WO2022126112A1

WO2022126112A1 - Formulations containing cannabinoids

Info

Publication number: WO2022126112A1
Application number: PCT/US2021/072807
Authority: WO
Inventors: Robert Fritz; David GUILFORD
Original assignee: Dt Ip Holdings I LLC
Current assignee: Dt Ip Holdings I LLC
Priority date: 2020-12-08
Filing date: 2021-12-08
Publication date: 2022-06-16
Anticipated expiration: 2023-06-08

Abstract

Provided herein are formulations comprising a nanogel comprising a first fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof, and a second fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof, wherein the hyaluronic acid of the first fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight of greater than about 500 kilodaltons, and the hyaluronic acid of the second fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight of less than about 250 kilodaltons; lecithin liposomes within the nanogel, the lecithin liposomes having a d75 of from about 25 nm to about 250 nm; and one or more cannabinoids. The formulations can be used to treat a variety of diseases, disorders or conditions beneficially treated by a cannabinoid.

Description

Formulations Containing Cannabinoids

RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63/122,734, filed on December 8, 2020, and claims priority under 35 U.S.C. § 119 or 365 to Canadian Application No. 3,101,894, filed on December 8, 2020. The entire teachings of these applications are incorporated herein by reference.

BACKGROUND

[0002] Many active ingredients can only be delivered effectively by injection or other invasive techniques, making them costly and often impractical. Cannabinoids may have therapeutic benefits, but are often inhaled or ingested for effect, which can be damaging to the lungs or have varying effects when ingested based on the individual.

[0003] Thus, there is a need for delivery systems for cannabinoids and other active substances, such as terpenes and terpenoids, that do not rely on the aforementioned techniques.

SUMMARY

[0004] Provided herein is a formulation comprising a nanogel comprising a first fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof, and a second fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof; lecithin liposomes within the nanogel; and one or more cannabinoids, or a pharmaceutically acceptable salt thereof. The hyaluronic acid of the first fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight of greater than about 500 kilodaltons, and the hyaluronic acid of the second fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight of less than about 250 kilodaltons. The lecithin liposomes having a d₇₅ of from about 25 nm to about 250 nm.

[0005] Also provided herein is a formulation comprising a first fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof; a second fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof; lecithin liposomes; and one or more cannabinoids, or a pharmaceutically acceptable salt thereof. The hyaluronic acid of the first fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight of greater than about 500 kilodaltons. The hyaluronic acid of the second fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight of less than about 250 kilodaltons. The lecithin liposomes have a d₇₅ of from about 25 nm to about 250 nm.

[0006] Also provided herein is a method of making a formulation described herein, comprising forming a mixture of lecithin liposomes, one or more cannabinoids, or a pharmaceutically acceptable salt thereof, and hyaluronic acid, or a pharmaceutically acceptable salt thereof; and inducing gelation of the mixture.

[0007] Also provided herein is a method of administering a formulation described herein to a subject, comprising applying the formulation to the skin, a mucous membrane, a cheek or an eye or under a tongue of the subject.

[0008] Also provided herein is a method of modulating (e.g., activating) a cannabinoid receptor in a subject (e.g., a subject in need thereof), comprising administering to the subject a formulation described herein (e.g., an effective amount of a formulation described herein). Also provided herein is a formulation described herein for use in modulating (e.g., activating) a cannabinoid receptor in a subject (e.g., a subject in need thereof). Also provided herein is a formulation described herein for the manufacture of a medicament for modulating (e.g., activating) a cannabinoid receptor in a subject (e.g., a subject in need thereof).

[0009] Also provided herein is a method of treating a disease, disorder or condition described herein (e.g., a disease, disorder or condition associated with cannabinoid receptor activity or expression) in a subject in need thereof, comprising administering to the subject an effective amount of a formulation described herein. Also provided herein is a formulation described herein for use in treating a disease, disorder or condition described herein (e.g., a disease, disorder or condition associated with cannabinoid receptor activity or expression) in a subject in need thereof. Also provided herein is a formulation described herein for the manufacture of a medicament for treating a disease, disorder or condition described herein (e.g., a disease, disorder or condition associated with cannabinoid receptor activity or expression) in a subject in need thereof.

[0010] The formulations described herein are expected to be efficient and non-invasive delivery systems for cannabinoids.

DETAILED DESCRIPTION

[0011] A description of example embodiments follows. Definitions

[0012] As used herein, “a,” “an” and “the” include plural referents, unless the context dictates otherwise. Thus, for example, “a cannabinoid” includes one cannabinoid and a plurality of cannabinoids. Further, the plurality can be a plurality of the same cannabinoid or a plurality of different cannabinoids.

[0013] As used herein, “about” means approximately, roughly, around, or in the region of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20 percent up or down (higher or lower), e.g., 15 percent up or down, 10 percent up or down, 5 percent up or down, 4 percent up or down, 3 percent up or down, 2 percent up or down, or 1 percent up or down.

[0014] As used herein, “pharmaceutically acceptable,” when used in reference to an ingredient in a formulation base or formulation described herein, means non-toxic when administered in amounts consistent with the intended use of the formulation base or formulation including the ingredient.

[0015] As used herein, “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, the relevant teachings of which are incorporated herein by reference in their entirety.

[0016] The compounds described herein (e.g., cannabinoids, terpenes, terpenoids) may be in free base form or in the form of a pharmaceutically acceptable salt or solvate (e.g., hydrate). Pharmaceutically acceptable salts of the compounds described herein include salts derived from suitable inorganic and organic acids, and inorganic and organic bases that are compatible with the treatment of subjects.

[0017] Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion-exchange. Other pharmaceutically acceptable acid addition salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0018] In some embodiments, exemplary inorganic acids which form suitable salts include, but are not limited to, hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di- and tricarboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2- phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids, such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.

[0019] In some embodiments, acid addition salts are most suitably formed from pharmaceutically acceptable acids, and include, for example, those formed with inorganic acids, e.g, hydrochloric, sulfuric or phosphoric acids and organic acids, e.g, succinic, maleic, acetic or fumaric acid.

[0020] Illustrative inorganic bases which form suitable salts include, but are not limited to, lithium, sodium, potassium, calcium, magnesium or barium hydroxides. Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines, such as methylamine, trimethyl amine and picoline, or ammonia. The selection criteria for the appropriate salt are known to one skilled in the art.

[0021] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺((C₄-C₄) alkyl)₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. [0022] As used herein, “cannabinoid” refers to any compound that interacts with (e.g., binds to; activates, for example, as by binding to; agonizes; inhibits), either directly or indirectly, a cannabinoid receptor, such as cannabinoid receptor type 1 (CB ,) and/or cannabinoid receptor type 2 (CB₂). Cannabinoids include natural cannabinoids, as well as endocannabinoids and synthetic cannabinoids.

[0023] As used herein, “natural cannabinoid” refers to a cannabinoid found in cannabis and/or a Cannabis plant. Non-limiting examples of natural cannabinoids include tetrahydrocannabinol (THC) (e.g., A⁹-THC, A⁸-THC), cannabidiol (CBD), tetrahydrocannabinolic acid, cannabidolic acid, cannabinol (CBN), cannabigerol (CBG), cannabicyclol, cannabivarin, tetrahydrocannabivarin, tetrahydrocannabiphorol, cannabidivarin, cannabichromevarin, cannabichromene (CBC), cannabigerovarin, cannabigerol monomethyl ether, cannabielsoin (CBL), and cannabicitran. Further nonlimiting examples of natural cannabinoids include cannabinodiol (CBND), cannabioxepane (CBX), cannabicounmaronic acid, cannabitetrol, cannabiripsol, cannabichromanone, cannabiglendol, cannabifuran, ethoxy droxy tetrahydrocannabinol, cannabitroil, cannabicyclovarin, cannabicyclolic acid, cannabicyclol, cannabiclsion, cannabidiolic acid, cannabidiol monomethyl ether, cannabinodivarian, cannabidivarinic acid, 7- hydroxycannabichromane, cannabichromevarinic acid A, methyl propyl benzopyrene, cannabichromenic acid, carnagerol, cannabinerolic acid A, cannabigerovarian, cannabigerolic acid A/B, delta-8 tetrahydrocannabinolic acid, tetrahydrocannabollate, tetrahydrocannabiorcolic acid, tetrahydrocannabiorcol, tetrahydrocannabivarin, tetrahydrocannabinolic acid A/B and cannabitriol (CBT).

[0024] As used herein, “endocannabinoid” refers to a cannabinoid produced by the human body. Non-limiting examples of endocannabinoids include arachidonoylethanolamine (AEA), 2-arachidonoylglycerol (2 -AG), 2-arachidonyl glyceryl ether, A-arachidonoyl dopamine (NADA), virodhamine and lysophosphatidylinositol.

