CROSS-REFERENCE TO RELATED APPLICATIONS

[1] This claims the benefit of United States Provisional Patent Application No. 63/108,351 filed November 1, 2020, the entirety of which is incorporated herein by reference.

BACKGROUND

Field of the Invention

[2] This relates generally to compositions comprising Cannabis extracts. More particularly this relates to methods of preparing nanoemulsions from compositions comprising cannabis extracts to make nutraceutical and/or pharmaceutical compositions.

Description of Related Art

[3] Cannabis spp. have been used medicinally for centuries. The therapeutic value of cannabis, and particularly the plant cannabinoids and other natural plant compounds found in Cannabis plants is the subject of many current studies.

Beneficial effects have been shown or reported for many conditions, including cancer, viral infections, inflammation, and certain neurological conditions. It is now well-established that the mammalian endocannabinoid system can be affected by exogenous cannabinoids, including plant-derived cannabinoids. The use of exogenous cannabinoids and their ability to regulate (particularly up- regulate) the endocannabinoid system in humans is being studied as a therapeutic approach.

[4] Cannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are major cannabinoids from Cannabis spp. More minor cannabinoids are continually being discovered, and we are learning more about the vast array of cannabinoids in plants. Our understanding of the role and potential therapeutic value of such compounds is ongoing.

[5] Other compounds such as terpenes, flavonoids, and other various botanicals found in Cannabis are known to provide certain beneficial functions when consumed or administered. [6] There is a need in the art for new and useful Cannabis compositions, and useful methods of preparing nanoemulsions for delivering the Cannabis compositions in vivo.

SUMMARY

[7] In a first of the several aspects of this disclosure, the inventor has discovered certain pharmaceutical and/or nutraceutical compositions generally comprising extracts of cannabis and mushrooms. The compositions are useful for treating multiple health conditions. This disclosure also provides nanoemulsions comprising those compositions. The nanoemulsions are distinguishable from the emulsions also discovered by the inventor (and the subject of a separate disclosure), they are more difficult to achieve (i.e., to make) but the droplet / particle sizes are several orders of magnitude smaller and provide the cannabinoids and other compounds present therein in a highly bioavailable form.

[8] Distillates containing major cannabinoids are now known to be primarily oilsoluble compounds with low or no solubility in water or aqueous solutions. Thus, adding any water-soluble compounds to compositions comprising oilsoluble cannabis extracts creates problems such as insolubility, precipitation, gelformation, and the like. Such problems can result in decreased ability to deliver compounds, quality issues (particularly with appearance and performance), fouling or blocking of production equipment, lack of acceptability for administration through various routes, decreased absorption, and decreased biological activity or bioavailability. Accordingly, the inventor has discovered that certain compositions have improved properties when prepared as nanoemulsions.

[9] The skilled artisan will appreciate that emulsions / nanoemulsions are colloidal dispersions of one liquid into another in which it is not soluble or miscible. These systems then include a "continuous phase" and a "dispersed" (or discontinuous) phase. Emulsions typically appear cloudy or even opaque because the interfaces between the smaller dispersed droplets and the continuous phase scatter light. Some emulsions appear white when the light is scattered throughout and does not pass through. Milk is a good example of an emulsion where the fat droplets (i.e., cream) are dispersed in the aqueous phase. It should be evident that emulsions like milk can be considered oil-in-water emulsions (or "O/W") emulsions where the dispersed phase is named first. On the other hand, butter is a water-in-oil (W / O) emulsion with small droplets of dispersed into a continuous oil phase.

[10] As is commonly seen with unhomogenized milk, the two phases are inherently unstable and immiscible, and will generally separate spontaneously over time. This happens with efforts to make emulsions, e.g., after dispersing one liquid phase in the other phase, they will naturally separate over time unless steps are taken to stabilize the emulsion. Without stabilization of the two phases, separation of an emulsion will occur in time (over a period that ranges from seconds to days or weeks) depending on the properties of the unstabilized emulsion. The less miscible the two phases are, the lower the viscosity of the continuous phase, and the larger the relative droplets in the dispersed phase, the stronger the forces driving the phases to separate, and the faster the emulsion will 'break' and separate.

[11] Stabilization can generally happen in a number of ways. One simple way to is to increase the viscosity of the continuous phase. That will enhance stability by slowing down the rate at which the discontinuous phase can e.g., aggregate and separate.

[12] Another way to stabilize emulsions is to reduce the surface tension between the continuous phase and the dispersed phase - i.e., at the interface. Adding compounds such as emulsifiers and detergents can help reduce the forces driving the emulsion to separate, particularly at the interfaces. Compounds with both hydrophilic and hydrophobic properties can be distributed at the interface. Examples include proteins, gums, soaps, salts of fatty acids, long chain alcohols, and the like. Mono- and di- glycerides can also serve as effective emulsifiers.

[13] Reducing the size of the droplets of the dispersed phase is also helpful to stabilize emulsions. Smaller size droplets will increase the time required for them to separate, and to prevent droplets from coalescing or flocculate (thereby increasing their effective size and rate of separation). Increased temperature will increase the rate of separation, and reducing temperatures can generally reduce separation, however, freeze-thawing, especially repeatedly, can result in completely 'broken' emulsions.

[14] The compositions provided herein can be emulsified by a variety of techniques based on the specific properties of the compositions and based on whether an O/ W or W/O emulsion is preferred. In preferred embodiments, the nanoemulsions comprise droplet size of ~2 microns or less. In other preferred embodiments, the droplet size is less than about 1 micron. More preferred presently are nanoemulsions with average droplet sizes of about 800, 700, 600, or even 500 nanometers or less. The inventors have found that it can be difficult to consistently produce nanoemulsions with droplet diameters of less than about 100 or 200 nanometers.

