WO2022016038A1

WO2022016038A1 - Formulation bases comprising hyaluronic acid and formulations of same

Info

Publication number: WO2022016038A1
Application number: PCT/US2021/041936
Authority: WO
Inventors: Robert Fritz; David GUILFORD
Original assignee: Dt Ip Holdings I, Llc
Priority date: 2020-07-17
Filing date: 2021-07-16
Publication date: 2022-01-20
Also published as: WO2024155274A1

Abstract

Provided herein are formulation bases 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; and lecithin liposomes within the nanogel, the 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. The formulation bases described herein provide for absorption of active substances contained therein into the body, e.g., transdermally, and, therefore, can be used as delivery systems to administer one or more active substances to a subject.

Description

Formulation Bases Comprising Hyaluronic Acid and Formulations Of Same

RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63/053,312, filed on July 17, 2020, U.S. Provisional Application No. 63/053,338, filed on July 17, 2020, and U.S. Provisional Application No. 63/145,569, filed on February 4, 2021. The entire teachings of the above 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

[0003] Accordingly, there is a need for delivery systems for active ingredients and other active substances that do not rely on injection or other invasive techniques, but provide for absorption of active ingredients and other active substances into the body.

SUMMARY

[0004] Provided herein is a formulation base 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; and lecithin liposomes within the nanogel, the 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.

[0005] Also provided herein is a formulation comprising a formulation base described herein and one or more active substances.

[0006] 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 the following nutraceuticals: alpha-lipoic acid, or a pharmaceutically acceptable salt thereof; glutathione, or a pharmaceutically acceptable salt thereof; N-acetyl-L-cysteine, or a pharmaceutically acceptable salt thereof; coenzyme Q10; vitamin D3, or a pharmaceutically acceptable salt thereof; vitamin C, or a pharmaceutically acceptable salt thereof; and zinc oxide. 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.

[0007] 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 the following nutraceuticals: ATP, or a pharmaceutically acceptable salt thereof; ribose, or a pharmaceutically acceptable salt thereof; citrulline, or a pharmaceutically acceptable salt thereof; magnesium orotate; beetroot; potassium nitrate; caffeine, or a pharmaceutically acceptable salt thereof; and coenzyme Q10. 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.

[0008] Also provided herein is a method of making a formulation base described herein, comprising forming a mixture of lecithin liposomes and hyaluronic acid ( e.g ., first and second fractions of hyaluronic acid), or a pharmaceutically acceptable salt thereof; and inducing gelation of the mixture.

[0009] Also provided herein is a method of making a formulation described herein, comprising forming a mixture of lecithin liposomes, one or more active substances (e.g., nutraceuticals), and hyaluronic acid (e.g, first and second fractions of hyaluronic acid), or a pharmaceutically acceptable salt thereof; and inducing gelation of the mixture.

[0010] Also provided herein is a method of administering a formulation base or formulation described herein to a subject, comprising applying the formulation base or formulation described herein to skin, a mucous membrane, a cheek, a nose or an eye, or under a tongue of the subject.

[0011] Also provided herein is a method of administering one or more active substances (e.g, nutraceuticals) to a subject, comprising applying a formulation comprising the one or more active substances to skin, a mucous membrane, a cheek, a nose or an eye, or under a tongue of the subject, wherein the formulation is a formulation described herein. [0012] Also provided herein is method of treating a subject in need of a formulation base or formulation described herein, comprising administering an effective amount of the formulation base or formulation to the subject. Also provided herein is a formulation base or formulation for use in treating a subject in need of the formulation base or formulation, wherein the formulation base or formulation is a formulation base or formulation described herein. Also provided herein is a formulation base or formulation described herein for the manufacture of a medicament for the treatment of a subject in need of the formulation base or formulation.

[0013] Also provided herein is method of treating a subject in need of one or more active substances ( e.g ., nutraceuticals), comprising administering an effective amount of a formulation described herein comprising the one or more active substances to the subject. Also provided herein is a formulation for use in treating a subject in need of one or more active substances (e.g., nutraceuticals), wherein the formulation is a formulation described herein comprising the one or more active substances. Also provided herein is a formulation comprising one or more active substances (e.g, nutraceuticals) for the manufacture of a medicament for the treatment of a subject in need of the one or more active substances, wherein the formulation is a formulation described herein comprising the one or more active substances.

[0014] Also provided herein is a method of treating a subject having a disease, disorder or condition that would benefit from administration of a formulation base or formulation described herein, comprising administering an effective amount of the formulation base or formulation described herein to the subject. Also provided herein is a formulation base or formulation described herein for use in treating a subject having a disease, disorder or condition that would benefit from administration of the formulation base or formulation.

Also provided herein is a formulation base or formulation described herein for the manufacture of a medicament for the treatment of a subject having a disease, disorder or condition that would benefit from administration of the formulation base or formulation. [0015] Also provided herein is a method of treating a subject having a disease, disorder or condition that would benefit from administration of one or more active substances, comprising administering an effective amount of a formulation described herein comprising the one or more active substances to the subject. Also provided herein is a formulation for use in treating a subject having a disease, disorder or condition that would benefit from administration of one or more active substances, wherein the formulation is a formulation described herein comprising the one or more active substances. Also provided herein is a formulation comprising one or more active substances for the manufacture of a medicament for the treatment of a subject having a disease, disorder or condition that would benefit from administration of the one or more active substances, wherein the formulation is a formulation described herein comprising the one or more active substances.

[0016] Also provided herein is a method of inhibiting and/or treating inflammation in a subject ( e.g ., a subject in need thereof), comprising administering a formulation base or formulation described herein (e.g., an effective amount of a formulation base or formulation described herein) to the subject. Also provided herein is a formulation base or formulation described herein for use in inhibiting and/or treating inflammation in a subject. Also provided herein is a formulation base or formulation described herein for the manufacture of a medicament for the inhibition and/or treatment of inflammation in a subject.

[0017] The formulation bases and formulations described herein are expected to be efficient and non-invasive delivery systems for nutrients and other active substances that provide for absorption of nutrients and other active substances into the body. For example, the formulation bases and formulations described herein are expected to have anti inflammatory properties that render them useful for inhibiting inflammation in a variety of settings, such as in treatment of a bug bite or sunburn. Formulations to support the immune system are expected to enhance immune function by inhibiting inflammatory response and viral replication by providing for absorption of neutraceuticals that support the immune system into the body. Formulations to support sports performance are expected to support sports performance by providing the body with vital nutrients through the skin to improve strength, endurance and recovery without adding substantial calories to the body.