[0025] As used herein, “synthetic cannabinoid” refers to a cannabinoid not found in cannabis and/or a Cannabis plant or produced by the human body. Stated otherwise, synthetic cannabinoids are non-natural cannabinoids. Thus, though a natural cannabinoid or endocannabinoid, such as THC, is produced synthetically, for example, in a laboratory, rather than extracted from a Cannabis plant, such a natural cannabinoid or endocannabinoid does not become a “synthetic cannabinoid” by its method of production because it is found in cannabis and/or a Cannabis plant or produced by the human body. Classically, synthetic cannabinoids were analogs of natural cannabinoids or endocannabinoids, but synthetic cannabinoids now come from structurally varied chemical classes, including, for example, aminoalkylindoles, 1,5-diarylpyrazoles, quinolines and arylsulfonamides. Non-limiting examples of synthetic cannabinoids include nabilone, dronabinol, HU-210, rimonabant, JWH-018, JWH-073, CP-55940, dimethylheptylpyran, SRR144528, WIN 52,212-2, JWH- 133, levonantradol, AM-2201 and eicosanoids (e.g., methandamide).

[0026] Terpenes represent a diverse set of hydrocarbon natural products. Typically, terpenes are made up of isoprene or isopentane unit(s), and many obey the “terpene rule.” Often, a terpene is an unsaturated hydrocarbon, and can be described by the formula (C₅H₈)_n, wherein n is an integer greater than or equal to one. Terpenes are commonly produced by plants, and can be volatile. Non-limiting examples of terpenes include myrcene, limonene, caryophyllene, pinene (e.g., alpha-pinene, beta-pinene), camphene, humulene, delta 3 carene and valencene. Other examples of terpenes include the triterpenes cycloartane, cucurbitane, dammarane, lupane, taraxastane, taraxerane, ursane and lanostane. Yet other examples of terpenes include terpinene, ocimene (e.g., cis-ocimene, trans-ocimene), curcumene, terpinolene, alpha-phellandrene, meta-cymene, farnesene (e.g., alpha-famesene, betafamesene), ledene, curcumene, gurjunene, cedrene (e.g., alpha-cedrene, beta-cedrene), bergamotene, guaiene, cadinene, eudesmadiene, sabinene, thuj opsene, guaiazulene, cuparene, isolongifolene and euphol.

[0027] As used herein, “terpenoid” refers to a derivative of a terpene that has an additional type(s) of atoms (beyond carbon and hydrogen), typically, oxygen, for example, due to oxidation of the terpene. Non-limiting examples of terpenoids include linalool, alpha- bisabolol, eucalyptol, nerolidol (e.g., trans-nerolidol, cis-nerolidol), borneol, terpineol, geraniol and phytol. Other non-limiting examples of terpenoids include beta-el emene, citral, celastrol, falcarinol, pristimerin, piperitone, camphor, fenchyl alcohol, eudesmol, citronellol, citronellal, fenchone, geranyl acetate, cuminaldehyde, alpha-thujone, menthol, linalyl acetate, isopulegol, carvone, carvacrol, menthofuran, pulegone, bornyl acetate, isocannabispiran, isoborneol, caryophyllene oxide, cedrol, farnesol, gauiol and salvinorin A. [0028] As used herein, “nanogel” refers to a collection of nanoparticles composed of a hydrogel, a three-dimensional network of hydrophilic polymers having at least 10% water by weight or volume.

[0029] As used herein, “treat,” “treating,” and “treatment,” and the like, refer to the administration of a substance (e.g., a formulation described herein) to a subject, such as a human, having a disease, disorder or condition of interest, and includes: (i) inhibiting the disease, disorder or condition, e.g., arresting its development; (ii) relieving the disease, disorder or condition, e.g., causing regression of the disease, disorder or condition; and (iii) relieving the symptoms resulting from the disease, disorder or condition.

[0030] As used herein, “subject” refers to a mammal (e.g., human, non-human primate, cow, sheep, goat, horse, dog, cat, rabbit, guinea pig, rat, mouse or other bovine, ovine, equine, canine, feline, or rodent organism). In a particular embodiment, the subject is a human.

[0031] As used herein, “subject in need thereof’ refers to a subject who has, or is at risk for developing, a particular disease, disorder or condition. A skilled medical professional (e.g., physician) can readily determine whether a subject has, or is at risk for developing, a particular disease, disorder or condition.

[0032] As used herein, an “effective amount” is an amount of a substance (e.g., a formulation described herein) that, when administered to a subject in need thereof, is sufficient to treat the subject under the conditions of administration, such as an amount sufficient to inhibit (e.g., reduce, decrease, prevent) a disease, disorder or condition in a subject (e.g., patient) and/or an amount sufficient to relieve one or more symptoms resulting from a disease, disorder or condition in a subject. The effectiveness of a substance can be determined by any suitable method known to those of skill in the art.

Formulations

[0033] Provided herein is a formulation comprising a formulation base, e.g., as described herein, and one or more cannabinoids, or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the one or more cannabinoids includes a natural cannabinoid (e.g., THC and/or CBD, or a pharmaceutically acceptable salt of either of the foregoing; a natural cannabinoid described herein). In some embodiments, the one or more cannabinoids is selected from a natural cannabinoid (e.g., THC and/or CBD, or a pharmaceutically acceptable salt of either of the foregoing; a natural cannabinoid described herein). In some embodiments, the one or more cannabinoids includes an endocannabinoid (e.g., an endocannabinoid described herein). In some embodiments, the one or more cannabinoids is selected from an endocannabinoid (e.g., an endocannabinoid described herein). In some embodiments, the one or more cannabinoids includes a synthetic cannabinoid (e.g., a synthetic cannabinoid described herein). In some embodiments, the one or more cannabinoids is selected from a synthetic cannabinoid (e.g., a synthetic cannabinoid described herein). In some embodiments, one or more cannabinoids includes THC (e.g., A⁹- THC and/or A⁸-THC) or CBD, or a pharmaceutically acceptable salt thereof. In some embodiments, one or more cannabinoids includes THC (e.g., A⁹-THC and/or A⁸-THC) and CBD, or a pharmaceutically acceptable salt of the foregoing. In some embodiments, one or more cannabinoids includes A⁸-THC. In some embodiments, one or more cannabinoids includes A⁹-THC.

[0035] In some embodiments, the formulation further comprises nicotine, or a pharmaceutically acceptable salt thereof. In other embodiments, the formulation further comprises nicotine, or a pharmaceutically acceptable salt thereof, or a nicotine derivative, or a pharmaceutically acceptable salt thereof, or a combination thereof.

[0036] Nicotine is a chiral alkaloid that is naturally produced in the nightshade family of plants (most predominantly in tobacco and Duboisia hopwoodii), and is widely used recreationally as a stimulant and anxiolytic. As a pharmaceutical drug, it is used for smoking cessation to relieve withdrawal symptoms. Nicotine acts as a receptor agonist at most nicotinic acetylcholine receptors (nAChRs), except at two nicotinic receptor subunits (nAChRa9 and nAChRalO) where it acts as a receptor antagonist. Nicotine is being researched in clinical trials for possible benefit in treating Parkinson’s disease, dementia, ADHD, depression and sarcoma. Nicotine reduces aggression in people with autism spectrum disorder. Nicotine-containing products are sometimes used for the performance-enhancing effects of nicotine on cognition. A 2010 meta-analysis of 41 double-blind, placebo-controlled studies concluded that nicotine or smoking had significant positive effects on aspects of fine motor abilities, alerting and orienting attention, and episodic and working memory. A 2015 review noted that stimulation of the a4p2 nicotinic receptor is responsible for certain improvements in attentional performance; among the nicotinic receptor subtypes, nicotine has the highest binding affinity at the a4p2 receptor (ki = 1 nM), which is also the biological target that mediates nicotine’s addictive properties. Nicotine has potential beneficial effects, but it also has paradoxical effects, which may be due to the inverted U-shape of the dose-response curve or pharmacokinetic features.

[0037] It has been proposed that terpenes and terpenoids present in cannabis can enhance the activity of cannabinoids via the so-called entourage effect, resulting in cannabis synergism. See, for example, Downer, E.J., ACS Chem. Neurosci. 2020, 11, 659-662; Nesterkina, M., et al., Structural Chemistry (2020) 31 : 947-954; Russo, E.B., British Journal of Pharmacology (2011) 163 1344-1364; Russo, E.B., Frontiers in Plant Science, January 2019, vol. 9, Article 1969, 8 pages; and Gongalves, E.C.D., et al. Molecules 2020, 25(7): 1567, the entire contents of which are incorporated herein by reference.

[0038] Thus, in some embodiments, the formulation further comprises one or more terpenes and/or terpenoids (e.g., a collection of terpenes and/or terpenoids, such as from one to 15, from one to 10, from one to five, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc. terpenes and/or terpenoids), or a pharmaceutically acceptable salt of the foregoing. In some embodiments, the one or more terpenes and/or terpenoids include one or more (e.g., one, two, three, four, five, etc.) of myrcene, limonene, caryophyllene, pinene, camphene, humulene, delta 3 carene, valencene, linalool, alpha-bisabolol, eucalyptol, nerolidol, borneol, terpineol, geraniol, phytol, terpinolene, valencene or ocimene (e.g., caryophyllene, limonene, humulene, linalool, myrcene, ocimene or pinene), or a pharmaceutically acceptable salt of the foregoing. In some embodiments, the one or more terpenes is selected from myrcene, limonene, caryophyllene, pinene, camphene, humulene, delta 3 carene, valencene, linalool, alpha-bisabolol, eucalyptol, nerolidol, borneol, terpineol, geraniol, phytol, terpinolene, valencene or ocimene (e.g., caryophyllene, limonene, humulene, linalool, myrcene, ocimene or pinene), or a pharmaceutically acceptable salt of the foregoing.