[15] It is also to be noted that not only the average size of the droplets, but the range of droplet size is important. Even a relatively low percentage of larger droplets can destabilize an otherwise useful emulsion. The skilled artisan will appreciate that an emulsion with an average droplet size of 500 nanometers, a range of about 50 nanometers to about 800 nanometer, and a median droplet size of 400 nanometers is likely to be more stable than an emulsion with an average droplet size of 380 nanometers, a range of about 30 nanometers to about 1 micron, and a median droplet size of 450 nanometers.

[16] Ideally, emulsions made according to the instant disclosure are shelf stable at room temperature and/or at refrigerator temperature for at least several weeks to about 12 months. Shelf-life of less than a few weeks makes commercial distribution difficult without additional techniques or methods.

[17] While the oil phase of the compositions disclosed here typically comprises Cannabis extracts, the aqueous phase can comprise other useful compounds. For example, edible and medical mushrooms are reported to provide many beneficial and therapeutic properties. While any part of the mushroom may be useful and provide beneficial properties, water-soluble or aqueous extracts have most frequently been reported on. Extracting oil soluble mushroom components and combining them with oil-soluble Cannabis extracts should be reasonably straight forward for the ordinarily skilled artisan in the art of making such extracts. However, the inventors have discovered that making compositions comprising both oil-soluble Cannabis extracts and water-soluble mushroom extracts is facilitated by use of nanoemulsions, of either the O/ W type or the W/O type.

[18] The mushroom or mushroom extract(s) present in the compositions is from any edible or medicinal mushroom species. The edible or medicinal mushroom in various embodiments comprises one or more of Agaricus bisporus, A. blazei, A. subrufescens, Agrocybe aegerita, A. cylindracea, Albatrellus caeruleoporus, A. confluens, Amanita muscaria, Antrodia camphorate, Boletus badius, Boletus edulis, Cantharellus cibarius, C. tubaeformis, Caripia montagnei, Clitocybe maxima, Cordyceps cicadicola, C. gunnii, C. liangshanensis, C. militaris, C. pruinose, C. sinensis, Cyathus africanus, C. hookeri, Daldinia childiae, Dictyophora indusiata (synonym: Phallus indusiatus), Elaphomyces granulatus, Flammulina velutipes, Pomes fomentarius, Fomitopsis pinicola, Funalia trogii, Ganoderma lucidum, Geastrum saccatum, Grifola frondosa, Hericium erinaceus, Inocybe umbrinella, Inonotus olbiquus, Lactarius deliciosus, L. flavidulus, L. rufus, Lentinula edodes, Lentinus edodes, L. polychrous, Lyophyllum decastes, Phellinus linteus, Pholiota nameko, Pleurotus ostreatus, P. pulmonarius, Poria cocos, Schizophyllum commune, Suillus placidus, Trametes versicolor, or Termitomyces albuminosus. In one embodiment the mushrooms include any one or more of Turkey Tail, Reishi, Shitake, Chaga, Cordyceps, Maitake, Lions Mane, Cubensis, or Reishi. Any part(s) of the mushrooms may be used herein and at any stage or cycle of the mushroom (not limited to fruiting bodies).

[19] The cannabis extracts may include any cannabinoids and can be derived from any Cannabis spp. The cannabis extracts may further comprise any number of useful terpenes and/or flavonoids. A presently preferred strain of Cannabis is Ringo's Gift.

[20] The compositions optionally include other nutraceutical or botanical compounds to provide additional. Examples include compound such as herbal extracts from one or more of Rehmanniae spp., Achyranthis spp., Corni spp., Moutan spp., Alismatis spp., Dioscorea spp., Plantaginis spp., Hoelen spp., Aconiti spp., Cinnamomi spp., Barosma betulina, Galium aparine, cornsilk from Zea mays, horsetail (Equisetum spp.), resiniferatoxin (or extract from Euphorbia resinifera), capsaicin, saw palmetto, bearberry, cranberry, St. John's Wort, stinging nettle, or combinations thereof. Additional compounds contemplated for use herein comprise S-adenosylmethionine, methylfolate, polyphenols, D-mannose, antioxidants, omega-3 fatty acids, or a B vitamin, vitamin A, vitamin C, vitamin D, vitamin E, or a compound providing a biologically available form thereof, or combinations thereof.

[21] The combinations may further optionally comprise one or more solvents, including but not limited to dimethyl sulfoxide or related amphipathic solvents, or other solvent capable of dissolving poorly soluble polar and non-polar molecules and which are relatively nontoxic in mammals and specifically humans. For example, dihydrolevoglucosenone cyrene (sold commercially as "CYRENE") has been reported to nontoxic, nonmutagenic, and relatively safe and is contemplated for use herein.

[22] The inventor has surprisingly discovered that a composition comprising an extract from one or more edible or medicinal mushrooms, or a cannabis extract, or combinations of the foregoing, has many benefits for therapeutic use. The compositions have useful properties, such as effectiveness including over a long period of time, low toxicity, no serious side effects, and good tolerance on the part of a wide range of subjects. The compositions also appear to have excellent biological activity in a variety of applications.

[23] These and/or further aspects, features, and advantages of the present invention will become apparent to those skilled in the art in view of this disclosure.

DETAILED DESCRIPTION

[24] Provided herein are compositions comprising Cannabis for therapeutic uses. Nanoemulsions comprising the compositions and methods for preparing such nanoemulsions are also provided. Surprisingly, the compositions allow a modern practitioner to utilize the therapeutic benefits of Cannabis in conveniently administered or utilized forms.

[25] The compositions in certain embodiments can further comprise certain useful compounds found in edible and medicinal mushrooms (such as used for centuries in Chinese and other traditional medicine practices, and by e.g., herbalists throughout the world), with the positive benefits of another natural substance, cannabis, also used for centuries. The compositions further include certain beneficial compounds derived from Cannabis and other natural or synthetic sources, and other nutraceutical or pharmaceutical compounds, particularly nutraceutical compounds known to be supportive of various health conditions. Used properly, these compositions have little risk, few side effects, and are effective for producing measurable and lasting results in patients suffering from a variety of conditions.

