500 ml Sterile Media bottle. The mixture is tured by adding an amphipathic molecule such as a phos blended using a Polytron Blender on Low Speed for 30 pholipid, including lecithin, Sterols, or fatty acids, to an seconds. Using a syringe, 90 mL of glycerin is injected into organic Solution of a terpene, hemp oil, cannabinoid or a the solution. The mixture is blended once more using the cannabinoid analog, a mixture of a cannabinoid or a can Polytron Blender on Low Speed for 30 seconds. 3.3 g nabinoid analog and a terpene, or a mixture of a cannabinoid lecithin is blended into 90 ml hemp oil at room temperature. or a cannabinoid analog and hemp oil. This solution is To this solution 7.5 ml of a terpene formulation is added. The rapidly injected into distilled water using (a) a Luer Lock mixture is homogenized using the Polytron Blender on Low Syringe equipped with a 22 gauge needle or (b) an ultrasonic Speed for 30 sec. The lecithin-hemp oil-terpene solution is atomizer nozzle, and the Suspension thus obtained is con centrated by rotary evaporation to obtain liposomes contain added to the cannabinoid-EtOH-Water-glycerol mixture. It ing a terpene, hemp oil, cannabinoid or a cannabinoid is homogenized using a Polytron Blender on Low Speed for analog, a mixture of a cannabinoid or a cannabinoid analog 30 seconds to create an homogenous emulsion. and a terpene, or a mixture of a cannabinoid or a cannabinoid analog and hemp oil. The physical properties such as size, II. Terpene Formulations composition and concentration of reagents within the lipo some can be controlled by the chemical properties of the I0081. The formulations of the present invention may terpenes, hemp oil and cannabinoids, and by the physical contain one or more terpenes. In certain embodiments, the properties of the organic solvent/aqueous environment used formulations contain a mixture of terpenes. This mixture to manufacture the inventive liposome formulation. contains a primary terpene in an amount of up to 50%, a 0077. In an exemplary composition, the hydrophobic/ secondary terpene in an amount from about 30% to about lipophilic membrane of the liposome can comprise about 40%, and a tertiary terpene in an amount from about 8% to 40% phosphatidylcholine, about 3.5% phosphatidyletha about 10%. The formulation also may optionally contain nolamine, about 6% phosphonophospholipids, and about trace amounts (0-5%) of other terpenes. The category of 0.5% of other phospholipids. According to another exem “terpene formulations' includes eight groups and several plary composition the hydrophobic/lipophilic membrane of subgroups as further described below: liposomes in the inventive composition can comprise about 26% phosphatidylcholine, about 10% phosphatidyletha Group I: Primary Terpene is C.-Pinene nolamine, about 13% phosphonophospholipids, and about 1% of other phospholipids. Subgroup A D. General Protocol for Encapsulation of Liposomes Secondary: Myrcene 0078. The present invention also provides a method for I0082 Tertiary: B-Pinene and t-caryophyllene encapsulating the inventive liposome Suspension. Pursuant to this method, a polymer or encapsulating matrix is added Trace: C.-Humulene, C-Bisabolol, Guaiene, Limonene, at a desired concentration to the liposome composition Ocimene, Terpinolene, 3-Carene US 2016/0279.073 A1 Sep. 29, 2016

Subgroup B Trace: C-Pinene, Guaiene, Linalool, Ocimene 0083 Secondary: B-pinene, Group VII. Primary Terpene is Myrcene Tertiary: t-Caryophyllene, B-Bisabolol, Trace: myercene, Guaiol, C-Terpineol, Limonene, Linalool Subgroup A Secondary: O-Pinene Subgroup C 0092. Tertiary: B-pinene and t-Caryophylene 0084 Secondary: t-Caryophyllene, Tertiary: myrcene, B-pinene Trace: 3-Carene, C-Bisabolol, Guaiene, Guaiol, Limonene, Linalool, Ocimene, Terpinolene Trace: C-Bisabolol, Guaiol, Limonene Subgroup B Group II. Primary Terpene is C.-Bisabolol (0093. Secondary: t-Caryophyllene I0085. Secondary: t-Caryophyllene Tertiary: Limonene, C.-Pinene Tertiary: C.-Pinene and Myrcene Trace: C.-Humulene, C-Bisabolol, B-Pinene, Guaiene, Guaiol, Limonene, Linalool, Ocimene, 0086 Trace: Guaiol, Linalool, C.