[0039] Terpenes and/or terpenoids can have various biological activities. For example: [0040] Camphene has been shown to have insecticidal activity. See, for example, Gongalves, E.C.D., et al. Molecules 2020, 25(7): 1567, the entire content of which is incorporated herein by reference.

[0041] Caryophyllene (also referred to as beta-caryophyllene), has been shown to be a cannabinoid receptor 2 (CB2) agonist, and to exhibit anti arthritic, anti-inflammatory, anxiolytic, anti-depressant, anti-compulsive, anti -microbial (e.g., antibacterial, antifungal, antiparasitic, such as antimalarial), antioxidant and anti-cancer (e.g., anti-colorectal cancer) activities. See, for example, Rufino, A.T., et al., European Journal of Pharmacology, 750 (2015) 141-150; Dahham, S.S., et al., Molecules 2015, 20, 11808-11829; Bahi, ., etal., Physiology & Behavior 135 (2014) 119-124; de Cassia da Silveira e Sa, R., et al., Int. J. Mol. Sci., 2017, 18, 2392; Gertsch, J., etal., PNAS, July 1, 2018 105(26): 9099-9104; Skold, M., et al., Food and Chemical Toxicology 44 (2006) 538-545; and Gertsch, Jr., Communicative & Integrative Biology 1 : 1 26-28: July/August/September 2008, the entire contents of which are incorporated herein by reference. Caryophyllene has also been shown to have gastroprotective, analgesic, anti-proliferative, anti -convulsive and neuroprotective activities, and to inhibit acetylcholinesterase. See, for example, See, for example, Goncalves, E.C.D., et al. Molecules 2020, 25(7): 1567; and Sommano, S.R., et al., Molecules 2020, 25, 5792, the entire contents of which are incorporated herein by reference. Caryophyllene oxide has been shown to have anti-fungal and insecticidal activities. Sommano, S.R., et al., Molecules 2020, 25, 5792, the entire content of which is incorporated herein by reference.

[0042] Celastrol has been shown to have antioxidant, anti-cancer and anti-inflammatory activities, and has been used to treat chronic disease, neurodegenerative disorders e.g., amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease), type 2 diabetes, obesity, atherosclerosis, cancer, inflammatory and autoimmune diseases (e.g., systemic lupus erythematosus, multiple sclerosis, IBD, psoriasis and rheumatoid arthritis). See, for example, Gongalves, E.C.D., et al. Molecules 2020, 25(7): 1567, the entire content of which is incorporated herein by reference.

[0043] Citral has been shown to have anti-inflammatory, anti-nociceptive, anticancer, antibiotic and antifungal activities. See, for example, Goncalves, E.C.D., et al. Molecules 2020, 25(7): 1567, the entire content of which is incorporated herein by reference.

[0044] Beta-elemene has been shown to exhibit anti-cancer and anti-lipidemic activities. See, for example, Gongalves, E.C.D., et al. Molecules 2020, 25(7): 1567, the entire content of which is incorporated herein by reference.

[0045] Euphol has been shown to have antiviral, antiparasitic, antimicrobial, antifungal, anti-cancer and anti-inflammatory activities. See, for example, Goncalves, E.C.D., et al. Molecules 2020, 25(7): 1567, the entire content of which is incorporated herein by reference. [0046] Falcarinol has been shown to have anticarcinogenic and anti-inflammatory activities. See, for example, Gongalves, E.C.D., et al. Molecules 2020, 25(7): 1567, the entire content of which is incorporated herein by reference.

[0047] Humulene has been shown to have anti-inflammatory (e.g., anti-airways allergic inflammation) activity. See, for example, Rogerio, A.P., et al., British Journal of Pharmacology (2009) 158, 1074-1087, the entire content of which is incorporated herein by reference.

[0048] Limonene (e.g., D-limonene, L-limonene) has been shown to exhibit anticancer (e.g., anti -lymphoma, mammary, gastric, liver, lung, breast cancer), anti-inflammatory, sedative, anxiolytic, antidepressant, anti-bacterial (e.g., anti-acne-causing bacteria) activities. D-Limonene has also been shown to enhance transdermal penetration of felodipine. See, for example, Baron, E.P., et al., The Journal of Headache and Pain (2018) 19: 37; Gurgel do Vale, T., et al., Phytomedicine 9: 709-714, 2002; Rufino, A.T., et al., European Journal of Pharmacology, 750 (2015) 141-150; de Cassia da Silveira e Sa, R., et al., Int. J. Mol. Sci., 2017, 18, 2392; Ciftci, O., et al., Toxicol Ind Health. 2011 Jun 27 (5):447-53. doi: 10.1177/0748233710388452. Epub 2011 Jan 18; Komori, T., et al., Neuroimmunomodulation. 1995 May-Jun;2(3): 174-80; Miller, J. A., et al., Nutr Cancer. 2010; 62(6): 783-788; Diez, I., et al., Journal of Drug Metabolism and Pharmacokinetics 1998, 23(1), 7-12; and Technology & Pharmacy Institute, Rio de Ja: Ingestion of essential oils betamyrcene and limonene can inhibit inflammation, Biotech Week; Atlanta, 22 Oct 2003: 422, the entire contents of which are incorporated herein by reference. D-Limonene has also been associated with gastroprotective, anti -nociceptive and neuroprotective activities. See, for example, Gongalves, E.C.D., et al. Molecules 2020, 25(7): 1567, the entire content of which is incorporated herein by reference.

[0001] Linalool has been shown to have anti-inflammatory, anxiolytic, anticonvulsant, antinociceptive, antimicrobial (e.g., leishmanicidal) and sedative activities. See, for example, Karsak, M., Science, Jun 8, 2007, New series, 316 (5830): 1494-1497; Perry, N.S., et al., J. Pharm., Pharmacol. 2000, 52: 895-902; Rosa, M., et al., Antimicrobial Agents and Chemotherapy, June 2003, p. 1895-1901; Li, X.-J., et al., Journal of Ethnopharmacology 179 (2016) 22-26; de Cassia da Silveira e Sa, R., et al., Int. J. Mol. Sci., 2017, 18, 2392; and Guzman-Gutierrez, S.L., et al., “Linalool and P-pinene exert their antidepressant-like activity through the monoaminergic pathway”, Life Sciences 128 (2015) 24-29, the entire contents of which are incorporated herein by reference. Linalool has also been shown to have anticancer activity and neuroprotective activity, e.g., against Alzheimer’s disease. See, for example, Gongalves, E.C.D., et al. Molecules 2020, 25(7): 1567, the entire content of which is incorporated herein by reference.

[0002] Myrcene has been shown to exhibit anti-carcinogenic, anti-inflammatory, sedative and analgesic activities. See, for example, Sommano, S.R., et al., Molecules 2020, 25, 5792; Applequist, W., Economy Botany, 59(1): 102-102, downloaded on Nov. 4, 2020; Islam, A.U.S., et al., Molecules 2020, 25, 4492; Jansen, C., et al., Channels, 2019, 13(01): 344-366; Gurgel do Vale, T., et al., Phytomedicine 9, 709-714, 2002; and Technology & Pharmacy Institute, Rio de Ja: Ingestion of essential oils beta-myrcene and limonene can inhibit inflammation, Biotech Week; Atlanta, 22 Oct 2003: 422, the entire contents of which are incorporated herein by reference.

[0003] Nerolidol has been shown to have anti-microbial, anti-inflammatory, anti-cancer and neuroprotective activities. See, for example, Goncalves, E.C.D., et al. Molecules 2020, 25(7): 1567, the entire content of which is incorporated herein by reference.

[0004] Ocimene has been shown to exhibit antifungal, antioxidant and anti-inflammatory activities. See, for example, Valente, J., et al., Food and Chemical Toxicology 62 (2013) 349-354, the entire content of which are incorporated herein by reference. Ocimene has also been shown to exhibit antiproliferative and anticonvulsant activities. See, for example, Gongalves, E.C.D., et al. Molecules 2020, 25(7): 1567, the entire content of which is incorporated herein by reference.

[0005] Pinene (e.g., alpha-pinene, beta-pinene) has been shown to exhibit antiinflammatory, bronchodilatory, antimicrobial (e.g., antibacterial, anti-viral, antifungal, antimalarial), analgesic, antidepressant and anti-acetylcholinesterase activities. See, for example, Sommano, S.R., et al., Molecules 2020, 25, 5792; Li, X-J., et al., Journal of Ethnopharmacology 179 (2016) 22-26; Falk, A. A., et al., Scand J. Work Environ Health 1990: 16: 372-8; Guzman-Gutierrez, S.L., et al., Life Sciences 128 (2015) 24-29; Bickers, D., et al., Food and Chemical Toxicology, 41 (2003) 919-942; and Nissen, L., et al., Fitoterapia 81 (2010) 413-419, the entire contents of which are incorporated herein by reference. Alphapinene has also been shown to exhibit sedative, anti-seizure, anti-cancer, antioxidant, antitumor, hypnotic and anxiolytic activities, as well as neuroprotective activity, e.g., against memory loss. See, for example, Gongalves, E.C.D., et al. Molecules 2020, 25(7): 1567, the entire content of which is incorporated herein by reference. Beta-pinene has also been shown to exhibit anti-cancer, antimicrobial and antioxidant activities. See, for example, Goncalves, E.C.D., et al. Molecules 2020, 25(7): 1567, the entire content of which is incorporated herein by reference.