Definitions & Abbreviations

[26] Unless expressly defined otherwise, all technical and scientific terms, terms of art, and acronyms used herein have the meanings commonly understood by one of ordinary skill in the art in the field(s) of the invention, or in the field(s) where the term is used. In accordance with this description, the following abbreviations and definitions apply.

[27] As the skilled artisan will appreciate, as used herein the term "edible" does not mean merely capable of being eaten. In that overly broad sense, even poisonous or toxic mushrooms are 'edible' however lethal or sickening or the like. In contrast "edible mushrooms" is used herein in the sense of mushrooms that are used traditionally or in modern times as sources of food, nutrients, nutraceuticals, flavors, and the like. Edible mushrooms are neither toxic nor poisonous as consumed.

[28] "Medicinal mushrooms" as used herein means any mushroom species that has been used traditionally or in modern times as a source of medicinal or therapeutic benefits, healing properties, and / or healthful compounds. It should be noted that the medicinal mushrooms may not be edible in all embodiments herein, and may in fact be poisonous if eaten, however, one or more extracts therefrom or components extracted or isolated therefrom may be perfectly useful herein.

[29] Notwithstanding the foregoing exception(s), generally, mushrooms that are edible or medicinal may be grouped together, as there may be many crossovers and it may be difficult to clearly distinguish between the two groups. Examples of edible and / or medicinal mushrooms useful herein include mushrooms of the genera Agaricus, Agrocybe, Albatrellus, Amanita, Antrodia, Auricularia, Boletus, Calvatia, Cantharellus, Caripia, Clitocybe, Cordyceps, Cyathus, Daldinia, Dictyophora, Elaphomyces, Flammulina, Pomes, Fomitopsis, Funalia, Ganoderma, Geastrum, Grifola, Hericium, Inocybe, Inonotus, Lactarius, Lentinus, Lentinula, Leucop axillus, Lyophyllum, Phellinus, Pholiota, Pleurotus, Poria, Russula, Sarcodona, Schizophyllum, Suillus, Termitomyces, Trametes, or Xerocomus. Species of particular interest include Agaricus bisporus, A. blazei, A. subrufescens, Agrocybe aegerita, A. cylindracea, Albatrellus caeruleoporus, A. confluens, Amanita muscaria, Antrodia camphorate, Boletus badius, Boletus edulis, Cantharellus cibarius, C. tubaeformis, Caripia montagnei, Clitocybe maxima, Cordyceps cicadicola, C. gunnii, C. liangshanensis, C. militaris, C. pruinose, C. sinensis, Cyathus africanus, C. hookeri, Daldinia childiae, Dictyophora indusiata (synonym: Phallus indusiatus), Elaphomyces granulatus, Flammulina velutipes, Pomes f omentar ius, Fomitopsis pinicola, Funalia trogii, Ganoderma lucidum, Geastrum saccatum, Grifola frondosa, Hericium erinaceus, Inocybe umbrinella, Inonotus olbiquus, Lactarius deliciosus, L. flavidulus, L. rufus, Lentinula edodes, Lentinus edodes, L. polychrous, Lyophyllum decastes, Phellinus linteus, Pholiota nameko, Pleurotus ostreatus, P. pulmonarius, Poria cocos, Schizophyllum commune, Suillus placidus, Trametes versicolor, or Termitomyces albuminosus.

[30] More generally, edible and/or medicinal mushrooms can be useful in connection with the current disclosure for treating many conditions, directly or indirectly.

[31] Getting proper rest, minimizing unhealthy stress, and eliminating inflammatory processes are helpful to healing or recovering from any condition, illness, or the like, and mushrooms with such properties or that assist with such efforts are generally useful herein. Reishi mushrooms, as an example, have been reported to calm the central nervous system and/or have neuroprotective effect, stimulate the immune system, and act as a prebiotic to support gut health. Reishi has been reported to have a beneficial effect on the adrenals, and to be anxiolytic; reducing anxiety and promoting sleep. Reishi has also been associated with improved memory, and sharpened concentration and focus. Lion's Mane reportedly calms mental activity and modulates certain neurotransmitters. Cordyceps has been reported to have adaptagenic properties and stimulate the adrenals glands and modulates the nervous system. For purposes herein, the publication by Elsayed, Elsayed A et al. entitled "Mushrooms: a potential natural source of anti-inflammatory compounds for medical applications." (Mediators of Inflammation Vol. 2014 (2014): 805841. doi:10.1155/2014/805841) provides a list of anti-inflammatory mushrooms and active components therein. Any of the mushrooms or anti-inflammatory components described in the publication, which is incorporated herein by reference, may be useful herein.

[32] “Cannabis" or "Cannabis spp." as used herein refers to any plant of the genus Cannabis, including plants that may be classified as Cannabis sativa, Cannabis indica, or Cannabis ruderalis. It is well known that despite the foregoing list, some experts believe that there are only 2 species, and still others consider that there is only a single species (generally, C. sativa). Whatever nomenclature is used, for purposes of this disclosure, “Cannabis" includes all possible members of the genus, without regard to the species to which they are assigned.

[33] As used herein 'cannabinoids' means any of a class of compounds that generally can interact with one or more cannabinoid receptors, including the receptors of the endocannabinoid system, in particular, CB1 and CB2. Cannabinoids include e.g., phytocannabinoids and synthetic cannabinoids. Phytocannabinoids are found in several plant species, especially Cannabis spp. Among the most prevalent and most studied cannabinoids are tetrahydrocannabinol (THC), and cannabidiol (CBD). However, there are at least ~120 known cannabinoids that have been identified in Cannabis within certain classes including the tetrahydrocannabinols, cannabidiols (including e.g., cannabidol (CBD) and cannabidivarin (CBDV)), cannabigerols, cannabinols, cannabichromenes, and cannabinodiol. Other cannabinoids, such as cannabicyclol, cannabieslsoin, and cannabitriol are currently classed as 'miscellaneous' by some researchers. THC is not only a major cannabinoid in Cannabis spp., it is generally the compound responsible for the psychoactive effects of consuming Cannabis. However, other cannabinoids, such as cannabinol may also be at least mildly psychoactive. Certain other cannabinoids such as CBD may help regulate or attenuate the psychoactive effects of other cannabinoids. For purposes herein, compositions may be created with various ratios of cannabinoids, such as the ratio of CBD to THC or other ratios depending the specific person or the specific condition being treated.