DETAILED DESCRIPTION

[0018] A description of example embodiments follows.

Definitions

[0019] As used herein, “a,” “an” and “the” include plural referents, unless the context dictates otherwise. Thus, for example, “a nutraceutical” includes one nutraceutical and a plurality of nutraceuticals. Further, the plurality can be a plurality of the same nutraceuticals or a plurality of different nutraceuticals.

[0020] 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.

[0021] 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. 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.

[0022] 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.

[0023] Examples of 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.

[0024] 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.

[0025] 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.

[0026] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺((C_I-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. [0027] As used herein, “support the immune system” and “supporting the immune system” refers to assisting, regulating, enhancing and/or boosting the immune system, and includes increasing the ability of the immune system to resist or fight off disease, such as viral infection, e.g. , as by reducing inflammation and/or increasing the number of immune cells, such as white blood cells, and/or antibodies in the blood; and/or reducing infection, e.g. , as by inhibiting viral replication.

[0028] As used herein, “support sports performance” and “supporting sports performance” refer to assisting, enhancing and/or boosting performance before, during and/or after sports and/or physical exercise, e.g. , as by inhibiting delayed onset muscle soreness, inhibiting inflammation, increasing blood oxygenation, decreasing oxidative stress, restoring and/or increasing ATP level, restoring and/or increasing nitric oxide level (e.g, in the intestine), restoring and/or increasing camosine level (e.g, in muscle), decreasing blood pressure (e.g, systolic blood pressure, as after aerobic activity), increasing strength, stamina and/or endurance, assisting recovery and/or delaying fatigue. Whether sports performance is supported by a formulation described herein can be determined by a person of ordinary skill in the art in view of this disclosure and the documents cited herein. Supporting sports performance includes, for example, restoring and/or increasing ATP level, restoring and/or increasing nitric oxide level ( e.g ., in the intestine), restoring and/or increasing camosine level ( e.g ., in muscle), decreasing blood pressure (e.g., systolic blood pressure, as after aerobic activity), increasing muscle strength (e.g, total weight lifted), improving fast-twitch muscle performance, increasing short burst and/or repeated short burst performance (e.g, sprinting), increasing maximal power and contractile speed of trained athletes performing multi -joint concentric actions, increasing time to exhaustion, decreasing perceived strain and/or decreasing recovery time.

[0029] “Booster,” as used herein, refers to an agent (e.g, a neutraceutical) that, upon administration to a subject (e.g, in an effective amount), augments or increases, directly or indirectly, the level of a reference substance in the subject. Thus, a “nitric oxide booster” is an agent that, upon administration to a subject (e.g, in an effective amount), augments or increases, directly or indirectly, the level of nitric oxide in the subject. A level can be increased directly as, for example, when the agent administered to the subject is the reference substance itself. For example, administration of ATP, an ATP booster, to a subject directly increases the level of ATP in the subject. A level can be increased indirectly as, for example, when the agent administered to the subject is a biosynthetic precursor to the reference substance or a cofactor in the biosynthesis of the reference subject. For example, administration of ribose, an ATP booster, to a subject indirectly increases the level of ATP in the subject because ribose is a biosynthetic precursor to ATP. For example, administration of citrulline, a nitric oxide booster, to a subject indirectly increases the level of nitric oxide in the subject because citrulline is a cofactor in nitric oxide production in the intestine.

[0030] As used herein, “treat,” “treating,” and “treatment,” and the like, refer to taking steps to deliver (e.g, as by administering) 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. [0031] 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, such as a pediatric human ( e.g ., a human aged 21 years-old or less, a human aged 18 years-old or less, a human aged 16 years-old or less, a human aged 12 years-old or less, a human aged 6 years-old or less). In some embodiments, the subject, such as a pediatric human, is also or alternatively greater than 6 months-old, greater than 2 years-old or greater than five years-old.

[0032] 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.

[0033] 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.

Formulation Bases

[0034] Provided herein is a formulation base comprising 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).

[0035] Also provided herein is a formulation base 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 (e.g, lecithin liposomes having a d₇₅ of from about 25 nm to about 250 nm). In some embodiments, the first and second fractions of hyaluronic acid, or a pharmaceutically acceptable salt thereof, form a nanogel within which are the lecithin liposomes (and one or active substances, if present).

[0036] Also provided herein is a formulation base comprising 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] Hyaluronic acid (HA) is a naturally-occurring glycosaminoglycan and a major component of the extracellular matrix. See , for example, Arpicco, S., etal., “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 -oxidative effects. See , for example, Petrey, A., el al ., “Hyaluronan, a crucial regulator of inflammation,” Frontiers in Immunology \ Inflammation , March 2014, Volume 5, Article 101; and Gupta R. C., etal. , “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.

[0038] 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 TRPVl 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., etal. , “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 anti inflammatory 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., etal., “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., el 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.

[0039] 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., el al, “Hyaluronic Acid; Molecular Mechanisms and Therapeutic Trajectory,” Front. Vet. Sci.

6: 192; and Litwiniuk, M., el 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.

[0040] 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.

[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 hyaluronic acid of the first fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight of greater than about 500 kilodaltons (e.g, greater than about 750 kilodaltons; from about 800 kilodaltons to about 1,500 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 ( e.g ., less than about 10 kilodaltons).

[0046] 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.

[0047] Methods of making nanogels comprising hyaluronic acid, or a pharmaceutically acceptable salt thereof, are known in the art. See, for example, Son, S. U., el al, Nanomaterials 2017, 7, 427; and Trombino, S., etal, Pharmaceutics 2019, 11, 407, the entire contents of which are incorporated herein by reference in their entireties.

[0048] 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, nutraceutical(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., etal., “Lipoic acid-derived cross- linked 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.

[0049] 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 oils, and egg yolk and milk. In some embodiments, the lecithin is raw lecithin. In some embodiments, the lecithin is sunflower lecithin.