[0006] Pristimerin has been shown to have anti-cancer and anti-metastatic activities. See, for example, Gongalves, E.C.D., et al. Molecules 2020, 25(7): 1567, the entire content of which is incorporated herein by reference. [0007] Salvinorin A has been shown to have anxiolytic, anti-inflammatory and antidepressant activities, and has been used to treat cocaine-seeking behavior and alcoholism. See, for example, Gongalves, E.C.D., et al. Molecules 2020, 25(7): 1567, the entire content of which is incorporated herein by reference.

[0008] Terpineol has been shown to have antinociceptive, neuroprotective, antifungal, anti-inflammatory and antidiarrheal activities. See, for example, Goncalves, E.C.D., et al. Molecules 2020, 25(7): 1567, the entire content of which is incorporated herein by reference. Terpineol has also been shown to have analgesic activity, e.g., in chronic pain conditions, such as fibromyalgia and cancer, and has been used prophylactically for opioid analgesic dependence and tolerance. See, for example, Goncalves, E.C.D., et al. Molecules 2020, 25(7): 1567, the entire content of which is incorporated herein by reference.

[0009] Terpinene (e.g., gamma-terpinene) has been associated with anti-inflammatory, antimicrobial, analgesic and anti-proliferative activities. See, for example, Goncalves, E.C.D., et al. Molecules 2020, 25(7): 1567, the entire content of which is incorporated herein by reference.

[0010] In some embodiments, the one or more terpenes and/or terpenoids include one or more of the terpenes and/or terpenoids having various biological activities discussed above. In some embodiments, the one or more terpenes and/or terpenoids are selected from the terpenes and/or terpenoids having various biological activities discussed above.

[0011] Terpenes and/or terpenoids are often grouped into collections based on a particular activity(ies). Often, one or more terpenes and/or terpenoids in a particular collection can cross over from one activity to another. Examples of activities include antiinflammatory (e.g., anti-irritable bowel disorder (IBD)), analgesic, sedative (e.g., sleepinducing, anti-anxiety), immunomodulatory, anti-diabetes and anti-convulsant (e.g., antiseizure). When one or more terpenes and/or terpenoids possessing a particular activity(ies) is incorporated into a composition described herein, it is believed that inclusion of the terpene and/or terpenoid in the composition will imbue the composition with that particular activity(ies). For example, when a terpene and/or terpenoid having anti-inflammatory activity is included in a composition described herein, it is expected that the composition will also have anti-inflammatory activity.

[0012] In some embodiments, a terpene and/or terpenoid has anti-inflammatory activity. Terpenes and/or terpenoids that have anti-inflammatory activity, and are thereby believed to possess utility in the treatment of, for example, IBD, airways allergic inflammation and renal inflammation, include caryophyllene, limonene, humulene, linalool, myrcene, ocimene, pinene (e.g., alpha-pinene), borneol, camphene, delta-3 -carene, valencene and bisabolol (e.g., alpha-bisabolol). Thus, in some embodiments, a composition (e.g., having anti-inflammatory activity) includes one or more of (e.g., one, two, three, four, five, etc., - the following terpenes and/or terpenoids) caryophyllene, limonene, humulene, linalool, myrcene, ocimene, pinene (e.g., alpha-pinene), borneol, camphene, delta-3 -carene, valencene and bisabolol (e.g., alpha- bisabolol), or a pharmaceutically acceptable salt of the foregoing.

[0013] In some embodiments, a terpene and/or terpenoid has analgesic activity. Terpenes and/or terpenoids that have analgesic activity include caryophyllene, limonene, linalool, myrcene, borneol, eucalyptol, geraniol and pinene (e.g., alpha-pinene). Thus, in some embodiments, a composition (e.g., having analgesic activity) includes one or more of (e.g., one, two, three, four, five, etc., - the following terpenes and/or terpenoids) caryophyllene, limonene, linalool, myrcene, borneol, eucalyptol, geraniol and pinene (e.g., alpha-pinene), or a pharmaceutically acceptable salt of the foregoing.

[0014] In some embodiments, a terpene and/or terpenoid has sedative activity. Terpenes and/or terpenoids that have sedative activity, and are thereby believed, for example, to induce sleep and/or possess utility in the treatment of, for example, sleep disorders and/or anxiety, include limonene, linalool, nerolidol (e.g., trans-nerolidol), caryophyllene, phytol, terpinolene, valencene and myrcene. Thus, in some embodiments, a composition (e.g., having sedative activity) includes one or more of (e.g., one, two, three, four, five, etc., - the following terpenes and/or terpenoids) limonene, linalool, nerolidol (e.g., trans-nerolidol), caryophyllene, phytol, terpinolene, valencene and myrcene, or a pharmaceutically acceptable salt of the foregoing.

[0015] In some embodiments, a terpene and/or terpenoid has immunomodulatory activity. Terpenes and/or terpenoids that have immunomodulatory activity include camphene, humulene, limonene, phytol, terpinolene and nerolidol (e.g., trans-nerolidol). Thus, in some embodiments, a composition (e.g., having immunomodulatory activity) includes one or more of (e.g., one, two, three, four, five, etc., - the following terpenes and/or terpenoids) camphene, humulene, limonene, phytol, terpinolene and nerolidol (e.g., trans-nerolidol), or a pharmaceutically acceptable salt of the foregoing.

[0016] In some embodiments, a terpene and/or terpenoid has anti-diabetes activity. Terpenes and/or terpenoids that have anti-diabetes activity, and are thereby believed to possess utility, for example, in treatment of diabetes, include myrcene and triterpenes and/or triterpenoids, including ursane, taraxastane, taraxerane, lupane, dammarane, cucurbitane, cycloartane and lanostane. See, for example, Putta, S., et al., Curr. Top. Med. Chem. 2016, 16(23): 2532-42; and Nazaruk, J. and Borzym-Kluczyk, M., Phythochem Rev. 2015, 14(4):675-690, the entire contents of which are incorporated herein by reference. Thus, in some embodiments, a composition (e.g., having anti-diabetes activity) includes one or more of (e.g., one, two, three, four, five, etc., - the following terpenes and/or terpenoids) myrcene, ursane, taraxastane, taraxerane, lupane, dammarane, cucurbitane, cycloartane and lanostane, or a pharmaceutically acceptable salt of the foregoing.

[0017] In some embodiments, a terpene and/or terpenoid has anti-convulsant activity. Terpenes and/or terpenoids that have anti-convulsant (e.g., anti-seizure) effect, and are thereby believed to possess utility in the treatment of, for example, convulsions and/or seizures, include linalool, nerolidol (e.g., trans-nerolidol), valencene and caryophyllene. Thus, in some embodiments, a composition (e.g., having anti-convulsant activity) includes one or more of (e.g., one, two, three, four; the following terpenes and/or terpenoids) linalool, nerolidol (e.g., trans-nerolidol), valencene and caryophyllene, or a pharmaceutically acceptable salt of the foregoing.

[0018] In some embodiments, the formulation is a nutraceutical formulation. In some embodiments, the formulation is a cosmetic formulation. In some embodiments, the formulation is a cosmeceutical formulation. In some embodiments, the formulation is a pharmaceutical formulation.

[0019] In some embodiments, one or more cannabinoids (e.g., THC and/or CBD, or a pharmaceutically acceptable salt of either of the foregoing) is encapsulated within the lecithin liposomes. Encapsulation, particularly of unstable compounds, can increase the amount of a compound that is ultimately delivered to a subject compared to unencapsulated delivery. Encapsulation can also be used to provide modified release (e.g., delayed release, extended release, sustained release) of an encapsulated compound.

[0020] Although not wishing to be bound by any particular theory, it is believed that the formulations described herein provide for rapid (e.g., less than about 10 minutes, less than about 5 minutes, less than about 1 minute) transdermal delivery of their constituents, including the hyaluronic acid, lecithin liposomes and one or more cannabinoids contained therein, directly to the bloodstream of a subject. For some applications, it is desirable to delay release of one or more constituents of a formulation, for example, to delay and/or extend the effect of an active agent, such as one or more cannabinoids, in the formulation. Thus, for example, CBD, or a pharmaceutically acceptable salt thereof, can be encapsulated within lecithin liposomes in a formulation described herein to provide modified release (e.g., delayed release, extended release, sustained release) of the CBD, or a pharmaceutically acceptable salt thereof. In another example, a first portion of CBD, or a pharmaceutically acceptable salt thereof, contained in a formulation described herein can be encapsulated within lecithin liposomes, while a second portion of CBD, or a pharmaceutically acceptable salt thereof, contained in the formulation is not encapsulated within the lecithin liposomes. In this latter example, release of the second portion is expected to precede release of the first portion of CBD, or a pharmaceutically acceptable salt thereof, providing immediate release of the second portion and modified release (e.g., delayed release, extended release, sustained release) of the first portion of CBD, or a pharmaceutically acceptable salt thereof.