[34] "Herbal extracts" as used herein comprise extracts from one or more of Rehmanniae spp., Achyranthis spp., Corni spp., Moutan spp., Alismatis spp., Dioscorea spp., Plantaginis spp., Hoelen spp., Aconiti spp., Cinnamomi spp., Barosma betulina, Galium aparine, cornsilk from Zea mays, horsetail (Equisetum spp.), resiniferatoxin (or extract from Euphorbia resinifera), capsaicin, saw palmetto, bearberry, cranberry, St. John's Wort, stinging nettle, and/or combinations thereof.

[35] Additional nutraceutical compounds that may be useful herein include but are not limited to S-adenosylmethionine, methylfolate, polyphenols, D-mannose, antioxidants, omega-3 fatty acids, or a B vitamin, vitamin A, vitamin C, vitamin D, vitamin E, or a compound providing a biologically-available form thereof, or combinations thereof.

[36] As used herein, "curcuminoids" means any of the compounds associated with turmeric or curcumin, as derived rhizome of the plant Curcuma longa, or synthetic versions or derivative thereof. Curcuminoids include but are not limited to curcumin (aka diferuloylmethane), analogs of curcumin such as demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC), turmerones, and turmeric oil. Also include are metabolites of curcumin such as tetrahydrocurcumin (THCU), hexahydrocurcumin, and octahydrocurcumin.

[37] Conjugates, such as curcumin glucuronide and curcumin sulfate, are also included herein. Conjugation may also provide opportunities for improved delivery of curcumins herein, for example, conjugation to peptide carriers, or polylactic-co-gly colic acid [PLGA]; as well as complexation with essential oils; coadministration with piperine; and encapsulation into nanoparticles, liposomes, phytosomes, polymeric micelles, and cyclodextrins may also be useful herein.

[38] As used herein, "terpenes" means any of the organic compounds commonly known as terpenes or terpenoids. Terpenes are generally aromatic compounds classified as isoprene derivatives. Terpenes suitable for use herein include hemiterpenes, monoterpenes, sesquiterpenes, diterpenes, sesterterpenes, triterpenes, sesquaterpenes, tetraterpenes, polyterpenes, and norisoprenoids. Exemplary terpenes that are particularly useful herein include alpha bisabolol, alpha pinene, beta caryophyllene, beta pinene, borneol, camphor, camphene, caryophyllene, cineole, delta-3 carene, eucalyptol, farnesenes, farnesol, fenchol, fenchone, geraniol, guaiol, humulene, isopulegol, limonene, linalool, menthol, myrcene, nerol, nerolidol, ocimene, pinene, phytol, pulegone, terpinene, terpineol, terpinolene, and valencene. In other embodiments phytol, limonene, humulene, myrcene, cineol, phellandrene, caryophyllene, terpinolene, linalool, ocimene, pinene, or a combination thereof are presently preferred.

[39] As used herein, "flavonoids" includes any of the class of polyphenolic molecules containing 15 carbon atoms that are naturally produced in plants and are soluble in water. Also included herein as "flavonoids" are natural or synthetic derivative or analogs thereof that have biological activity. Flavonoids of use herein can generally be divided in to 6 groups of structurally related compounds: chaicones, flavones, isoflavonoids, flavanones, anthoxanthins, and anthocyanins. Also useful are flavanols and catechins, as well as glucosides or other derivatives or analogs of any of the foregoing. The flavonoids are found in most fruits and vegetables, particular colorful ones. They are also prevalent in legumes (including soybeans), grains, green and black teas, as well as red wine.

[40] Flavonoids have numerous functions in plants, and act as important cell messengers. Various flavonoids are believed to provide healthful benefits and functions to humans such as anti-cancer, anti-inflammatory, anti-allergic, and antioxidant properties. They may also be cardio-protective, cholesterol-lowering, and anti-atherosclerotic. Natural or synthetic flavonoids from any source may be used herein. Generally natural flavonoids are preferred. Flavonoids isolated from Cannabis, such as cannaflavins A, B, and or C, are of interest in certain applications, as are vitexin, isovitexin, apigenin, kaempferol, quercetin, orientin, and luteolin, as well as the catechins found in Cannabis.

[41] "Traditional Jamaican medicinal plants" means any plant that has been used in traditional or indigenous medicine or herbalism practices in Jamaica or other Caribbean states. The book, “Common Medicinal Plants of Portland, Jamaica" by Thomas and Austin, provides a useful list of a number of such plants. The book was published in its second edition in 2010 by CIEER and is incorporated herein by reference. For purposes herein, the definition of such traditional Jamaican medicinal plants" expressly excludes Cannabis spp.

[42] As used herein "emulsion" means any oil-in-water (O/ W) or water-in-oil (W / O) emulsion, and particular emulsions comprising cannabis extracts and mushroom extract. Generally, the preferred emulsions referenced herein will have an oil phase comprising a Cannabis extract, and a water phase comprising a mushroom extract, herbal extract, or other beneficial component or extract, such as a water-soluble nutraceutical. However, in other embodiments, an emulsion can comprise an oil phase comprising mushroom extract (e.g., one or more lipid- soluble mushroom components), or herbal extracts or lipid-soluble beneficial components or extracts (e.g., lipid-soluble plant extracts or nutraceuticals) with or without cannabis components present. The corresponding water phase for such emulsions can comprise a water phase with a water-soluble extract of cannabis, and/or other water-soluble components. As long as the emulsion is an O/ W or W/O emulsion, and has at least some cannabis extract or component and at least some mushroom, herbal or other nutraceutical component, it is considered an "emulsion" for purposes herein. Merely creating an O/ W or W/O emulsion consisting of a Cannabis extract, while useful, is not an emulsion for purposes herein. A "nanoemulsion" is an emulsions with average droplet or particle size of ~2 microns or less.