[0050] In some embodiments, the lecithin liposomes have a d₇₅ 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. [0051] Methods of making lecithin liposomes, encapsulating substances (e.g, vitamin D3, glutathione, zinc oxide, N-acetyl-L-cysteine; 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, the examples set forth herein; and 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.

[0052] 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, poloxamers (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).

[0053] 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.

[0054] The formulation bases described herein are particularly suitable for topical administration. The formulation bases 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.

[0055] 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 or formulation base described herein may be local or, preferably, systemic. Non-limiting 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 formulation bases and formulations 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. In some embodiments, the formulation base or formulation described herein is administered to skin of a subject.

[0056] The formulation bases and 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 a variety of applications, including nutraceutical, pharmaceutical, cosmeceutical and cosmetic. For rectal administration or administration to the lower intestinal tract, the formulation base or 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, formulation bases and 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 formulation bases and formulations can be formulated as ointments, for example, with petrolatum. For nasal administration (e.g, inhalation), formulation bases and 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.

[0057] The formulation bases and formulations described herein can provide for immediate release or sustained/delayed release of one or more active substances (e.g, nutraceuticals, such as nutraceuticals that support the immune system and/or nutraceuticals that support sports performance) contained therein.

Formulations

[0058] Also provided herein is a formulation comprising a formulation base described herein and one or more active substances. In some embodiments, the formulation is a nutraceutical formulation, e.g, comprises one or more nutraceuticals. In some embodiments, the formulation is a cosmetic formulation, e.g, comprises one or more cosmetics. In some embodiments, the formulation is a cosmeceutical formulation, e.g. , comprises one or more cosmeceuticals. In some embodiments, the formulation is a pharmaceutical formulation, e.g. , comprises one or more pharmaceuticals.

[0059] As used herein, “active substance” refers to a substance that, upon administration to a subject, has a biological activity or produces a biological (e.g, pharmacological) effect. Examples of active substances include neutraceuticals, cosmeceuticals and pharmaceuticals. [0060] In some embodiments, the one or more active substances comprise a neutraceutical. Examples of neutraceuticals include adenosine triphosphate, glutathione, N- acetyl-L-cysteine, coenzyme Q10 (CoQ-10), vitamin A, a B vitamin (e.g, vitamin B_i2), vitamin D3, vitamin C, vitamin E, a probiotic, echnicacea, garlic, astragalus, a beta-glucan, docosahexaenoic acid, colostrum, ginseng, a thymic extract, zinc, selenium, iron, folic acid or alpha-lipoic acid.

[0061] In some embodiments, the one or more active substances comprise a cosmeceutical. Examples of cosmeceuticals include marine algal compounds (e.g, phlorotannins, sulfated polysaccharides, tyrosinase inhibitors).

[0062] In some embodiments, the one or more active substances comprises a pharmaceutical. Examples of pharmaceuticals include glutathione and zinc.

[0063] In some embodiments, one or more of the one or more active substances (e.g, nutraceuticals, such as neutraceuticals that support the immune system, nutraceuticals that support sports performance) is encapsulated within the lecithin liposomes. Encapsulation, particularly of unstable, active substances, can increase the amount of an active substance that is ultimately delivered to a subject compared to unencapsulated delivery.

[0064] Also provided herein are formulations to support the immune system. Thus, some embodiments provide a formulation comprising a formulation base described herein and one or more nutraceuticals that support the immune system.

[0065] Examples of nutraceuticals that support the immune system include glutathione, N-acetyl-L-cysteine, coenzyme Q10 (CoQ-10), vitamin A, a B vitamin, vitamin D3, vitamin C, vitamin E, a probiotic, echnicacea, garlic, astragalus, a beta-glucan, docosahexaenoic acid, colostrum, ginseng, a thymic extract, zinc (e.g, zinc oxide), selenium, iron, folic acid and alpha-lipoic acid, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the one or more nutraceuticals that support the immune system comprise, consist essentially of or consist of glutathione, N-acetyl-L-cysteine, coenzyme Q10 (CoQ- 10), vitamin A, a B vitamin, vitamin D3, vitamin C, vitamin E, a probiotic, echnicacea, garlic, astragalus, a beta-glucan, docosahexaenoic acid, colostrum, ginseng, a thymic extract, zinc ( e.g ., zinc oxide), selenium, iron, folic acid and alpha-lipoic acid, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the one or more nutraceuticals that support the immune system are selected from glutathione, N-acetyl-L-cysteine, coenzyme Q10 (CoQ-10), vitamin A, a B vitamin, vitamin D3, vitamin C, vitamin E, a probiotic, echnicacea, garlic, astragalus, a beta-glucan, docosahexaenoic acid, colostrum, ginseng, a thymic extract, zinc (e.g., zinc oxide), selenium, iron, folic acid or alpha-lipoic acid, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the one or more nutraceuticals that support the immune system comprise, consist essentially of or consist of glutathione, N-acetyl-L-cysteine, CoQ-10, vitamin D3, vitamin C, zinc (e.g, zinc oxide) and alpha-lipoic acid, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the one or more nutraceuticals that support the immune system are selected from glutathione, N-acetyl-L-cysteine, CoQ-10, vitamin D3, vitamin C, zinc (e.g, zinc oxide) or alpha-lipoic acid, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the one or more nutraceuticals that support the immune system comprise, consist essentially of or consist of (e.g, are) alpha-lipoic acid, or a pharmaceutically acceptable salt thereof; glutathione, or a pharmaceutically acceptable salt thereof; N-acetyl-L-cysteine, or a pharmaceutically acceptable salt thereof; coenzyme Q10; vitamin D3, or a pharmaceutically acceptable salt thereof; vitamin C, or a pharmaceutically acceptable salt thereof; and zinc oxide.