[0021] Thus, in some embodiments, a first portion of at least one of the one or more cannabinoids (e.g., a first portion of one of the one or more cannabinoids; a first portion of each of the cannabinoids, wherein the first portion (by weight, by weight percent) of each of the cannabinoids is the same or different) is encapsulated within the lecithin liposomes, and a second portion (typically, the remaining portion) of the at least one of the one or more cannabinoids is not encapsulated within the lecithin liposomes. In some aspects of these embodiments, wherein the at least one of the one or more cannabinoids includes CBD or THC, or a pharmaceutically acceptable salt of either of the foregoing, a first portion of CBD or THC, or a pharmaceutically acceptable salt of either of the foregoing, is encapsulated within the lecithin liposomes, and a second portion of CBD or THC, respectively, or a pharmaceutically acceptable salt of either of the foregoing, is not encapsulated within the lecithin liposomes.

[0022] The temporal control provided by liposomal encapsulation can also be used, for example, to provide immediate release of a first cannabinoid and modified release (e.g., delayed release, extended release, sustained release) of a second cannabinoid, for example, as when a formulation comprises more than one cannabinoid (e.g., a first cannabinoid, such as CBD, and a second cannabinoid, such as THC; a first cannabinoid, such as THC, and a second cannabinoid, such as CBD).

[0023] Thus, in some embodiments, the formulation comprises a first cannabinoid (e.g., CBD, THC, or a pharmaceutically acceptable salt of either of the foregoing) and a second cannabinoid (e.g., THC, CBD, respectively, or a pharmaceutically acceptable salt of either of the foregoing), and the first cannabinoid is encapsulated within the lecithin liposomes. In some aspects of these embodiments, the second cannabinoid is not encapsulated within the lecithin liposomes.

[0024] When a formulation further comprises one or more terpenes and/or terpenoids (e.g., a collection of terpenes and/or terpenoids), or a pharmaceutically acceptable salt of the foregoing, the one or more terpenes and/or terpenoids, or a pharmaceutically acceptable salt of the foregoing, can be encapsulated within the lecithin liposomes, either with or without one or more cannabinoids. Thus, in some embodiments, the one or more terpenes and/or terpenoids, or a pharmaceutically acceptable salt of the foregoing, are encapsulated within the lecithin liposomes, and the one or more cannabinoids, or a pharmaceutically acceptable salt thereof, are not encapsulated within the lecithin liposomes. In some embodiments, the one or more terpenes and/or terpenoids, or a pharmaceutically acceptable salt of the foregoing, and at least one of the one or more cannabinoids, or a pharmaceutically acceptable salt thereof, or a portion of either of the foregoing, are encapsulated within the lecithin liposomes. Alternatively, the one or more cannabinoids, or a pharmaceutically acceptable salt thereof, may be encapsulated within the lecithin liposomes, while the one or more terpenes and/or terpenoids, or a pharmaceutically acceptable salt of the foregoing, are not encapsulated within the lecithin liposomes.

[0025] When a constituent of a formulation described herein in not encapsulated within lecithin liposomes, it is typically dispersed (e.g., uniformly dispersed) within the nanogel formed by the hyaluronic acid matrix.

[0026] Typically, from about 1% to about 99%, from about 50% to about 99%, from about 75% to about 99%, from about 90% to about 99%, about 90%, about 91% about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% of the formulation by weight is the formulation base. In some embodiments, the nanogel (e.g., including both aqueous and hyaluronic acid components) is from about 75% to about 99.9%, from about 90% to about 99.9%, from about 95% to about 99.9%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8% or about 99.9% by weight of the formulation base. In some embodiments, the hyaluronic acid, or a pharmaceutically acceptable salt thereof, is from about 0.1% to about 10%, from about 0.1% to about 7.5%, from about 0.1% to about 5%, from about 1% to about 10%, from about 1% to about 5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10% by weight of the formulation base. In some embodiments, the first fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof, is from about 0.1% to about 10%, from about 0.1% to about 7.5%, from about 0.1% to about 5%, from about 1% to about 10%, from about 1% to about 5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10% by weight of the formulation base. In some embodiments, the second fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof, is from about 0.1% to about 10%, from about 0.1% to about 7.5%, from about 0.1% to about 5%, from about 0.1% to about 3%, from about 0.1% to about 1%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4% or about 5% by weight of the formulation base. In some embodiments, the lecithin liposomes are from about 0.1% to about 10%, from about 0.1% to about 7.5%, from about 0.1% to about 5%, from about 0.1% to about 1%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9% or about 1% by weight of the formulation base.

[0027] Typically, the one or more cannabinoids, terpenes and terpenoids, or a pharmaceutically acceptable salt of the foregoing, taken individually or collectively, are from about 0.1% to about 30%, from about 0.1% to about 20%, from about 0.1% to about 10%, from about 0.1% to about 7.5%, from about 0.1% to about 5%, from about 1% to about 30%, from about 1% to about 20%, from about 1% to about 10%, from about 1% to about 2.5%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 2.5%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10% of the formulation by weight. In some embodiments, the one or more terpenes and/or terpenoids, or a pharmaceutically acceptable salt of the foregoing, taken individually or collectively, are from about 0.001% to about 10%, e.g., from about 0.001% to about 5%, from about 0.001% to about 3%, from about 0.005% to about 5%, from about 0.005% to about 3%, from about 0.01% to about 10%, from about 0.01% to about 5%, from about 0.01% to about 3%, from about 0.1% to about 10%, from about 0.1% to about 5% or from about 0.01% to about 3%, of the formulation by weight.

[0028] The formulations described herein are particularly suitable for topical administration. The formulation described herein can, however, also be administered orally, parenterally (including subcutaneously, intramuscularly, intravenously, intradermally, by inhalation, topically, rectally, nasally and vaginally) or buccally, or via an implanted reservoir. The term “parenteral,” as used herein, includes subcutaneous, intracutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intra-arterial, intra- synovial, intrasternal, intrathecal, intralesional, intrahepatic, intraperitoneal intralesional and intracranial injection or infusion techniques.

[0029] As used herein, “topical administration” refers to administration of a substance (e.g., a formulation base or formulation, such as a formulation base or formulation described herein) to a particular place or particular places on or in the body of a subject without regard to the location of the effect of the substance, if any. Thus, the effect of a formulation comprising a formulation base described herein may be local or, preferably, systemic. Nonlimiting examples of topical routes of administration include transdermal, transmucosal (e.g., oral, nasal, vaginal, urethral), sublingual, buccal, nasal and ocular routes of administration. It follows that the formulations (and formulation bases) described herein can, in some embodiments, be administered to the skin, a mucous membrane (e.g., oral, nasal, vaginal, urethral mucous membrane), under the tongue, the cheek, the nose and/or the eye of a subject.

[0030] In some embodiments, a formulation described herein is formulated for topical administration. In some embodiments, the formulation is formulated for transdermal administration. In some embodiments, the formulation is formulated for sublingual administration.

[0031] The formulations described herein can take the form of an emulsion, or a gel (e.g., hydrogel, nanogel), cream, foam, lotion, ointment, paste, spray or drop, and are suitable for use in formulations with a variety of applications, including nutraceutical, pharmaceutical, cosmeceutical and cosmetic. For rectal administration or administration to the lower intestinal tract, the formulation can be in the form of a suppository. A suppository is typically formulated with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and, therefore, will melt in the rectum. Such excipients include cocoa butter, beeswax and polyethylene glycols. For ophthalmic use, formulations can be provided as micronized suspensions in isotonic, pH-adjusted sterile saline, or, preferably, as solutions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the formulations can be formulated as ointments, for example, with petrolatum. For nasal administration (e.g., inhalation), formulations can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. [0032] The formulations described herein can further include an excipient (e.g., a pharmaceutically acceptable excipient), e.g., to increase the stability of the formulation, or other physical characteristic of the formulation. Typically, such carriers are non-bioactive, meaning they have insubstantial or no biological activity and/or produce insubstantial or no biological effect, e.g., in the amount administered. Examples of excipients include preservatives, such as sodium hydroxymethylglycinate (Suttocide™ A) and optiphen, flavor enhancers, such as orange oil, diluents, solvents, glycerin, gelatin, albumin, lactose, starch, stabilizers, melting agents, emulsifying agents, such as polysorbates (e.g., polysorbate 40), suspending agents, salts and buffers. An excipient can be organic or inorganic.

[0033] Typically, excipient(s), taken individually or collectively, are from about 0.1% to about 30%, from about 0.1% to about 20%, from about 0.1% to about 10%, from about 0.1% to about 7.5%, from about 0.1% to about 5%, from about 1% to about 30%, from about 1% to about 20%, from about 1% to about 10%, from about 1% to about 5%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 2.5%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10% of the formulation by weight.

[0034] The formulations described herein can provide for immediate release or modified release (e.g., delayed release, extended release, sustained release) of one or more active substances (e.g., cannabinoids) with which they are combined.

Formulation Bases

[0035] The formulation bases described herein comprise a nanogel comprising hyaluronic acid, or a pharmaceutically acceptable salt thereof; and lecithin liposomes within the nanogel (e.g., lecithin liposomes having a d₇₅ of from about 25 nm to about 250 nm).

[0036] In some embodiments, a formulation base comprises a nanogel comprising a first fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof, having a first molecular weight, and a second fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof, having a second molecular weight different from the first molecular weight; and lecithin liposomes within the nanogel (e.g., lecithin liposomes having a d₇₅ of from about 25 nm to about 250 nm).