-Humulene, alpha-terpi neol Terpinolene Subgroup C Group III. Primary Terpene is f-Pinene Secondary: Terpinolene 0087 Secondary: C-pinene Tertiary: t-Caryophyllene and Terpinolene 0094 Tertiary: t-Caryophyllene and Ocimene Trace: Myrcene Trace: O-Pinene, B-Pinene, Guaiol, Limonene Subgroup D Secondary: Ocimene Group IV. Primary Terpene is Guaiene (0095 Tertiary: t-Caryophyllene and C-Pinene 0088 Secondary: t-Caryophyllene Trace: O-Pinene, B-Pinene, Limonene, Terpinolene Tertiary: Myrcene and C.-Humulene Subgroup E Trace: C.-Pinene, C-Bisabolol, B-Pinene, Limonene, Secondary: Limonene Ocimene, Terpinolene (0096. Tertiary: t-Caryophyllene Group V. Primary Terpene is Guaiol Trace: O-Pinene, B-Pinene, Linalool, Ocimene Secondary: C-Bisabolol Subgroup F I0089. Tertiary: t-Caryophyllen and Myrcene Secondary: Linalool (0097. Tertiary: t-Caryophyllene Trace: O-Pinene, C-Terpineol, C.-Humulene, Terpinolene Trace: C-Terpineol, B-Pinene, Limonene Group VI. Primary Terpene is Limonene Group VIII. Primary Terpene is Ocimene Subgroup A 0098 Secondary: t-Caryophyllene 0090 Secondary: t-Caryophyllene Tertiary: Myrcene and Limonene Tertiary: Linalool, Myrcene Trace: 3-Carene, C.-Pinene, B-Pinene, Terpinolene Trace: C.-Humulene, C.-Pinene, C.-Terpineol, B-Pinene, III. Micelle Terpene/Cannabinoid Formulations Fenchol, Guaiene Example 1 Subgroup B Micelle Suspension of Terpenes and Cannabinoids without Stabilizer Secondary: Myrcene 0099 Micelle formulations in accordance with the pres 0091 Tertiary: B-pinene and t-Caryophyllene ent invention containing terpenes and cannabinoids in US 2016/0279.073 A1 Sep. 29, 2016

amounts described above can be prepared by dissolving 0103) The final maximum concentration of terpene in the 750-1500 mg of terpenes and a cannabinoid extract contain liposomes obtained using the above described method was ing THC, CBC, CBD or mixtures of these cannabinoids or 70 g/L and the aqueous liposomal Suspension was stable for one or more analogs of a naturally occurring cannabinoid or more than 3 months at 25° C. Moreover, the average a Formula I cannabinoid in 95% ethanol and the volume of diameter of the liposomes was in the range from about 200 this solution is brought to 20 ml using 95% EtOH. The nm about 400 nm. Oil immersion microscopic analysis ethanolic Solution containing terpenes and cannabinoids is showed the liposomes to have an aqueous core. cooled to 10° C. prior to injecting this solution into 195 ml of distilled water (25°C.), at a pressure of 50 psi and a flow Example 4 rate of 10 mL/min using a 50 mL. Luer Lock syringe equipped with a 22 gauge needle. The resultant solution is Liposomal Suspensions of Terpenes and rotary evaporated under a reduced pressure to remove etha Cannabinoids nol and provide an aqueous micelle composition containing 0104 Liposome formulations in accordance with the a mixture of terpenes and cannabinoids. present invention containing terpenes and cannabinoids in amounts described above can be prepared by dissolving 15 Example 2 g of terpenes and an extract comprising one or more can nabinoids (e.g., THC, CBC, CBD, their mixtures or analogs) Micelle Suspension of Terpenes and Cannabinoids in 95% ethanol and the final volume of this solution is with Stabilizer brought to 30 ml using 95% EtOH. To the solution of terpene 0100. The protocol for the manufacture of a stabilized and cannabinoids is added an ethanolic Solution of lecithin micelle Suspension containing a mixture of terpenes and 50 (30 ml) that is separately prepared by dissolving 15 grams cannabinoids in amounts described above is similar to the of lecithin-50 into 95% EtOH (30 ml). After cooling to 10° one described above. Briefly, 750-1500 mg of one or more C. the ethanolic Solution containing a mixture of lipid, terpenes and a cannabinoid extract are dissolved in 95% terpene and cannabinoid is injected into 540 ml of distilled ethanol. The final volume of this solution is brought to 20 ml water (25°C.), at a pressure of 50 psi and a flow rate of 10 with 95% EtOH. After cooling to 10° C. the ethanolic mL/min using a 100 mL. Luer Lock syringe equipped with solution is injected at a pressure of 50 psi and a flow rate of a 22 gauge needle to obtain an aqueous ethanolic