[0066] Some embodiments provide a formulation comprising a formulation base described herein and the following nutraceuticals: alpha-lipoic acid, or a pharmaceutically acceptable salt thereof; glutathione, or a pharmaceutically acceptable salt thereof; N-acetyl-L- cysteine, or a pharmaceutically acceptable salt thereof; coenzyme Q10; vitamin D3, or a pharmaceutically acceptable salt thereof; vitamin C, or a pharmaceutically acceptable salt thereof; and zinc oxide. In some embodiments, the formulation base comprises 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; and lecithin liposomes having a d₇₅ of from about 25 nm to about 250 nm. In some further embodiments, 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 nutraceuticals. In some embodiments, the formulation comprises about 2.2% by weight of the first fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof; about 0.4% by weight of the second fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof; about 0.2% by weight of the lecithin liposomes; about 0.2% by weight alpha-lipoic acid, or a pharmaceutically acceptable salt thereof; about 1.1% by weight glutathione, or a pharmaceutically acceptable salt thereof; about 0.2% by weight N-acetyl-L-cysteine, or a pharmaceutically acceptable salt thereof; about 0.4% by weight coenzyme Q10; about 0.4% by weight vitamin D3, or a pharmaceutically acceptable salt thereof; about 0.4% by weight vitamin C, or a pharmaceutically acceptable salt thereof; and about 0.4% by weight zinc oxide. In some embodiments, the formulation further comprises water ( e.g ., in some embodiments, about 91% by weight water). In some embodiments, at least one of the nutraceuticals (e.g., in some embodiments, glutathione, or a pharmaceutically acceptable salt thereof; N-acetyl-L-cysteine, or a pharmaceutically acceptable salt thereof; vitamin D3, or a pharmaceutically acceptable salt thereof; and zinc oxide) is encapsulated within the lecithin liposomes.

[0067] Also provided herein are formulations to support sports performance. Thus, some embodiments provide a formulation comprising a formulation base described herein and one or more nutraceuticals that support sports performance.

[0068] In some embodiments, the one or more neutraceuticals that support sports performance comprise a nitric oxide and/or arginine (e.g, nitric oxide) booster. Non-limiting examples of nitric oxide boosters include citrulline, beetroot, potassium nitrate and coenzyme Q-10 (CoQ-10).

[0069] In some embodiments, the one or more neutraceuticals that support sports performance comprise an ATP booster. Non-limiting examples of ATP boosters include ATP and ribose, or a pharmaceutically acceptable salt of either of the foregoing.

[0070] In some embodiments, the one or more nutraceuticals that support sports performance comprise a carnosine booster. Non-limiting examples of camosine boosters include magnesium orotate.

[0071] Non-limiting examples of nutraceuticals that support sports performance include ATP, ribose, citrulline, orotate (e.g, magnesium orotate), beetroot, nitrate (e.g, potassium nitrate), caffeine and CoQ-10, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the one or more neutraceuticals that support sports performance comprise, consist essentially of or consist of ATP, ribose, citrulline, orotate (e.g, magnesium orotate), beetroot, nitrate (e.g, potassium nitrate), caffeine and CoQ-10, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the one or more nutraceuticals that support sports performance comprise, consist essentially of or consist of ATP, or a pharmaceutically acceptable salt thereof; ribose, or a pharmaceutically acceptable salt thereof; citrulline, or a pharmaceutically acceptable salt thereof; magnesium orotate; beetroot; potassium nitrate; caffeine, or a pharmaceutically acceptable salt thereof; and CoQ-10, or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more nutraceuticals that support sports performance are selected from ATP, or a pharmaceutically acceptable salt thereof; ribose, or a pharmaceutically acceptable salt thereof; citrulline, or a pharmaceutically acceptable salt thereof; magnesium orotate; beetroot; potassium nitrate; caffeine, or a pharmaceutically acceptable salt thereof; or CoQ-10, or a pharmaceutically acceptable salt thereof.

[0072] Some embodiments provide a formulation comprising a formulation base described herein and the following nutraceuticals: ATP, or a pharmaceutically acceptable salt thereof; ribose, or a pharmaceutically acceptable salt thereof; citrulline, or a pharmaceutically acceptable salt thereof; magnesium orotate; beetroot; potassium nitrate; caffeine, or a pharmaceutically acceptable salt thereof; and coenzyme Q10. In some embodiments, the formulation base comprises 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; and lecithin liposomes having a d₇₅ of from about 25 nm to about 250 nm. In some further embodiments, 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 nutraceuticals. In some embodiments, the formulation comprises about 0.1% by weight of the first fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof; about 1.2% by weight of the second fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof; about 0.4% by weight of the lecithin liposomes; about 1.8% by weight ATP, or a pharmaceutically acceptable salt thereof; about 0.2% by weight ribose, or a pharmaceutically acceptable salt thereof; about 0.1% by weight citrulline, or a pharmaceutically acceptable salt thereof; about 0.4% by weight magnesium orotate; about 0.4% by weight beet root powder; about 0.2% by weight potassium nitrate; about 10% by weight caffeine, or a pharmaceutically acceptable salt thereof; and about 0.2% by weight coenzyme Q10. In some embodiments, the formulation further comprises water ( e.g ., in some embodiments, about 84% by weight water). In some embodiments, at least one of the nutraceuticals (e.g., in some embodiments, magnesium orotate) is encapsulated within the lecithin liposomes.

[0073] 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 65% to about 99%, from about 75% to about 99%, from about 75% to about 95%, from about 90% to about 90%, from about 90% to about 99%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99% by weight of the formulation. 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 2%, about 2.6%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10% by weight of the formulation. 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 2.2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10% by weight of the formulation. 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. 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. [0074] Typically, the one or more active substances ( e.g ., nutraceuticals, such as nutraceuticals that support the immune system, nutraceuticals that support sports performance), 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.

[0075] 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), 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.

[0076] 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.

[0077] Suitable routes of administration and forms of the formulations described herein include those routes of administration and forms described herein with respect to formulation bases.

Uses

[0078] The formulation bases described herein can be incorporated into formulations comprising a formulation base described herein and one or more active substances. Upon administration to a subject, the formulation base and/or formulation is expected to be an efficient and non-invasive delivery system for the one or more active substances of the formulation, providing for absorption of the one or more active substances into the body of the subject. In addition, HA itself has been shown to play a role in inflammation and pain and, therefore, is expected to impart utility to the formulation base, even in the absence of other active substances.

[0079] Accordingly, provided herein is a method of administering a formulation base or formulation described herein to a subject, comprising applying the formulation base or formulation to a subject. In some embodiments, the formulation base or formulation is applied topically. In some embodiments, the formulation base or formulation is applied to skin, a mucous membrane ( e.g ., oral, nasal, vaginal, urethral mucous membrane), a cheek, a nose and/or an eye, and/or under a tongue of a subject (e.g., skin, a mucous membrane, a cheek or an eye or under a tongue of the subject). In some embodiments, the formulation base or formulation is applied to skin of a subject.