[0037] In some embodiments, a formulation base comprises a first fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof; a second fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof; and lecithin liposomes (e.g. , lecithin liposomes having a d₇₅ of from about 25 nm to about 250 nm), wherein the hyaluronic acid of the first fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight of greater than about 500 kilodaltons, and the hyaluronic acid of the second fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight of less than about 250 kilodaltons.

[0038] Hyaluronic acid (HA) is a naturally-occurring glycosaminoglycan and a major component of the extracellular matrix. See, for example, Arpicco, S., et al., “Hyaluronic Acid Conjugates as Vectors for the Active Targeting of Drugs, Genes and Nanocomposites in Cancer Treatment,” Molecules 2014, 19, 3193-3230, the content of which is incorporated herein by reference in its entirety. HA has been shown to play a role in inflammation, and to exert anti-inflammatory and anti -oxi dative effects. See, for example, Petrey, A., et al., “Hyaluronan, a crucial regulator of inflammation,” Frontiers in Immunology \ Inflammation, March 2014, Volume 5, Article 101; and Gupta R. C., et al., “Hyaluronic Acid; Molecular Mechanisms and Therapeutic Trajectory,” Front. Vet. Sci. 6: 192, the contents of which are incorporated herein by reference in their entireties. Without wishing to be bound by any particular theory, it is believed that HA can be used to reduce inflammation.

[0039] It has also been reported that HA (high molecular weight HA, in particular, such as HA having a molecular weight of greater than about 500 kDa) reduces nociceptor sensitization, attenuating inflammatory and neuropathic hyperalgesia and pain. Caires, R., et al., “Hyaluronon modulates TRPV1 channel opening, reducing peripheral nociceptor activity and pain,” Nature Communications doi: 10.1038/ncomms9095 (27 Aug 2015); Ferrari, L.F., et al, “CD44 Signaling Mediates High Molecular Weight Hyaluranon-Induced Antihyperalgesia,” The Journal of Neuroscience, January 10, 2018, 38(2):308-321; Gupta R. C., et al., “Hyaluronic Acid; Molecular Mechanisms and Therapeutic Trajectory,” Front. Vet. Sci. 6: 192; and Bonet, I.J.M., et al., “Mechanisms Mediating High-Molecular-Weight Hyaluron-Induced Antihyperalgesia,” The Journal of Neuroscience, August 19, 2020, 40(34):6477-6488, the contents of which are incorporated herein by reference in their entireties. Although high molecular weight HA displays immunosuppressive and antiinflammatory properties, low molecular weight HA has been observed to recruit immune cells and promote inflammation. Litwiniuk, M., et al, “Hyaluronic Acid in Inflammation and Tissue Regeneration,” Wounds 2016; 28(3):78-88; Krasinski, R. and Tchorzewski, H. “Hyaluronan-mediated regulation of inflammation,” Postepy Hig Med Dosw . 2007; 61 :683- 689; and Tolg, C., et al., “A RHAMM Mimetic Peptide Blocks Hyaluronan Signaling and Reduces Inflammation and Fibrogenesis in Excisional Skin Wounds,” AJP 2012, Vol. 81, No. 4, 1250-1270. These observations suggest that HA (e.g., high molecular weight HA) may inhibit pain, such as inflammatory pain or neuropathic pain, and be useful in treating such pain or diseases, disorders or conditions associated with such pain, such as osteoarthritis. See also Gotoh, S., et al., “Effects of the molecular weight of hyaluronic acid and its action mechanisms on experimental joint pain in rats,” Annals of the Rheumatic Diseases, 1993; 52: 817-822, the content of which is incorporated herein by reference in its entirety. These observations also suggest that HA (e.g., high molecular weight HA) may be useful in inhibiting inflammation and suppressing immune cell function.

[0040] HA has also been implicated in wound healing, tissue regeneration, ophthalmic conditions, such as keratoconjunctivitis sicca and dry eye disease, and cancer, suggesting that HA could be useful in promoting wound healing (e.g., in skin wounds, such as excisional skin wounds) and/or treating ophthalmic conditions or cancer. See Gupta R. C., et al, “Hyaluronic Acid; Molecular Mechanisms and Therapeutic Trajectory,” Front. Vet. Sci.

6: 192; and Litwiniuk, M., et al., “Hyaluronic Acid in Inflammation and Tissue Regeneration,” Wounds 2016; 28(3): 78-88, the contents of which are incorporated herein by reference in their entireties.

[0041] In some embodiments, the nanogel (e.g., including both aqueous and hyaluronic acid components) is from about 75% to about 99.9%, from about 90% to about 99.9%, from about 95% to about 99.9%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8% or about 99.9% by weight of the formulation base. In some embodiments, the hyaluronic acid, or a pharmaceutically acceptable salt thereof, is from about 0.1% to about 10%, from about 0.1% to about 7.5%, from about 0.1% to about 5%, from about 1% to about 10%, from about 1% to about 5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10% by weight of the formulation base. In some embodiments, the first fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof, is from about 0.1% to about 10%, from about 0.1% to about 7.5%, from about 0.1% to about 5%, from about 1% to about 10%, from about 1% to about 5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10% by weight of the formulation base. In some embodiments, the second fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof, is from about 0.1% to about 10%, from about 0.1% to about 7.5%, from about 0.1% to about 5%, from about 0.1% to about 3%, from about 0.1% to about 1%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4% or about 5% by weight of the formulation base. In some embodiments, the lecithin liposomes are from about 0.1% to about 10%, from about 0.1% to about 7.5%, from about 0.1% to about 5%, from about 0.1% to about 1%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9% or about 1% by weight of the formulation base.

[0042] In some embodiments, the hyaluronic acid of the first fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight (e.g., mean molecular weight) of greater than about 500 kilodaltons, e.g., greater than about 750 kilodaltons or greater than about 800 kilodaltons. In some embodiments, the hyaluronic acid of the first fraction, or a pharmaceutically acceptable salt of the foregoing, has a molecular weight (e.g., mean molecular weight) of less than 5,000 kilodaltons, e.g., less than about 2,500 kilodaltons, less than about 2,000 kilodaltons, less than about 1,500 kilodaltons, less than about 1,000 kilodaltons. In some embodiments, the hyaluronic acid of the first fraction, or a pharmaceutically acceptable salt of the foregoing, has a molecular weight (e.g., mean molecular weight) of from about 800 kilodaltons to about 1,500 kilodaltons.

[0043] In some embodiments, the hyaluronic acid of the second fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight (e.g., mean molecular weight) of less than about 100 kilodaltons, e.g., less than about 50, about 25 or about 10 kilodaltons. In some embodiments, the hyaluronic acid of the second fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight (e.g., mean molecular weight) of from about 150 to about 250 kilodaltons.

[0044] In some embodiments, the second fraction of hyaluronic acid is ultra-short chain hyaluronic acid. As used herein, “ultra-short chain hyaluronic acid” refers to hyaluronic acid having a molecular weight of less than about 10 kilodaltons. In some embodiments, ultra- short chain hyaluronic acid has a molecular weight of less than about 7.5 kilodaltons. In some embodiments, ultra-short chain hyaluronic acid has a molecular weight of from about 2.5 to about 10 or from about 5 to about 7 kilodaltons.

[0045] In some embodiments, the weight ratio of the first fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof, to the second fraction of hyaluronic acid (e.g., ultra- short chain hyaluronic acid), or a pharmaceutically acceptable salt thereof, is from about 1 : 15 to about 10: 1, e.g., from about 1 : 15 to about 1 : 1, from about 1 : 15 to about 1 :10, from about 1 : 1 to about 10: 1, from about 2.5: 1 to about 7.5:1, or about 1 : 15, 1 : 12, 1 : 10, 3: 1, 4:1, 5: 1, 6: 1 or 7 : 1.

[0046] Methods of making nanogels comprising hyaluronic acid, or a pharmaceutically acceptable salt thereof, are known in the art. See, for example, Son, S. U., et al., Nanomaterials 2017, 7, 427; and Trombino, S., et al., Pharmaceutics 2019, 11, 407, the entire contents of which are incorporated herein by reference in their entireties.

[0047] Liposomes are lipid-based delivery systems that can be used to encapsulate both hydrophobic and hydrophilic molecules. Liposomes can be used to protect encapsulated active substance(s) (e.g., cannabinoid(s)) during delivery to the bloodstream of a subject, where the liposomes are broken down, releasing the encapsulated substance(s). See, for example, Shade, C., “Liposomes as Advanced Delivery Systems for Nutraceuticals,” Integr Med (Encinitas), 2016 Mar; 15(1): 33-36; and Ling, L., et al., “Lipoic acid-derived crosslinked liposomes for reduction-responsive delivery of anticancer drug,” International Journal of Pharmaceutics 560 (2019) 246-260, the contents of which are incorporated herein by reference in their entireties.

[0048] Lecithin includes raw lecithin and lecithin fractions, such as those obtained by purification of raw lecithin, from a variety of sources. Suitable sources of lecithin include various seed oils, such as sunflower, soybean and canola, and egg yolk and milk. In some embodiments, the lecithin is raw lecithin. In some embodiments, the lecithin is sunflower lecithin.