liposome 10 ml/min into 195 ml of distilled water (25°C.), using a 50 formulation containing terpene and cannabinoid. mL Luer Lock syringe equipped with a 22 gauge needle. The 0105 Liposomes containing a mixture of a terpene and a resultant solution is concentrated using a rotary evaporator cannabinoid also can be prepared by injecting an ethanolic to remove ethanol and 0.2g, (0.1% w/v) guar gum is added solution (30°C.) containing the mixture of lipid, terpene and in 10 mg portions (0.2 g), to the concentrated solution to cannabinoid into distilled water using a 0.17 mm stainless obtain a stabilized micelle composition comprising a mix steel orifice and an injection pressure of 300 psi. Alterna ture of terpenes and cannabinoids. tively, an Ultrasonic Atomizer Nozzle (60 Hz, 20 um drop size, flow rate 10 mL/min) can be used to inject the ethanolic IV. Liposomal Terpene Formulations Solution of lipid, terpene and cannabinoid into 1.2 L of distilled water. The aqueous ethanolic liposomal formulation Example 3 produced pursuant to any of the above described protocols can be concentrated to a Volume of 200 mL using rotary Liposomal Suspensions of Terpenes evaporation while maintaining the temperature of the solu tion below 55° C. to obtain an aqueous liposome formulation 0101 15 g of terpene was dissolved in 95% ethanol and containing a mixture of a terpene and a cannabinoid. the final volume of this solution was brought to 30 ml with 0106 The liposome formulations pursuant to any of the 95% EtOH. To this ethanolic solution of terpene was added above methodologies should contain a mixture of terpene 30 ml of an ethanolic solution of lecithin-50 which was and cannabinoid. The concentration of terpene in Such a prepared by dissolving 15 grams of lecithin-50 in 95% EtOH formulation can be in the range of about 0.001 g/L to about and bringing the volume of the lipid/EtOH solution to 30 ml 100 g/L, while the cannabinoid concentration can be from by the addition of 95% EtOH. After cooling to 10° C. the about 0.1 g/L to about 100 g/L. The aqueous liposomal ethanolic lipid/terpene solution was injected at a pressure of suspension, moreover, should be stable for more than 3 50 psi and a flow rate of 10 mL/min, into 540 ml of distilled months at 25° C. and the average size of liposomes in Such water (25°C.), using a 100 mL. Luer Lock syringe equipped a formulation should be in the range from about 200 nm to with a 22 gauge needle. about 400 nm in diameter. 0102 Alternatively, the ethanolic solution of the lipid and terpene at 30°C. was injected into distilled water through a V. Encapsulation Formulations 0.17 mm stainless steel orifice at 300 psi. According to yet Example 5 another embodiment, an ethanolic solution of the lipid and terpene at 25°C. was injected into 1.2 L of distilled water Calcium Alginate Encapsulation of Liposomal (25°C.), using an Ultrasonic Atomizer Nozzle at 60 Hz. The Suspensions size of the drops injected into water were about 20 um and the lipid and terpene was injected at a flow rate of 10 0107 Encapsulated liposome formulations in accordance mL/min. The ethanolic/aqueous Suspension thus obtained with the present invention containing terpenes and cannabi was concentrated to a volume of about 200 mL by rotary noids in amounts described above can be prepared by adding evaporation keeping the temperature of the solution below 4 g sodium alginate to 200 ml of an aqueous liposomal 550 C. formulation of terpenes or a liposomal Suspension of a US 2016/0279.073 A1 Sep. 29, 2016 terpene/cannabinoid mixture obtained using the protocols VI. Liposome Formulation described above in Examples 3 and 4. 