[43] As used herein, the singular form of a word includes the plural, and vice versa, unless the context clearly dictates otherwise. Thus, the references "a", "an", and "the" are generally inclusive of the plurals of the respective terms. For example, reference to "a composition" or "a mushroom extract" includes a plurality of such "compositions" or "mushroom extracts."

[44] The words "comprise", "comprises", and "comprising" are to be interpreted inclusively rather than exclusively. Likewise, the terms "include", "including" and "or" should all be construed to be inclusive, unless such a construction is clearly prohibited from the context. Further, forms of the terms "comprising" or "including" are intended to include embodiments encompassed by the phrases "consisting essentially of" and "consisting of". Similarly, the phrase "consisting essentially of" is intended to include embodiments encompassed by the phrase "consisting of".

[45] Where used herein, ranges are provided in shorthand, so as to avoid having to list and describe each and every value within the range. Any appropriate value within the range can be selected, where appropriate, as the upper value, lower value, or the terminus of the range.

[46] The methods and devices and / or other advances disclosed here are not limited to particular methodology, protocols, and/or structures described herein because, as the skilled artisan will appreciate, they may vary. Further, the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to, and does not, limit the scope of that which is disclosed or claimed.

[47] Although any devices, methods, articles of manufacture, or other means or materials similar or equivalent to those described herein can be used in the practice of the present invention, the preferred compositions, methods, articles of manufacture, or other means or materials are described herein.

[48] All patents, patent applications, publications, technical and/or scholarly articles, and other references cited or referred to herein are in their entirety incorporated herein by reference to the extent permitted under applicable law. Any discussion of those references is intended merely to summarize the assertions made therein. No admission is made that any such patents, patent applications, publications or references are prior art, or that any portion thereof is either relevant or material to the patentability of what is claimed herein.

Applicant specifically reserves the right to challenge the accuracy and pertinence of any assertion that such patents, patent applications, publications, and other references are prior art, or are relevant, and/or material.

Abbreviations

[49] The following abbreviations apply unless indicated otherwise:

APM: "Apollon Medical" strain of C. sativa

CBD: cannabidiol;

CBG: cannabigerol;

CBN: cannabinol;

DMT: N,N-Dimethyl tryptamine;

5-HT: 5-hydroxytryptamine; kHz: kilohertz;

KNN: K Nearest Neighbor;

MCT: Medium Chain Triglycerides;

NK: natural killer cells;

NS AID: nonsteroidal anti-inflammatory drugs; O/W: oil-in-water (emulsion);

SFL: Sunflower lecithin;

SVM: Support Vector Machines;

T80: TWEEN 80

THC: tetrahydrocannabinol;

WPE: Whole plant extract; and

W/O: water-in-oil (emulsion).

Detailed Description of Illustrative Embodiments

[50] In a first of its several aspects, this disclosure provides certain pharmaceutical and/or nutraceutical compositions generally comprising extracts of Cannabis and edible or medical mushrooms. The compositions are useful for treating multiple conditions. The compositions alternatively or further generally comprise one or more cannabis extracts or purified or partially-purified cannabinoids, in combination with mushroom extracts, herbal extracts, or other components with nutraceutical properties. In certain embodiments, the compositions are emulsified as O/W or W/O nanoemulsions.

[51] The cannabis extracts can be derived from any Cannabis spp., and may include any cannabinoids. The cannabis extracts may further comprise any number of useful terpenes and/or flavonoids.

[52] In various embodiments, an extract of Cannabis is prepared to maximize one or more lipid-soluble fractions present in the plant, or any portion thereof, such as the buds or other portions that may be useful. Pressing or other mechanical means of removing oils from plants can be used in connection with the compositions herein. Extraction of lipids from Cannabis can be done by any method known in the art. In one embodiment, extraction is preferably done using a solvent that can be readily removed without leaving traces of toxic compounds, such as hexane or other organic solvents. Presently preferred are extraction methods such an ethanolic extraction or supercritical CO ₂ extraction.

[53] Extraction of Cannabis sativa strains can be from marijuana strains that comprise substantial amounts of the psychoactive cannabinoid, tetrahydrocannabinol ("THC"). In various embodiments, the extract comprises compounds from one or more of Ringo's Gift, OG Kush, Strawberry Cough, Orange Cookies, Jack Herer-derived strains or extracts (e.g., Black Jack, Super Jack, JI, and XJ13), and/or the Lemon family of strains of Cannabis sativa or extracts thereof. In other embodiments, the extracts comprise Ringo's Gift, Harle Tsu, ACDC, Charlotte's Web, The Gift, and/or Pineberry strains. Extracts comprising compounds from extracted from proprietary strains that are commercially available from Apollon Formularies, such as "Apollon Medical" ("APM"), are also useful herein. The skilled artisan will appreciate that multiple strains can be extracted for use together.

[54] In certain embodiments, preferably the cannabinoids are derived from hemp strains that comprise less than 0.3% THC by weight. In various embodiments, the THC content may be less than 0.2, or even less than 0.1% of the composition. Alternatively, the cannabinoids are derived from marijuana strains but the THC content is reduced or removed from the cannabinoids such that THC is present in the composition at less than about 0.3 percent. In other embodiments, the ratio of cannabinoids is set in the compositions. For example, in certain embodiments, the ratio of CBD to THC ranges from about 1:5 to about 30:1 or more. In other embodiments the ratio may range from about 1:2 to about 10:1. In still other embodiments, the ratio of CBD to THC may be about 1:1 to 5:1. In a presently preferred embodiment, the ratio is about 1:1.