[0049] In some embodiments, the lecithin liposomes have a d?5 of from about 25 nm to about 250 nm, e.g., from about 30 nm to about 150 nm or from about 35 nm to about 125 nm. [0050] Methods of making lecithin liposomes, encapsulating substances (e.g., citrulline, or a pharmaceutically acceptable salt thereof) within lecithin liposomes and characterizing lecithin liposomes are described herein and known in the art. See, for example, C. W. Shade, Integrative Medicine 15, 33-36, 2016; and Laouini, A. et al., Journal of Colloid Science and Biotechnology 1, 147-168, 2012, the contents of which are incorporated herein by reference in their entireties.

[0051] In some embodiments, the formulation base further comprises a gelling agent. Examples of gelling agents include polyvinyl carboxy polymers (e.g., poly(acrylic acid), or a salt thereof, such as sodium polyacrylate; a carbomer, such as carbomer 940), acacia, alginic acid, bentonite, carboxymethyl cellulose, ethylcellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, magnesium aluminum silicate (VEEGUM®), methylcellulose, pol oxamers (PLURONICS®), polyvinyl alcohol, alginates (e.g., sodium alginate), tragacanth, and xanthan gum. In some embodiments, the gelling agent is poly(acrylic) acid, or a salt (e.g., pharmaceutically acceptable salt) thereof, such as sodium polyacrylate. In some embodiments, the gelling agent is a carbomer e.g., carbomer 940, carbomer 980). Carbomer 940 is a polyvinyl carboxy polymer crosslinked with ethers of pentaerythritol. Carbomer 980 is a polyvinyl carboxy polymer crosslinked with ethers of pentaerythritol. Carbomer 980 is soluble in water, has a pH value of from 2.7 to 3.3 (0.5% solution at 25 °C) and a viscosity of from 54,000 to 60,000 cps (0.5% solution) and from 18,000 to 25,000 cps (0.2% solution). In some embodiments, the gelling agent is a polyvinyl carboxy polymer (e.g., crosslinked with ethers of pentaerythritol; carbomer 940; carbomer 980).

[0052] Typically, the gelling agent is less than about 25%, less than about 10%, less than about 5%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.1%, less than about 0.05% or less than about 0.01% (e.g., about 0.006%) by weight of the formulation base and/or the formulation.

Uses

[0053] The formulations described herein are expected to provide efficient and non- invasive delivery of the one or more cannabinoids in the formulation to a subject for absorption of the one or more cannabinoids into the body of the subject. Accordingly, provided herein is a method of administering one or more cannabinoids to a subject, comprising applying a formulation described herein to the skin, a mucous membrane (e.g., oral, nasal, vaginal, urethral mucous membrane), under the tongue, the cheek, the nose and/or the eye of a subject (e.g., skin, a mucous membrane, a cheek or an eye or under a tongue of the subject).

[0054] Also provided herein is a method of modulating (activating) a cannabinoid receptor (e.g., CB | and/or CB₂) in a subject (e.g., a subject in need thereof, such as a subject having a disease, disorder or condition described herein), comprising administering to the subject a formulation described herein e.g., an effective amount of a formulation described herein).

[0055] Also provided herein is a method of treating a disease, disorder or condition in a subject in need thereof, comprising administering to the subject an effective amount of a formulation described herein. The beneficial effects of cannabinoids, terpenes and terpenoids, taken each alone or in combination, on a variety of diseases, disorders and conditions has now been documented. See, for example, Goncalves, E.C.D., et al. Molecules 2020; 25(7): 1567, the entire content of which are incorporated herein by reference. Thus, in some embodiments, the disease, disorder or condition is a disease, disorder or condition beneficially treated by a cannabinoid, terpene and/or terpenoid, e.g., a disease, disorder or condition described herein. In some embodiments, the disease, disorder or condition is a disease, disorder or condition associated with a cannabinoid receptor (e.g., CBx and/or CB₂). [0056] As used herein, a “disease, disorder or condition associated with cannabinoid receptor activity or expression” refers to any disease, disorder or condition in which a cannabinoid receptor (e.g., CB | and/or CB₂) plays a role.

[0057] Non-limiting examples of diseases, disorders and conditions amenable to treatment in accordance with the methods disclosed herein include, for example, pain (e.g., chronic pain, neuropathic pain), inflammation, an inflammatory disorder, anxiety, depression, nausea, Alzheimer’s disease, diabetes, a sleep disorder, seizures, IBD, loss of appetite, cancer, Crohn’s disease, eating disorders (e.g, anorexia), epilepsy, glaucoma, multiple sclerosis and muscle spasms. Further non-limiting examples of diseases, disorders and conditions amenable to treatment in accordance with the methods disclosed herein include, for example, a cognitive impairment, Parkinson’s disease and schizophrenia.

[0058] Thus, in some embodiments, the disease, disorder or condition is pain, inflammation, an inflammatory disorder, anxiety, depression, nausea, Alzheimer’s disease, diabetes, a sleep disorder, seizures, IBD, loss of appetite, cancer, Crohn’s disease, an eating disorder, epilepsy, glaucoma, multiple sclerosis or muscle spasms. In some embodiments, the disease, disorder or condition is pain, inflammation, an inflammatory disorder, IBD, anxiety, depression, a sleep disorder, diabetes or seizures. In some embodiments, the disease, disorder or condition is a cognitive impairment, Parkinson’s disease or schizophrenia.

[0059] Cannabinoids can also relieve stress and improve mood. Thus, also provided herein is a method for relieving stress in a subject in need thereof, comprising administering to the subject an effective amount of a formulation described herein. Also provided herein is a method for improving mood in a subject in need thereof, comprising administering to the subject an effective amount of a formulation described herein.

[0060] In any of the aforementioned methods, administering a formulation described herein comprises applying the formulation to the skin, a mucous membrane (e.g., oral, nasal, vaginal, urethral mucous membrane), under the tongue, the cheek, the nose and/or the eye of a subject (e.g., skin, a mucous membrane, a cheek or an eye or under a tongue of the subject). [0061] Specific dosage and treatment regimens for any particular subject will depend upon a variety of factors, such as the disease, disorder or condition, the activity of the specific substance employed (e.g., in the disease, disorder or condition being treated), the age, body weight, general health status, sex and/or diet of the subject, time of administration, rate of excretion, drug combination, the severity and course of the disease, disorder, condition or symptom, the subject’s disposition to the disease, disorder, condition or symptom, and the judgment of the treating physician. Selection of specific dosage and treatment regimens is within the skill of a person of ordinary skill in the art in view of the present disclosure and the references cited herein.

Methods of Making

[0062] In some embodiments, a method of making a formulation or formulation base described herein comprises forming a mixture of lecithin liposomes (e.g., according to any of the embodiments or combinations of embodiments described herein) and hyaluronic acid (e.g., the first and second fractions of hyaluronic acid, according to any of the embodiments or combinations of embodiments described herein), or a pharmaceutically acceptable salt thereof; and inducing gelation of the mixture. Without wishing to be bound by any particular theory, it is believed that gelation of the aforementioned mixture results in formation of a hyaluronic acid-based nanogel having within it (e.g., dispersed or uniformly dispersed within it) the lecithin liposomes.

[0063] In some embodiments, a method of making a formulation described herein comprises forming a mixture of lecithin liposomes (e.g., according to any of the embodiments or combinations of embodiments described herein), one or more cannabinoids and/or terpenes and/or terpenoids (e.g., according to any of the embodiments or combinations of embodiments described herein), or a pharmaceutically acceptable salt of the foregoing, and hyaluronic acid (e.g., the first and second fractions of hyaluronic acid, according to any of the embodiments or combinations of embodiments described herein), or a pharmaceutically acceptable salt thereof; and inducing gelation of the mixture. Without wishing to be bound by any particular theory, it is believed that gelation of the aforementioned mixture results in formation of a hyaluronic acid-based nanogel having within it (e.g., dispersed or uniformly dispersed within it) the lecithin liposomes and the cannabinoids and/or terpenes and/or terpenoids, or a pharmaceutically acceptable salt of the foregoing.

[0064] It will be appreciated that although there may be active substances (e.g., cannabinoids, terpenes, terpenoids, or a pharmaceutically acceptable salt of the foregoing) encapsulated within the lecithin liposomes recited in the aforementioned methods of making, unless otherwise indicated, the cannabinoids and/or terpenes and/or terpenoids, or a pharmaceutically acceptable salt of the foregoing, recited in the aforementioned methods of making are not encapsulated within the lecithin liposomes.

[0065] However, by forming lecithin liposomes in the presence of one or more cannabinoids and/or terpenes and/or terpenoids, or a pharmaceutically acceptable salt of the foregoing, lecithin liposomes encapsulating one or more cannabinoids and/or terpenes and/or terpenoids, or a pharmaceutically acceptable salt of the foregoing, can be produced. Thus, in some embodiments, the methods of making further comprise forming lecithin liposomes. In some embodiments, forming lecithin liposomes includes combining one or more cannabinoids and/or terpenes and/or terpenoids, or a pharmaceutically acceptable salt of the foregoing, and lecithin under conditions suitable to form lecithin liposomes encapsulating the one or more cannabinoids and/or terpenes and/or terpenoids, or a pharmaceutically acceptable salt of the foregoing.

[0066] In some embodiments, inducing gelation comprises adding a gelling agent (e.g., according to any of the embodiments described herein) to the mixture. In some embodiments, the gelling agent is poly(acrylic) acid, or a salt (e.g., pharmaceutically acceptable salt) thereof, such as sodium polyacrylate. In some embodiments, the gelling agent is a carbomer (e.g., carbomer 940, carbomer 980).