0108. To promote encapsulation, the aqueous formula Example 8 tion of alginate and liposome is poured into 40 mL of a stifling aqueous solution of calcium chloride (25 wt %) and Liposomal Suspensions of Hemp Oil the entire reaction mixture is allowed to stir for an additional 0112 Liposome formulations in accordance with the 10 minutes to permit complete crosslinking of the aliginic present invention containing hemp oil in amounts described acid. The Solid mass of calcium alginate-encapsulated lipo above can be prepared by dissolving 15 g of Hemp oil in somes is then cold pressed to remove water and air-dried for 95% ethanol and the final volume of this solution is brought 24 hours in warm air at 50° C. The air-dried material is to 30 ml using 95% EtOH. In a separate flask, 15 grams of milled to obtain a free flowing yellow-white powder that can lecithin-50 is dissolved in 30 ml of 95% EtOH and this be dissolved in buffer. Encapsulated liposomes obtained solution of lecithin-50 is added to the solution of hemp oil using the above described methodology permit complete to obtain a lecithin-hemp oil mixture. After cooling the release of terpene or the mixture of terpene and cannabinoid lecithin-hemp oil mixture to 10° C., the cold solution is in 60 mM citrate buffer (pH 7). injected into 540 ml of distilled water at a pressure of 50 psi and a flow rate of 10 ml/min, using a 100 ml Luer Lock Example 6 Syringe equipped with a 22 gauge needle to obtain an aqueous-ethanolic liposome formulation of hemp oil. Film Formation of Liposomal Suspensions 0113 Alternatively, liposomes containing hemp oil are obtained by introducing a 30° C. ethanol solution of hemp 0109. A film of the inventive liposome formulation con oil into distilled water using a 0.17 mm stainless steel orifice taining a final concentration of terpenes and cannabinoids in at a pressure of 300 psi. An Ultrasonic Atomizer Nozzle (60 amounts described above is prepared by adding sodium Hz, 20 um drop size, and a flow rate of 10 ml/min), also can alginate to the liposomal Suspensions prepared in Examples be used to introduce the ethanolic solution of hemp oil into 3 and 4 above to obtain a composition having a final alginate distilled water (1.2 L). The resultant aqueous alcoholic concentration of 4% w/v (8 grams). This solution is stirred liposome Suspension is concentrated by rotary evaporation at room temperature to dissolve the alginate and then poured keeping the temperature of the solution in the flask below into a flat tray to form a layer having a depth of about 0.5 55° C. to obtain an aqueous Suspension of liposomes con cm. An aqueous solution of calcium chloride is then mixed taining hemp oil. with the aqueous layer containing alginate and liposome and 0114. The final maximum concentration of hemp oil in an the resultant mixture is permitted to stand at room tempera aqueous Suspension of liposomes prepared using the above ture to promote the formation of a film through crosslinking described methodology is in the range from about 0.01 g/L of the alginic acid. (0.01 mg/mL) to about 200 g/L (200 mg/mL) and liposomes 0110. The film thus formed is pressed to remove water formulations of hemp oil obtained using the protocol and dried for 24 hours using warm air at 50° C. The dried described above should be stable for more than 3 months at film, about 1 mm in thickness, can be cut into readily 250 C. consumable strips or milled to a free flowing powder. The films obtained using the above described methodology Example 9 should permit complete release of terpene or the mixture of Liposomal Suspensions of Hemp Oil and terpene and cannabinoid in distilled water. Cannabinoids Example 7 0.115. A protocol similar to the one described above in Example 8 can be used for the manufacture of liposome Formation of a Dispersible Dry Powder containing a mixture of hemp oil and cannabinoids. Such formulations should contain hemp oil in an amount from 0111. The liposomal preparations obtained in Examples 3 about 0.001 g/L to 200 g/L and cannabinoids in an amount and 4 can be diluted 1:10 with distilled water. To 200 ml of from about 0.01 g/L to about 100 g/L as described above. the diluted Solution is added 40 grams of lactose or Sucrose Briefly, a mixture of hemp oil (15 g) and one or more (200 mg/ml) and 0.12 grams L-leucine (0.6 mg/ml). Fol cannabinoids or a cannabinoid analog obtained by contact lowing dissolution of the added components, the entire ing a Formula I compound with a cannabinoid synthase is Suspension is poured into a flat tray to form a layer having dissolved in 30 mL of 95% ethanol. This ethanolic hemp a depth of about 0.5 cm. This layer is allowed to set to form oil-cannabinoid