[0080] Also provided herein is a method of treating a subject in need of a formulation base or formulation described herein, comprising administering an effective amount of the formulation base or formulation to the subject. Also provided herein is a method of treating a subject having a disease, disorder or condition that would benefit from administration of a formulation base or formulation described herein, comprising administering an effective amount of the formulation base or formulation to the subject. Examples of subjects in need of the formulation bases and/or formulations described herein, and examples of diseases, disorders or conditions that would benefit from administration of a formulation base or formulation described herein are as set forth herein.

[0081] Inflammation of the skin, such as that resulting from bug bites, sunburn and inflammatory skin disease, such as psoriasis and dermatitis, is expected to particularly benefit from the anti-inflammatory, analgesic and anti -nociceptive properties of HA. Thus, also provided herein is a method of inhibiting inflammation in a subject (e.g, a subject in need thereof, such as a pediatric subject), comprising administering to the subject a formulation base or formulation described herein (e.g, an effective amount of a formulation base or formulation described herein). Also provided herein is a method of treating inflammation in a subject (e.g, a subject in need thereof, such as a pediatric subject), comprising administering to the subject a formulation base or formulation described herein (e.g, an effective amount of a formulation base or formulation described herein). In some embodiments, the inflammation is inflammation of the skin, such as that resulting from a bug bite or bum (e.g, sunburn). [0082] Also provided herein is a method of treating a bug bite or burn ( e.g ., sunburn), comprising administering to a subject (e.g., a subject in need thereof, such as a pediatric subject; a subject having a bug bite or burn, such as a pediatric subject having a bug bite or burn), a formulation base or formulation described herein (e.g, an effective amount of a formulation base or formulation described herein).

[0083] Burns can result from exposure to radiation, such as ultraviolet (e.g, UVA, UVB and/or UVC) radiation. Sunburns typically result from over-exposure to sunlight, although they can also be the result of over-exposure to other sources of ultraviolet radiation, such as tanning beds and ultraviolet therapies.

[0084] Also provided herein is a method of inhibiting pain (e.g, inflammatory pain, neuropathic pain) in a subject (e.g, a subject in need thereof), comprising administering to the subject a formulation base or formulation described herein (e.g, an effective amount of a formulation base or formulation described herein). Also provided herein is a method of treating pain (e.g, inflammatory pain, neuropathic pain) in a subject (e.g, a subject in need thereof), comprising administering to the subject a formulation base or formulation described herein (e.g, an effective amount of a formulation base or formulation described herein). [0085] HA is also expected to be useful in wound healing, for example, post-surgery. Thus, also provided herein is a method of promoting wound healing and/or tissue regeneration in a subject (e.g, a subject in need thereof), comprising administering to the subject a formulation base or formulation described herein (e.g, an effective amount of a formulation base or formulation described herein). In some embodiments, the method promotes wound healing and/or tissue regeneration of a skin wound, such as an excisional skin wound, in a subject.

[0086] In some embodiments, a formulation base described herein is administered to the subject (e.g, pediatric subject). In some embodiments, a formulation described herein is administered to the subject.

[0087] Also provided herein is a method of administering one or more active substances (e.g, nutraceuticals, such as nutraceuticals that support the immune system and/or nutraceuticals that support sports performance) to a subject, comprising applying a formulation described herein to the subject. In some embodiments, the formulation is applied topically. In some embodiments, the formulation is applied skin, a mucous membrane (e.g, oral, nasal, vaginal, urethral mucous membrane), a cheek, a nose and/or an eye, and/or under a tongue of a subject ( e.g ., skin, a mucous membrane, a cheek or an eye or under a tongue of the subject). In some embodiments, the formulation is applied to skin of a subject.

[0088] Also provided herein is a method of treating a subject in need of one or more active substances (e.g., nutraceuticals, such as nutraceuticals that support the immune system and/or nutraceuticals that support sports performance), comprising administering an effective amount of a formulation described herein comprising the one or more active substances to the subject. Also provided herein is a method of treating a subject having a disease, disorder or condition that would benefit from administration of one or more active substances (e.g, nutraceuticals, such as nutraceuticals that support the immune system and/or nutraceuticals that support sports performance), comprising administering an effective amount of a formulation described herein comprising the one or more active substances to the subject. Examples of subjects in need of the one or more active substances described herein, and examples of diseases, disorder or conditions that would benefit from administration of one or more active substances described herein are as set forth herein.

[0089] Risks associated with COVID-19, SARS, MERS and other pathogens can be mitigated by active ingredients and other active substances that support the immune system.

For example, glutathione has been implicated in regulation of innate and adaptive immune system function, particularly in the context of viruses, protection of cells from oxidative damage, reduction of inflammation and maintenance of redox homeostasis. See, for example, Minich, D.M. and Brown, B.I. Nutrients 2019, 11, 2073; Lee, C. Oxidative Medicine and Cellular Longevity 2018, Article ID 6208067; Forman, H.J., et al, Molecular Aspects of Medicine 30(2009), 1-12; Ghezzi, P., International Journal of General Medicine 2011 :4, 105-113; Horowitz, R.I., et al, Respiratory Medicine Case Reports 30(2020), 101063; and Polonikov, A. ACS Infect. Dis., https://dx.doi.org/10.1021/acsinfecdis.0c00288, the entire contents of which are incorporated herein by referenced in their entireties. Glutathione also plays a role in regulating nitric oxide synthase, which synthesizes nitric oxide, a reactive oxygen species that may help to reduce respiratory tract infection, such as COVID-19, by inactivating viruses and inhibiting viral replication. See, for example, Kobayashi, J. and Murata, F, “Nitric oxide inhalation as an interventional rescue therapy for COVID-19- induced acute respiratory distress syndrome”, Annals of Intensive Care, (2020) 10:61; Akerstrom, S., et al., “Nitric Oxide Inhibits the Replication Cycle of severe Acute Respiratory Syndrome Coronavirus”, Journal of Virology, Feb 2005, p. 1966-1969;

Zamanian, R.T., et al., “Outpatient Inhaled Nitric Oxide in a Patient with Vasoreactive Idiopathic Pulmonary Arterial Hypertension and COVID-19 Infection ” , American Journal of Respiratory and Critical Care Medicine, 202(1), July 1, 2020, 130-132; Ko, Y.-F., etal., “Could nasal nitric oxide help to mitigate the severity of COVID-1?”, Microbes and Infection , 22 (2020 168-171; and Harbrecht, B.G., etal., “Glutathione Regulates Nitric Oxide Synthase in Cultured Hepatocytes”, Annals of Surgery , 225(1): 76-87 (1997), the entire contents of which are incorporated herein by reference in their entireties.