[0067] Methods of making the formulation bases and formulations described herein are further described in the Exemplification.

EXEMPLIFICATION

Example 1. Preparation of a Formulation Base

[0068] A formulation base, e.g., for containing a cannabinoid, was prepared using the following process:

A. Charged steam distilled water into a steam jacketed kettle (final mixing tank). Started warming the water to 40 °C.

B. Added sodium hyaluronate (0.80-1.50 million Daltons) slowly into vortex while mixing using a propeller lOO-lOOOrpm until completely dissolved. Typically, this addition occurred over 10 minutes.

C. Added SUTTOCIDE™/Optiphen slowly into vortex while mixing until completely dissolved. D. Added sodium hyaluronate (<10,000 daltons) slowly into vortex while mixing until completely dissolved.

E. Added carbomer 980 slowly into vortex while mixing until completely dispersed and uniform.

F. Using the in-line, high-shear emulsifier, circulated the content of the kettle thru the high shear emulsifier for 30 minutes.

G. Allowed resulting product to cool to room temperature.

Example 2. Preparation of a Formulation Containing CBD

[0069] A formulation containing CBD was prepared using the following process.

A. Filled bottom of a large pot with water sufficient to create a bath for a 2000ml flask.

B. Began heating water to 135-140 °F.

C. Upon water reaching 135-140 °F, filled 2,000 ml flask with 1,000 mg medium chain triglyceride oil (fractionalized coconut oils).

D. Dissolved 500 mg CBD into heated fluid. Feathered CBD in slowly for about 12-20 minutes, stirring gently.

E. When CBD and fractionalized coconut oils were in solution, turned off heat.

F. Immediately and slowly, mixed the emulsification from step E into the formulation base produced in Example 1.

G. Slowly added potassium sorbate up to 25 mg, as needed until an off-white colorization appeared. This color change was rapid and signified product completion.

H. Allowed product to return to room temperature.

[0070] The formulation containing CBD can be applied to clean, dry skin topically to effect transdermal administration. Application may be repeated, as desired or as recommended by a healthcare professional.

[0071] The teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.

[0072] While example embodiments have been particularly shown and described, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the embodiments encompassed by the appended claims.

Claims

CLAIMS What is claimed is:

1. A formulation comprising: a nanogel comprising a first fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof, and a second fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof, wherein the hyaluronic acid of the first fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight of greater than about 500 kilodaltons, and the hyaluronic acid of the second fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight of less than about 250 kilodaltons; lecithin liposomes within the nanogel, lecithin liposomes having a d₇₅ of from about 25 nm to about 250 nm; and one or more cannabinoids, or a pharmaceutically acceptable salt thereof.

2. A formulation comprising: a first fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof, wherein the hyaluronic acid of the first fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight of greater than about 500 kilodaltons; a second fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof, wherein the hyaluronic acid of the second fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight of less than about 250 kilodaltons; lecithin liposomes having a d₇₅ of from about 25 nm to about 250 nm; and one or more cannabinoids, or a pharmaceutically acceptable salt thereof.

3. The formulation of claim 2, further comprising water.

4. The formulation of claim 2 or 3, wherein the first and second fractions of hyaluronic acid, or a pharmaceutically acceptable salt thereof, form a nanogel within which are the lecithin liposomes and the one or more cannabinoids, or a pharmaceutically acceptable salt thereof.

5. The formulation of any one of claims 1-4, wherein the one or more cannabinoids includes a natural cannabinoid. The formulation of claim 5, wherein the natural cannabinoid is tetrahydrocannabinol (THC) or cannabidiol (CBD), or a pharmaceutically acceptable salt thereof. The formulation of any one of claims 1-6, wherein the one or more cannabinoids includes a synthetic cannabinoid. The formulation of any one of claims 1-7, wherein the one or more cannabinoids includes an endocannabinoid. The formulation of any one of claims 1-8, wherein the one or more cannabinoids includes A⁸-THC, or a pharmaceutically acceptable salt thereof. The formulation of any one of claims 1-9, wherein the one or more cannabinoids includes A⁹-THC, or a pharmaceutically acceptable salt thereof. The formulation of any one of claims 1-10, wherein the one or more cannabinoids includes CBD. The formulation of any one of claims 1-11, further comprising nicotine, or a pharmaceutically acceptable salt thereof. The formulation of any one of claims 1-12, further comprising one or more terpenes or terpenoids, or a pharmaceutically acceptable salt of the foregoing. The formulation of claim 13, wherein the one or more terpenes or terpenoids includes a terpene or terpenoid selected from myrcene, limonene, caryophyllene, pinene, camphene, humulene, delta 3 carene, valencene, linalool, alpha-bisabolol, eucalyptol, nerolidol, borneol, terpineol, geraniol, phytol, terpinolene, valencene or ocimene, or a pharmaceutically acceptable salt of the foregoing. The formulation of claim 14, wherein the one or more terpenes or terpenoids includes a terpene or terpenoid selected from caryophyllene, limonene, humulene, linalool, myrcene, ocimene or pinene, or a pharmaceutically acceptable salt of the foregoing. The formulation of claim 13, 14 or 15, wherein at least one of the one or more terpenes or terpenoids, or a pharmaceutically acceptable salt of the foregoing, is encapsulated within the lecithin liposomes. The formulation of any one of claims 1-16, wherein at least one of the one or more cannabinoids, or a pharmaceutically acceptable salt thereof, is encapsulated within the lecithin liposomes. The formulation of any one of claims 1-17, wherein a first portion of at least one of the one or more cannabinoids, or a pharmaceutically acceptable salt thereof, is encapsulated within the lecithin liposomes and a second portion of the at least one of the one or more cannabinoids, or a pharmaceutically acceptable salt thereof, is not encapsulated within the lecithin liposomes. The formulation of any one of claims 1-18, comprising a first cannabinoid, or a pharmaceutically acceptable salt thereof, and a second cannabinoid, or a pharmaceutically acceptable salt thereof, wherein the first cannabinoid, or a pharmaceutically acceptable salt thereof, is encapsulated within the lecithin liposomes, and the second cannabinoid, or a pharmaceutically acceptable salt thereof, is not encapsulated within the lecithin liposomes. The formulation of any one of claims 1-19, for topical administration. The formulation of any one of claims 1-20, for transdermal, transmucosal, sublingual, buccal, nasal or ocular administration. The formulation of any one of claims 1-21, in the form of an emulsion. The formulation of any one of claims 1-22, in the form of a gel, cream, foam, lotion, ointment, paste, spray or drop. The formulation of any one of claims 1-23, wherein the hyaluronic acid of the first fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight of greater than about 750 kilodaltons. The formulation of claim 24, wherein the hyaluronic acid of the first fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight of from about 800 kilodaltons to about 1,500 kilodaltons. The formulation of any one of claims 1-25, wherein the hyaluronic acid of the second fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight of less than about 10 kilodaltons. The formulation of any one of claims 1-26, wherein the weight ratio of the first fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof, to the second fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof, is from about 1 : 1 to about 10: 1. The formulation of claim 27, wherein the weight ratio of the first fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof, to the second fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof, is about 5: 1. The formulation of any one of claims 1-28, wherein the lecithin liposomes have a d₇₅ of from about 30 nm to about 150 nm. The formulation of any one of claims 1-29, wherein the formulation is a nutraceutical formulation. The formulation of any one of claims 1-30, wherein the formulation is a cosmetic formulation. The formulation of any one of claims 1-31, wherein the formulation is a pharmaceutical formulation. The formulation of any one of claims 1-32, further comprising a gelling agent. The formulation of claim 33, wherein the gelling agent is poly(acrylic acid), or a salt thereof. The formulation of claim 33 or 34, wherein the gelling agent is a carbomer. A method of making the formulation of any one of claims 1-35, comprising forming a mixture of the lecithin liposomes, the hyaluronic acid, or a pharmaceutically acceptable salt thereof, and one or more cannabinoids, or a pharmaceutically acceptable salt thereof; and inducing gelation of the mixture. A method of making the formulation of any one of claims 13-35, comprising forming a mixture of the lecithin liposomes, the hyaluronic acid, or a pharmaceutically acceptable salt thereof, one or more cannabinoids, or a pharmaceutically acceptable salt thereof, and one or more terpenes or terpenoids, or a pharmaceutically acceptable salt of either of the foregoing; and inducing gelation of the mixture. A method of administering a formulation of any one of claims 1-35 to a subject, comprising applying the formulation to the skin, a mucous membrane, a cheek or an eye or under a tongue of the subject. A method of activating a cannabinoid receptor in a subject, comprising administering to the subject a formulation of any one of claims 1-35. A method of treating a disease, disorder or condition associated with cannabinoid receptor activity or expression in a subject in need thereof, comprising administering to the subject an effective amount of a formulation of any one of claims 1-35. The method of claim 40, wherein the disease, disorder or condition is pain, inflammation, an inflammatory disorder, IBD, anxiety, depression, a sleep disorder, diabetes or seizures. The method of any one of claims 39-41, wherein administering the formulation comprises applying the formulation to the skin, a mucous membrane, a cheek or an eye or under a tongue of the subject.