solution is combined with 30 ml of a 95% a gel like solid which can be used directly. Alternatively, the ethanol solution of lecithin-50 prepared according to the gel is compressed to remove water and the resultant Solid protocol described above in Example 8. The lecithin-hemp can be further dried at room temperature or spray-dried with oil/cannabinoid solution is cooled to 10°C. prior to injecting a forced air spray dryer at a temperature of 55° C. to obtain the cold solution (pressure—50 psi and flow rate—10 a crystalline solid that can be milled to a free flowing ml/min), into 540 ml of distilled water using a 100 ml Luer powder. The powder thus obtained should dissolve com Lock syringe equipped with a 22 gauge needle. The resultant pletely in water and release greater than 90% of the lipo mixture is an aqueous-ethanolic Suspension of liposomes Somes. The amount of cannabinoid or cannabinoid analogue containing a mixture of hemp oil and cannabinoids or hemp in the aqueous terpenefcannabinoid solution is from about oil and a cannabinoid analog. 10% w/w to about 80% w/w and the amount of terpene in the 0116. Alternatively, liposomes containing a mixture of aqueous terpene-cannabinoid solution is from about 1% w/w hemp oil and cannabinoids or a cannabinoid analog can be to about 10% w/w. obtained by introducing a 30° C. ethanol solution of a US 2016/0279.073 A1 Sep. 29, 2016

mixture of hemp oil and cannabinoids or hemp oil and a dextrin, lactose or Sucrose (200 mg/ml) and 0.12 grams cannabinoid analog into distilled water using a 0.17 mm L-leucine (0.6 mg/ml) are added to 200 ml of each the stainless steel orifice at a pressure of 300 psi. An Ultrasonic liposome compositions. The resultant solutions are frozen Atomizer Nozzle (60 Hz, 20 um drop size, and a flow rate using a dry icefacetone bath and then freeze dried to a of 10 ml/min) also can be used to introduce the ethanolic powder. Alternatively, the liposome solutions containing Solution containing a mixture of hemp oil and cannabinoids Sugar and leucine can be spray-dried using a forced air spray or a cannabinoid analog into distilled water (1.2 L). The dryer at a temperature of 55° C. to obtain a crystalline solid resultant aqueous alcoholic liposome suspension is then than can be milled to obtain a free flowing powder. concentrated by rotary evaporation, keeping the temperature I0121 The dry powder thus obtained should contain of the solution within the flask below 55° C., to obtain an approximately 10% to 80% hemp oil or a mixture of hemp aqueous Suspension of liposomes containing a mixture of oil and a cannabinoid and should dissolve completely in hemp oil and cannabinoids or a cannabinoid analog. The water and release greater than 90% of the starting liposomes liposome Suspension obtained using the methods described into Solution. above should be stable for more than 3 months at 25°C. 0.122 The scope of the claims should not be limited by the preferred embodiments set forth in the examples, but VII. Encapsulation Formulations should be given the broadest interpretation consistent with Example 10 the description as a whole. 1. A stable, aqueous liposome formulation of a terpene Calcium Alginate Encapsulation of Liposomal comprising: Suspensions a primary terpene selected from the group consisting of 0117 Sodium alginate (4 g) is dissolved in 200 ml of the C-pinene, C.-bisabolol, B-pinene, guaiene, guaiol, limo hemp oil liposomal suspension prepared in Example 8 or the nene, myrcene and ocimene; liposomal Suspension of hemp oil and cannabinoid accord a secondary ing to Example 9. The resultant mixture is poured into 40 ml terpene; and a of an aqueous solution of 25% calcium chloride to initiate tertiary terpene, crosslinking of alginic acid and promote the encapsulation wherein the amount of the primary terpene is 50% (w/w), of liposomes. The solid mass of calcium alginate encapsu the amount of the secondary terpene is from about 30% lated liposomes thus obtained are cold-pressed to remove to about 40% (w/w) and the amount of the tertiary excess water, followed by air drying at 50° C. for 24 hours. pinene is from about 8% to about 10% (w/w) of the The air-dried