[0090] N-acetylcysteine has been shown to increase GSH, improve T cell response, inhibit viral replication, attenuate influenza and influenza-like episodes, improve cell- mediated immunity and modulate inflammation. See, for example, Poe, F.L. and Corn, J. Medical Hypotheses 143 (2020) 109862; Geiler, J., et al, Biochemical Pharmacology 79 (2010) 413-420; De Flora, S., et al, Eur. Resp. J., 1997, 10, 1535-1541, the entire contents of which are incorporated herein by reference in their entireties.

[0091] Alpha-lipoic acid is known to have antioxidant and anti-inflammatory properties. See, for example, Tibullo, D., et al, Inflamm. Res. (2017) 66:947-959; Zhang, G., et al, Molecular Medicine Reports 12:180-186 (2015); and Shen, H.-H., et al, Mediators of Inflammation 2019, Article ID 8187529, the entire contents of which are incorporated herein by reference in their entireties.

[0092] Zinc has been shown to regulate antiviral and antibacterial immunity and inflammatory response, and inhibit viral replication, and is known to be important for the growth, development and maintenance of immune function. See, for example, Skalny, A.V., et al, International Journal of Molecular Medicine 46:17-26, 2020; Zhang, J., et al, Brain, Behavior, and Immunity 87(2020), 59-73; te Velthuis, A.J.W., et al, PLoS Pathogens 2010,

6, 11, el001176; Read, S.A., etal, Adv. Nutr., 2019, 10:696-710; Barnett, J.B., etal, Nutrition Reviews 68(l):30-37; Mocchegiani, E., et al , Mechanisms of Ageing and Development 121(2000), 21-35, the entire contents of which are incorporated herein by reference in their entireties.

[0093] Coenzyme Q-10 (CoQ-10) has been found to reduce oxidative stress. See, for example, Tsai, K.-L., etal, Journal of Nutritional Biochemistry 23(2012), 458-468; Sangsefidi, Z.S., et al, Food Sci. Nutr. 2020; 8; 1766-1776; and Knott, A., et al, Biofactors, 2015, 383-390, the entire contents of which are incorporated herein by reference in their entireties.

[0094] Vitamin D supplementation has been found to reduce the risk of having acute respiratory infections. See, for example, Martineau, A.R., et al, Health Technology Assessment 23(2), 2019; and Martineau, A.R., Annals of Internal Medicine , doi:10.7326/ACPJC-2017-166-10-051, the entire contents of which are incorporated herein by reference in their entireties.

[0095] Thus, also provided herein is a method of supporting the immune system of 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), such as a formulation comprising one or more nutraceuticals that support the immune system.

[0096] Also provided herein is a method of inhibiting viral replication 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), such as a formulation comprising one or more nutraceuticals that support the immune system.

[0097] Also provided herein is a method of inhibiting inflammation 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), such as a formulation comprising one or more nutraceuticals that support the immune system, and/or a formulation comprising one or more nutraceuticals that support sports performance.

[0098] Also provided herein is a method of treating a viral infection 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), such as a formulation comprising one or more nutraceuticals that support the immune system.

[0099] Muscle contraction during heavy exercise can lead to constricted blood flow, increased oxidative stress and ultimately delayed onset muscle soreness (DOMS), which can be mitigated by active ingredients and other active substances that support sports performance. For example, ATP acts as a vasodilator, among other things, increasing blood flow throughout the body when administered by intra-arterial infusion and intravenously. The effects of ATP at appropriate dosages are comparable to that of histamine or acetylcholine, without the uncomfortable local or general symptoms. See, for example, Duff, F., el al., “A Quantitative Study of the Response to Adenosine Triphosphate of the Blood Vessels of the Human Hand and Forearm,” J. Physiol., 1954;125(3):581-589; and Shepherd, T, etal., “Prolonged adenosine triphosphate infusion and exercise hyperemia in humans,” J. Appl. Physiol. 121: 629-635, 2016, the contents of which are incorporated herein by reference in their entireties. Furthermore, ATP has been shown to increase repeated sprint ability and muscle excitability, showing an increase in short burst performance and repeated short burst performance. See, for example, Purpura, M., etal., “Oral Adenosine-5 '-triphosphate (ATP) Administration Increases Postexercise ATP Levels, Muscle Excitability, and Athletic Performance Following a Repeated Sprint Bout,” Journal Of The American College of Nutrition, 2017, Vol. 36, No. 3, 177-183, the content of which is incorporated herein by reference in its entirety. Adenosine compounds, such as ATP, also appear to exert an analgesic effect, particularly in the post-surgery context and the context of chronic neuropathic pain. See , for example, Hayashida, M., el al., “Clinical application of adenosine and ATP for pain control,” J. Anesth. (2005) 19:225-235, the content of which is incorporated herein by reference in its entirety. Without wishing to be bound by any particular theory, it is believed that ATP increases vascularity, performance and endurance. [00100] Ribose is a precursor to ATP and supports ATP production. Furthermore, ribose has been shown to increase performance in exercise and benefits perceived exertion, particularly in lower-fitness adults undergoing high-intensity exercise. See, for example, Seifert, J., et al, “The influence of D-ribose ingestion and fitness level on performance and recovery,” Journal of the International Society of Sports Nutrition (2017) 14:47, the content of which is incorporated herein by reference in its entirety. See also Mahoney, D.E., et al, “Understanding D-Ribose and Mitochondrial Function f Adv. Biosci. Clin. Med. 2018; 6(1): 1-5; Bayram, M., et al, “D-Ribose aids heart failure patients with preserved ejection fraction and diastolic dysfunction: a pilot study,” Ther. Adv. Cardiovasc. Dis. 2015, 9(3): 56-65; Herrick, J., et al, “D-Ribose - an additive with caffeine,” Medical Hypotheses 72 (2009), 499-500; Derosa, G., et al, “A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effectiveness of a Food Supplement Containing Creatine and D-Ribose Combined with a Physical Exercise Program in Increasing Stress Tolerance in Patients with Ischemic Heart Disease,” Nutrients 2019, 11, 3075, the contents of which are incorporated herein by reference in their entireties. Ribose also helps with the recovery of decreased ATP levels from exercise.