[55] In other cases, the ratio of e.g., CBD to CBG or CBN may be set based on any of a variety of factors, including the health status of the subject being treated, the symptoms of the subject, the condition(s) being treated, and or one or more physiological or genetic criteria.

[56] Synthetic cannabinoids may also be useful herein. Certain such synthetic cannabinoids are presently FDA-approved, such as MARINOL, SYNDROS, and CESAMET and can be readily incorporated into the compositions and nanoemulsions.

[57] In various embodiments, the edible or medicinal mushroom(s) comprise one or more of the species Agaricus blazei, A. bisporus, A. subrufescens, Agrocybe aegerita, A. cylindracea, Albatrellus caeruleoporus, Amanita muscaria, Boletus edulis, Cantharellus cibarius, C. tubaeformis, Cordyceps militaris, C. pruinose, Caripia montagnei, Cyathus africanus, C. hookeri, Daldinia childiae, Dictyophora indusiata (synonym: Phallus indusiatus), Elaphomyces granulatus, Flammulina velutipes, Fomitopsis pinicola, Grifola frondosa, Ganoderma lucidum, Geastrum saccatum, Inonotus obliquus, Lactarius deliciosus, L. rufus, Lentinus edodes, L. polychrous, Lyophyllum decastes, Phellinus linteus, Pholiota nameko, Pleurotus pulmonarius, Poria cocos, and Termitomyces albuminosus. The mushroom(s) in other embodiments comprise one or more species such as Albatrellus confluens, Antrodia camphorate, Boletus badius, Clitocybe maxima, Cordyceps sinensis, Cordyceps liangshanensis, Cordyceps gunnii, Cordyceps cicadicola, Pomes fomentarius, Funalia trogii, Hericium erinaceus, Inocybe umbrinella, Lactarius flavidulus, Pleurotus ostreatus, Schizophyllum commune, Suillus placidus, or Trametes versicolor.

[58] More generally, mushrooms of the genera Agaricus, Agrocybe, Albatrellus, Amanita, Antrodia, Auricularia, Boletus, Calvatia, Cantharellus, Caripia, Clitocybe, Cordyceps, Cyathus, Daldinia, Dictyophora, Elaphomyces, Flammulina, Fames, Fomitopsis, Funalia, Ganoderma, Geastrum, Grifola, Hericium, Inocybe, Inonotus, Lactarius, Lentinus, Lentinula, Leucop axillus, Lyophyllum, Phellinus, Pholiota, Pleurotus, Poria, Russula, Sarcodona, Schizophyllum, Suillus, Termitomyces, Trametes, or Xerocomus may be useful herein.

[59] These mushrooms are all well known edible and/or medicinal mushrooms with a long history of use. Without limiting the invention to any particular theory of operation, mushrooms, such as Reishi, shitake, maitake, turkey tail, and many others have a plethora of beneficial and potentially therapeutic compounds present in them. For example, the polysaccharides, peptides, and/or other small molecules in various mushrooms have been shown to regulate the production of certain molecular mediators of inflammation and functions of immune cells (e.g., B- and/or T-cells) as well as pro-inflammatory lymphocytes, T-helper cells, T- killer cells, and macrophages. For example, the beta-1,3 D-glucans from certain mushrooms and other glycans may suppress cytokines such as interleukins tumor necrosis factor (TNF-a), and still other compounds

[60] Regardless of the mechanism(s) responsible, the compositions preferably comprise the benefits of such edible or medicinal mushroom(s) as described above.

[61] The edible or medicinal mushrooms or extracts can be present as fresh mushrooms, or as a dried mushroom or extract thereof, a lyophilized mushroom preparation, a mushroom powder, or an aqueous or alcohol extract (e.g., an ethanolic or other alcohol extract) of mushroom. Extracts for purposes herein can include hot- or cold-water extracts. Mushroom concentrates, or partially purified or even extensively purified mushroom fractions, or fully purified components or isolates from a mushroom are also useful herein.

[62] In certain embodiments, preferably, various extracts, concentrates, or partially purified fractions, or the like, are enriched for one or more advantageous mushroom component, or compounds with desirable effects on treatment of inflammation, immune status, or general health. In one embodiment, the extract, concentrate, partially purified fraction, or the like are enriched for one or more phenolic acids, flavonoids, triterpenes, carotenoids, stilbenes, sterols, fatty acids, lignans, chitosan, polyphenols, polysaccharides, glycosides, glucans, polysaccharide-protein complexes, glycoproteins, polysaccharopeptide, krestin, tocopherols, peptides, cyclic peptides, or other amino compounds found in the mushroom.

[63] While certain edible and / or medicinal mushrooms have been explored for their use in supporting or improving certain health conditions, the inventors have discovered that by providing mushroom extracts with additional compounds such as cannabinoids, terpenes, flavonoids, and other components, health benefits can be derived from the treatments with better outcomes and fewer side effects.

[64] In various presently preferred embodiments, the cannabinoids are derived from Cannabis spp. or an extract thereof. Cannabis can generally be concentrated or extracted (e.g., via mechanical or chemical means) to obtain cannabinoids. Mechanical means of extracting oils from plants, such as pressing, have been used for centuries, and may be suitable for use herein. Extraction via chemical means includes extraction with various volatile solvents that range from hydrocarbon solvents such as butane, hexanes, or propane, to supercritical fluids, alcohol (e.g., isopropanol, butanol, or ethanol), steam, or even water. Two very common methods are extraction with supercritical carbon dioxide, or ethanol, both of which are particularly useful herein. Extracts can also be distilled to e.g., remove additional compounds of interest, or to concentrate them. Certain components can be removed, e.g., by treatment with steam to strip certain volatiles, which can be captured as an additional component from the Cannabis. [65] The compositions, in various embodiments, include terpenes comprising one or more monoterpenes, one or more sesquiterpenes, or a combination thereof. The terpenes generally comprise one or more of alpha bisabolol, alpha pinene, beta caryophyllene, beta pinene, borneol, camphor, camphene, caryophyllene oxide, cineole, delta-3 carene, eucalyptol, farnesenes, farnesol, fenchol, fenchone, geraniol, guaiol, humulene, isopulegol, limonene, linalool, menthol, myrcene, nerol, nerolidol, ocimene, pinene, phytol, pulegone, terpinene, terpineol, terpinolene, or valencene.