material is milled to a free flowing powder that formulation. is dissolved in buffered water prior to use. 2. The formulation according to claim 1, further compris 0118. The amount of hemp oil in the alginate powder as ing one or more cannabinoids or cannabinoid analogues, described above is from about 10% w/w to about 80% w/w. wherein the average diameter of the liposome in the formu When a liposome formulation containing a mixture of lation is in a range between 50 nm and 1000 nm. cannabinoid and hemp oil is used for encapsulation, the 3. The formulation according to claim 2, wherein the final cannabinoid content in the alginate powder is from about maximum concentration of cannabinoids or cannabinoid 10% to about 80% while the amount of hemp oil is from analogues is from about 0.01 g/L to about 100 g/L. about 90% to about 20%. The powder should completely 4. (canceled) release the encapsulated components when contacted with 5. (canceled) 60 mM citrate buffer at pH 7. 6. The formulation according to claim 2, wherein the one Example 11 or more cannabinoids or cannabinoid analogues are selected from the group consisting of cannabinol, cannabidiol. Film Formation of Liposomal Suspensions A9-tetrahydrocannabinol, A8-tetrahydrocannabinol, 11-hy 0119 Films of liposome suspensions are obtained by droxy-tetrahydrocannabinol, 11-hydroxy-A9-tetrahydrocan adding Sodium alginate to the liposome Suspensions manu nabinol, levonantradol, A11-tetrahydrocannabinol, tetrahy factured using the protocol described in Examples 8 and 9. drocannabivarin, dronabinol, amandamide and nabilone and The final concentration of Sodium alginate in the liposome a combination of two or more of these compounds. Suspensions is 4% w/v (8 grams). The resultant solution is 7. The formulation according to claim 2, further compris stirred at room temperature to dissolve the alginate and then ing a stabilizer selected from the group consisting of guar poured into a flat tray to form a layer having a depth of about gum, Xyanthan gum cellulose hyaluronic acid, polyvinyl 0.5 cm. Calcium chloride is added to the solution in the tray pyrrolidone (PVP), alginate, chondritin Sulfate, poly gamma to crosslink the alginic acid-liposome mixture and form a gel glutamic acid, gelatin, chitisin, corn starch and flour, in an like solid. This gel like solid can be desiccated in a drying amount from about 0.1% to about 2% (w/v). cabinet at a temperature of 50° C. to obtain a 1 mm thick 8. The formulation according to claim 1, wherein the film. The final film should contain approximately 10% to primary terpene is C-pinene; the secondary terpene is 80% hemp oil or a mixture of hemp oil and cannabinoids, selected from the group consisting of myrcene, 3-pinene and and should completely dissolve in distilled water. t-carophyllene; the tertiary terpene is selected from the group consisting of B-pinene, t-carophyllene, C.-bisabolol Example 12 and myrcene, and the Suspension further comprises trace amounts of one or more terpenes selected from the group Formation of a Dispersible Dry Powder consisting of C-humulene, C.-bisabolol, guaiene, limonene, 0120 Liposomal compositions according to Examples 8 ocimene, terpinolene, 3-carene, myercene, guaiol, C-terpi and 9 are diluted 1:10 with distilled water. 40 grams malto neol and linalool. US 2016/0279.073 A1 Sep. 29, 2016

9. The formulation according to claim 1, wherein the (c) injecting the solution from step (b) into distilled water primary terpene is C.-bisabolol; the secondary terpene is to obtain an aqueous alcoholic liposomal formulation t-carophyllene; the tertiary terpene is selected from the of terpenes; and group consisting of C-pinene and myrcene, and the Suspen (d) removing the ethanol from the aqueous ethanolic sion further comprises trace amounts of one or more ter liposome formulation of terpenes, thereby producing a penes selected from the group consisting of C-humulene, stable aqueous liposomal formulation of one or more C-terpineol guaiol, and linalool. terpenes; 10. The formulation according to claim 1, wherein the wherein the final maximum concentration of terpenes in the primary terpene is B-pinene; the secondary terpene