[00101] Citrulline has been shown to increase muscle protein synthesis by reallocating mitochondrial fuel to the protein synthesis machinery. See, for example, Goron, A., et al, “Citrulline stimulates muscle protein synthesis, by reallocating ATP consumption to muscle protein synthesis”, Journal of Cachexia, Sarcopenia and Muscle, 2019: 10: 919-928, the content of which is incorporated herein by reference in its entirety. Citrulline has also been shown to increase resistance exercise performance (RPE) in both male and female subjects, suggesting citrulline increases muscle performance and endurance. See, for example, Glenn, J.M., etal ., “Acute citrulline malate supplementation improves upper- and lower-body submaximal weightlifting exercise performance in resistance-trained females”, Eur J Nutr., 2017 Mar; 56(2): 775-784. doi: 10.1007/s00394-015-l 124-6, the content of which is incorporated herein by reference in its entirety. Citrulline has also shown an ability to regulate protein synthesis and fight oxidative stress. See , for example, Cynober, L., etal ., “The 2009 ESPEN Sir David Cuthbertson. Citrulline: A new major signaling molecule or just another player in the pharmaconutrition game?, Clinical Nutrition , 29 (2010) 545-551, the content of which is incorporated herein by reference in its entirety. Citrulline has also been shown to protect from muscle wasting by increasing protein synthesis. See , for example, Ham, D.J., etal ., “Citrulline protects muscle cells from wasting in an mTOR independent manner in vitro ”, Proceedings of the Australian Physiological Society , http://aups.org.au/Proceedings/4413P; and Le Plenier, S., etal., “Effects of leucine and citrulline versus non-essential amino acids on muscle protein synthesis in fasted rat: a common activation pathway?, Amino Acids, (2012) 43: 1171-1178, the contents of which are incorporated herein by reference in their entireties. Citrulline also play a role in nitric oxide production in the intestine. By restoring nitric oxide production in the intestine, citrulline has been shown to decrease oxidative stress and magnify the effects of nitric oxide. See, for example, Wijnands, K.A.P., et al, “Citrulline a More Suitable Substrate than Arginine to Restore NO Production and the Microcirculation during Endotoxemia”, PLoS ONE, May 2012 7(5): e37439, the content of which is incorporated herein by reference in its entirety. Without wishing to be bound by any particular theory, it is believed that citrulline can be used to relieve oxidative stress and, thus, fatigue caused by exercise-induced respiratory muscle fatigue, and increase muscle performance and endurance.

[00102] Magnesium orotate has been shown to stimulate production of beta-alanine, which is synthesized into camosine and thereby increases muscle concentrations of carnosine. See, for example, Perim, P., etal., “Can the Skeletal Muscle Carnosine Response to Beta-Alanine Supplementation Be Optimized”, Frontiers in Nutrition, August 1019, volume 6, Article 135, 10 pages, the content of which is incorporated herein by reference in its entirety. Carnosine, in turn, increases muscle performance both in duration and intensity. See, for example, Baguet, A., et al., “Important role of muscle camosine in rowing performance,” J. Appl. Physiol. 109: 1096-1101, 2010, the content of which is incorporated herein by reference in its entirety. Furthermore, beta-alanine supplementation has been shown to decrease fatigue in high intensity/high volume workouts. See, for example, Hoffman, J., “Short-duration beta- alanine supplementation increases training volume and reduces subjective feelings of fatigue in college football players,” Nutr. Res. 2008;28(1):31-35, the content of which is incorporated herein by reference in its entirety. Without wishing to be bound by any particular theory, it is believed that magnesium orotate decreases fatigue and increases endurance.

[00103] Beetroot provides precursors to L-arginine, from which nitric oxide (NO) is synthesized. NO derived from beetroot has been shown to increase muscle performance in intense endurance exercise. NO has also shown beneficial effects in “improving fatigue resistance, augmenting fiber contractility, and ultimately enhancing whole body exercise tolerance or performance.” See , for example, Jones, A., etal ., “Fiber Type-Specific Effects of Dietary Nitrate,” Exerc. Sport Sci. Rev., Vol. 44, No. 2, pp. 53Y60, 2016, the content of which is incorporated herein by reference in its entirety. In addition, NO supplementation has been shown to improve exercise capacity, decrease oxidative stress and improve recovery time from intense workouts. See, for example, Handzlik, M., el al., “Likely Additive Ergogenic Effects of Combined Preexercise Dietary Nitrate and Caffeine Ingestion in Trained Cyclists,” 1 SRN Nutrition, Volume 2013, Article ID 396581, 8 pages; Nyakayiru, J., etal, “Beetroot Juice Supplementation Improves High-Intensity Intermittent Type Exercise Performance in Trained Soccer Players,” Nutrients, 2017, 9, 314; and Kelly, J., et al,

“Dietary nitrate supplementation: effects on plasma nitrite and pulmonary 0₂ uptake dynamics during exercise in hypoxia and normoxia,” Am. J. Physiol. Regul. Integr. Comp. Physiol. 307: R920-R930, 2014, the contents of which are incorporated herein by reference in their entireties. NO has also been shown to increase maximal power and contractile speed of trained athletes performing multi-joint concentric actions. See, for example, Rimer, E., et al, “Acute Dietary Nitrate Supplementation Increases Maximal Cycling Power in Athletes,” Int. J. Sports Physiol. Perform. 2016 September; 11(6): 715-720, the content of which is incorporated herein by reference in its entirety. NO has also been shown to improve cognitive performance. See, for example, Thompson, C., et al, “Dietary nitrate supplementation improves sprint and high-intensity intermittent running performance,” Nitric Oxide, 61 (2016) 55-61, the content of which is incorporated herein by reference in its entirety. Without wishing to be bound by any particular theory, it is believed that beetroot increases endurance and muscle strength performance, and improves recovery time and fast twitch muscle performance.