[66] In one embodiment, the terpenes comprise phytol, limonene, humulene, myrcene, cineol, phellandrene, caryophyllene, terpinolene, linalool, ocimene, pinene, or a combination thereof. In other embodiments, the terpenes preferably comprise one or more of limonene, myrcene, beta-caryophyllene, linalool, alpha pinene, or a combination thereof. In one embodiment the terpenes include beta- ocimene, 1,8-cineole, alpha-pinene and / or beta-pinene, linalool, limonene, phytol, humulene, myrcene, phellandrene, caryophyllene, terpinolene, linalool, or other cineols or ocimenes, or any combination thereof, and the strains used to isolate terpenes are high in those terpenes, relative to other strains.

[67] In presently preferred embodiments, the terpenes are derived from Cannabis spp. or an extract thereof. The terpenes can be derived from any source and in certain embodiments, they can be present in steam distillate or an ethanolic extract of Cannabis sativa.

[68] The compositions in certain embodiments include extracts of Cannabis spp, such as C. sativa as a source of cannabinoids and/or terpenes. In various embodiments, the C. sativa comprises one or more of Ringo's Gift, OG Kush, Strawberry Cough, Orange Cookies, Jack Herer-derived strains, Lemon family strains, Harle Tsu, ACDC, Charlotte's Web, The Gift, or Pineberry strains. In other embodiments, the C. sativa comprises the proprietary Apollon Formularies strain, APM.

[69] In various other embodiments, the compositions may further comprise one or more flavonoids. The flavonoids can comprise chaicones, flavones, isoflavonoids, flavanones, anthoxanthins, anthocyanins, flavonols, or glucosides or other biologically active derivatives or analogs thereof, and combinations of any number of the foregoing. In certain embodiments, flavonoids are included in the compositions are isolated or derived from a plant, mushroom, or other natural source.

[70] In another embodiment, the composition still further comprises an extract or fraction from one or more traditional Jamaican medicinal plants other than Cannabis spp.. Any of the traditional Jamaican or Carribbean medicinal plants may be useful herein. Examples of Jamaican plants useful herein include ackee, aloe vera, avocado, breadflower, ginger, leaf of life, sorrel, soursop, tamarind, and trumpet. In one embodiment, the traditional medicinal plants comprise Jamaican sorrel Hibiscus sabdariffa), guinea hen weed (Petiveria alliacea), and/or soursop (Annona murata). In a presently preferred embodiments, the compositions include a whole plant extract, or an extract from any parts or portion thereof including but not limited to leaves (dried, fresh, or extracted), stems, flowers, roots, fruit, seeds, or the like.

[71] In terms of compounding the compositions, the skilled artisan will appreciate that methods of maximizing the efficacy of the composition such as by enhancing the bioavailability of one or more components, or by providing the components in optimized ratios, for example one component to another with which it interacts, or each component to the others in ratio(s) that optimize the absorption into the gut or bloodstream, or enhance the therapeutic effect of the composition. The skilled artisan will also understand that some information useful in improving the compounding may be obtained empirically.

[72] In various embodiments, the compositions, or one or more components thereof, may be solubilized, micronized, provided as, for example, extracts, powders, lyophilized powders, concentrates, tinctures, essential oils, aqueous or lipid suspensions, nanoemulsions, or in whole or part as liposomal, vesicular, or other delivery systems. As described below, the compounding or formulation of any of the compositions provided herein may be optimized for the intended delivery route.

[73] The compositions and nanoemulsions in various embodiments may be administered and delivered as pharmaceuticals, however, it is also contemplated that one or more of the compositions may be formulated for administration and delivery by oral routes that include as food and beverages, including solid, semisolid, and liquid foods, such as smoothies, shakes, pudding, broths, teas, and soups. The food and or beverage compositions can also include hot, cold, or even frozen foods (such as frozen desserts).

[74] Example 1: An embodiment of a preparation of a Mushroom composition and nanoemulsion in accordance with the specification

[75] Equipment and Supplies:

[76] Magnetic stirring hotplate

[77] Homogenizer

[78] Glass beakers

[79] Glass pipettes

[80] Ingredients:

[81] Mushrooms

[82] Selected mushroom extracts:

[83] Turkey Tail, Reishi, Shitake, Chaga, Cordpeeps, Maitake, Lions Mane, Cubensis, Reishi spores

[84] Other Ingredients

[85] Water: Reverse Osmosis purified

[86] Ethanol;

[87] Supercritical CO ₂ ;

[88] Medium Chain Triglyceride ("MCT") oil

[89] Sunflower lecithin (SFL)

[90] Tween 80 (T80)

[91 ] Process for preparing basic mushroom extract:

[92] A mushroom variety, multiple mushroom varieties, or a combination of such mushrooms is selected. The mushroom(s) are dried using a dehydrating process, such as a freeze dryer, low heat, vacuum drying, spray drying, or the like. The dried mushroom(s) are ground to a fine powder, (the size is determined by the formulator, and/or is based on the extraction method selected).

[93] The extraction is carried in a single, dual, or multiple step process depending on the fraction sought. Extraction can be via water, alcohol, alcohol/ water mixture, with added salts, buffer, pH control, osmotic conditions, etc., as required. Extraction temperature will generally be controlled but may be hot (e.g., hot water, 40-100 C), cold (e.g., 10 C, 4 C, 0 C, or lower), room temperature, or any temperature that is desired to recover useful components in active form. Any known extraction methods may be used.