is liposomal formulation is from about 0.001 g/L to about 100 C-pinene; the tertiary terpene is selected from the group g/L consisting of t-carophyllene and terpinolene; and the Sus 22. The method of claim 21, wherein the final maximum pension further comprises trace amounts of myrcene. concentration of terpenes in the liposomal formulation is 11. The formulation according to claim 1, wherein the from about 10 g/L to about 70 g/L. primary terpene is guaiene; the secondary terpene is t-caro 23. The method of claim 21, wherein step (a) further phyllene; the tertiary terpene is selected from the group comprises dissolving one or more cannabinoids or cannabi consisting of myrcene and C-humulene; and the Suspension noid analogues selected from the group consisting of can further comprises trace amounts of C-pinene, bisabolol. nabinol, cannabidiol, A9-tetrahydrocannabinol, A8-tetrahy B-pinene, limonene, Ocimene and terpinolene. drocannabinol, 11-hydroxy-tetrahydrocannabinol, 12. The formulation according to claim 1, wherein the 11-hydroxy-A9-tetrahydrocannabinol, levonantradol, A11 primary terpene is guaiol; the secondary terpene is C.-bis tetrahydrocannabinol, tetrahydrocannabivarin, dronabinol, abolol; the tertiary terpene is selected from the group amandamide, nabilone, and a combination thereof. consisting of t-carophyllene myrcene; and the Suspension 24. The method of claim 23, wherein the average diameter further comprises trace amounts of C-pinene, C-terpineol. of the liposome is in a range between 50 nm and 1000 nm, C-humulene and terpinolene. and wherein the final maximum concentration of cannabi 13. The formulation according to claim 1, wherein the noids or cannabinoid analogues in the Suspension is from primary terpene is limonene; the secondary terpene is about 0.01 g/L to about 100 g/L. selected from the group consisting of myrcene and t-caro 25. (canceled) phyllene; the tertiary terpene is selected from the group 26. (canceled) consisting of linalool, myrcene, B-pinene and t-carophyl 27. (canceled) lene, C.-bisabolol and myrcene, and the Suspension further 28. (canceled) comprises trace amounts of one or more terpenes selected 29. (canceled) from the group consisting of C-humulene, C-pinene, 30. (canceled) B-pinene, fenchol, guaiene, linalool, ocimene and C-terpin 31. (canceled) eol. 32. (canceled) 14. The formulation according to claim 1, wherein the 33. (canceled) primary terpene is myrcene; the secondary terpene is 34. (canceled) selected from the group consisting of C-pinene, t-carophyl 35. (canceled) lene, terpinolene, ocimene, limonene and linalool; the ter 36. (canceled) tiary terpene is selected from the group consisting of 37. (canceled) B-pinene, t-carophylene, limonene, Ocimene and myrcene; 38. (canceled) C-pinene, bisabolol and myrcene, and the Suspension further 39. An aqueous solution of a terpene and a cannabinoid comprises trace amounts of one or more terpenes selected comprising a primary terpene, a secondary terpene, a tertiary from the group consisting of C-humulene, C.-bisabolol. terpene, and one or more cannabinoids or cannabinoid guaiene, limonene, ocimene, 3-carene, analogues, wherein the total amount of the terpene and B-pinene, C-pinene, myercene, guaiol, C-terpineol, terpi cannabinoid or terpene and cannabinoid analog is 50 g/liter. nolene and linalool. 40. The aqueous solution according to claim 38, wherein 15. (canceled) the solution is in form of a fast-acting pharmaceutical 16. (canceled) composition, a nutraceutical composition, or a food or 17. (canceled) beverage for administration to a Subject. 18. (canceled) 41. The aqueous according to claim 40, wherein the 19. (canceled) pharmaceutical composition and the nutraceutical composi 20. (canceled) tion are fast-acting formulations for oral, enteral, parenteral, 21. A method of producing a stable liposomal formulation intravenous, pulmonary, mucosal. Sub-mucosal or topical of one or more terpenes comprising the steps of administration. (a) dissolving one or more terpenes in ethanol to obtain an 42. (canceled) ethanolic Solution of terpenes; 43. (canceled) (b) adding a phospholipid to the ethanolic solution of 44. (canceled) terpenes;