[94] Additional steps such as a combination of water-soaking, heating, and filtration may be used. The final filtrate may be dried, such as spray dried. Alternatively, or additionally, a step of ethanol-soaking may be used, but is not needed for all mushroom types.

[95] Crude extracts may be used, or desired components may be separated and recovered by a distillation and condensation. Similarly, undesired volatiles can be removed by a distillation process.

[96] Preparation of Mushroom Emulsions:

[97] Once the desired extract or fraction(s) of mushroom(s) are obtained, emulsions can be prepared by sonication. In one embodiment, 45 g dried mushroom extract is combined with 90 ml H ₂ O and sonicated 6 times for, 10 sec pulses at 25khz. The material is filtered through a filter (e.g., 100 micron filter, 50 micron filter, 10 micron filter); and the filtrate is combined with 10 ml MCT oil, 2.5 ml SFL, and 2.5 ml Tween 80. The mixture is sonicated at 24 khz for six 10 sec pulses.

[98] Example 2: An embodiment of a preparation of a Cannabis composition and emulsion in accordance with the specification

[99] Equipment and Supplies:

[ 100] Magnetic stirring hotplate

[101] Homogenizer

[ 102] Glass beakers

[103] Glass pipettes

[104] Ingredients:

[105] Cannabis components

Whole plant extract (WPE) 1:1 Oil (WPE), CBD/CBDV Distillate) THC oil (distillate) CBG (isolate),

RG Terpenes (essential oil blend) Triterpenes

[106] Other Ingredients

[107] Water: Reverse Osmosis purified

[108] Ethanol;

[109] Supercritical CO ₂ ;

[110] Medium Chain Triglyceride ("MCT") oil

[111] Sunflower lecithin (SFL)

[112] Tween 80 (T80)

[113] Process for preparing basic Cannabis extract:

[114] The basic Cannabis starting materials are selected e.g., a whole plant, whole plant extract, distillate, isolate depending on desired components. The selected material is subjected to an extraction process for example, whole plants may be steam distilled, alcohol extracted (at any temperature desired, including 'cryogenically' wherein the ethanol or other alcohol cooled to a minimum of -20 C), or extracted via a falling film process, rotovap process, or a wiped film distillation. Supercritical CO ₂ processes and other extraction processes (such as extract with organic solvents or other volatiles) may also be used.

[115] Isolates may be obtained in a variety of ways depending on the properties of the fractions sought. The skilled artisan will understand how to obtain e.g., isolated cannabinoids such as THC, and/or isolated fractions without THC present. Distillates are obtained via distillation based on extraction of plant material or prior extraction with a solvent that can be distilled off. The desired fraction is left behind as distillate.

[116] Preparation of Cannabis Emulsions:

[117] Emulsions can be prepared by combining cannabinoids with other components and homogenizing and/or sonicating. In one embodiment 15,000 mg of cannabinoids is combined with 10 ml MCT and 2.5 ml SFL. The mixture is warmed to 30 C while stirring 600rpm and the warmed mixture is then homogenized at 5000 rpm for 20 seconds. 45ml H ₂ O and 2.5 ml Tween 80 are added before sonicating at 24 kHz for six 10 sec pulses.

[118] Example 3: An embodiment of a preparation of a Cannabis - mushroom nanoemulsion in accordance with the specification.

[119] Process for preparing Cannabis plus mushroom nanoemulsions-.

[120] The mushroom and water solution as prepared in Example 1 is the aqueous (or dispersed) phase, which is added to a cannabinoid /MCT/SFL mixture as prepared in Example 2. The mixture is sonicated, for example, at 24 kHz with 3 ml Tween 80.

[121] Where THCA oil was used, it was not heated, but instead was mixed overnight in MCT oil/SFL until dissolved. Some cannabis compositions were adjusted by combining 10 g of WPE with 2 g of each CBD, CBG, THC, and THCA, and 2 ml of terpenes.

[122] Turkey Tail mushroom extract (45 g) was soaked in 160-proof grain alcohol for 2 hours. The supernate was removed and the alcohol was distilled off. The distillate containing the compounds of interest was mixed with 45 ml water, 10 ml MCT, 2.5 ml SFL, and 2.5ml Tween 80.

[123] The resultant nanoemulsion had an average droplet size less than about 2 microns, 1 micron , 800 nanometers ,600 nanometers, or even 500 nanometers in various embodiments. However, the nanoemulsions were not satisfactory in that they continued to have large droplets in excess of several microns and even larger.

[124] To resolve this issue, several methods were utilized to attempt to more uniformly reduce the droplet size to an acceptable nanoemulsion size. Contrary to expectations and traditional thinking, merely providing additional sonication did not produce acceptable nanoemulsification. Difficulties persisted and failing the efforts to reduce the size of droplets, the inventor(s) decided to remove the large / 'resistant' droplets. The inventor(s) discovered that removal steps such as filtration through e.g. 10, 5, and 2 micron filters, and even 1 micron filters, combined with additional rounds of sonication sufficed to produce acceptable nanoemsulsifications of cannabis extracts and mushroom extracts. [125] The resultant nanoemulsions were more uniform in size distribution and also stable in that they did not readily separate if stored for at least several weeks or longer at 4 C or 25 C.

[126] The scope of the invention is set forth in the claims appended hereto, subject, for example, to the limits of language. Although specific terms are employed to describe the invention, those terms are used in a generic and descriptive sense and not for purposes of limitation. Moreover, while certain presently preferred embodiments of the claimed invention have been described herein, those skilled in the art will appreciate that such embodiments are provided by way of example only. In view of the teachings provided herein, certain variations, modifications, and substitutions will occur to those skilled in the art. It is therefore to be understood that the invention may be practiced otherwise than as specifically described, and such ways of practicing the invention are either within the scope of the claims, or equivalent to that which is claimed, and do not depart from the scope and spirit of the invention as claimed.