[00104] Potassium nitrate, like beetroot, provides precursors to L-arginine. Potassium nitrate has been shown to increase force production in fast-twitch muscle, and reduce perceived exertion for a task, thereby improving perceived strength and endurance for the task. See , for example, Hernandez, A., etal ., “Dietary nitrate increases tetanic [Ca²⁺]i and contractile force in mouse fast-twitch muscle,” J. Physiol ., 2012 Aug 1; 590 (Pt 15): 3575- 3583, the content of which is incorporated herein by reference in its entirety. Nitrate supplementation has also been shown to decrease systolic blood pressure and improve antioxidant response after aerobic exercise. See , for example, Menezes, E., etal ., “Potential Benefits of Nitrate Supplementation on Antioxidant Defense System and Blood Pressure Responses after Exercise Performance,” Oxidative Medicine and Cellular Longevity, Volume 2019, Article ID 7218936, 10 pages, the content of which is incorporated herein by reference in its entirety. Without wishing to be bound by any particular theory, it is believed that by decreasing blood pressure, potassium nitrate can decrease exercise-induced stress on the body. [00105] Caffeine is an ergogenic aid that improves peak aerobic capacity and peak pulmonary ventilation. Furthermore, caffeine has been shown to increase muscle oxygen saturation, and improve performance in short duration, high intensity, repeated sprinting.

See , for example, Ruiz-Moreno, C., et al ., “Acute caffeine intake increases muscle oxygen saturation during a maximal incremental exercise test,” Br. J. Clin. Pharmacol. 2020;86:861- 867; and Wickham, K., etal., “Administration of Caffeine in Alternate Forms,” Sports Med (2018) 48 (Suppl 1):S79-S91, the contents of which are incorporated herein by reference in their entireties. Caffeine has also been shown to increase total weight lifted and improve fatigue index. See, for example, Mielgo-Ayuso, J., et al., “Effect of Caffeine Supplementation on Sports Performance Based on Differences Between Sexes: A Systematic Review,” Nutrients 2019, 11, 2313, the content of which is incorporated herein by reference in its entirety. When co-ingested with dietary nitrate, such as that derived from beetroot, caffeine has been shown to delay time to exhaustion. See, for example, Handzlik, M., et al., “Likely Additive Ergogenic Effects of Combined Preexercise Dietary Nitrate and Caffeine Ingestion in Trained Cyclists,” ISBN Nutrition, Volume 2013, Article ID 396581, 8 pages, the content of which is incorporated herein by reference in its entirety. Without wishing to be bound by any particular theory, it is believed that caffeine will improve sports performance, muscle performance, endurance and fatigue, and decrease oxidative stress. Sources of caffeine include green tea. Thus, in some embodiments, caffeine is from green tea.

[00106] CoQ-10 improves the production of nitric oxide synthase, while decreasing oxidative stress. Furthermore, CoQ-10 has been shown to increase antioxidant capacity and suppress downstream inflammatory mediators. See, for example, Tsai, K.-L., etal, Journal of Nutritional Biochemistry 23(2012), 458-468; Sangsefidi, Z.S., et al., Food Sci. Nutr. 2020; 8; 1766-1776; and Knott, A., et al, Biofactors , 2015, 383-390, 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 CoQ-10 will increase endurance and delay fatigue by virtue of decreased oxidative stress. Without wishing to be bound by any particular theory, it is believed that CoQ-10 will magnify the effects of other nitric oxide boosters, such as citrulline, beetroot and potassium nitrate, as well as assist in reducing reactive oxygen species and decrease oxidative stress.

[00107] Thus, also provided herein is a method of supporting the sports performance of a subject ( e.g ., a subject in need thereof, such as an athlete), comprising administering to the subject a formulation described herein (e.g., an effective amount of a formulation described herein), such as a formulation comprising one or more nutraceuticals that support sports performance.

[00108] Also provided herein is a method of inhibiting delayed onset muscle soreness in a subject (e.g, a subject in need thereof, such as an athlete), comprising administering to the subject a formulation described herein (e.g, an effective amount of a formulation described herein), such as a formulation comprising one or more nutraceuticals that support sports performance.

[00109] Also provided herein is a method of increasing blood oxygen level in a subject (e.g, a subject in need thereof, such as an athlete), comprising administering to the subject a formulation described herein (e.g, an effective amount of a formulation described herein), such as a formulation comprising one or more nutraceuticals that support sports performance. [00110] Also provided herein is a method of decreasing oxidative stress in a subject (e.g, a subject in need thereof, such as an athlete), comprising administering to the subject a formulation described herein (e.g, an effective amount of a formulation described herein), such as a formulation comprising one or more nutraceuticals that support sports performance. [00111] Also provided herein is a method of increasing strength, stamina and/or endurance in a subject (e.g, a subject in need thereof, such as an athlete), comprising administering to the subject a formulation described herein (e.g, an effective amount of a formulation described herein), such as a formulation comprising one or more nutraceuticals that support sports performance.

[00112] Also provided herein is a method of increasing nitric oxide level in a subject (e.g, a subject in need thereof, such as an athlete), comprising administering to the subject a formulation described herein ( e.g ., an effective amount of a formulation described herein), such as a formulation comprising one or more nutraceuticals that support sports performance. [00113] Also provided herein is a method of reducing fatigue (e.g., exercised-induced fatigue) in a subject (e.g, a subject in need thereof, such as an athlete), comprising administering to the subject a formulation described herein (e.g, an effective amount of a formulation described herein), such as a formulation comprising one or more nutraceuticals that support sports performance.

[00114] In any of the aforementioned methods, particularly those involving a formulation comprising one or more nutraceuticals that support sports performance, the formulation is administered to the subject prior to physical activity (e.g, exercise, a workout). Alternatively or in addition, the formulation can be administered to the subject during physical activity (e.g, exercise, a workout). Alternatively or in addition, the formulation can be administered to the subject after physical activity (e.g, exercise, a workout).

[00115] In any of the aforementioned methods, in some embodiments, administering a formulation base or formulation described herein comprises applying the formulation to the skin, a mucous membrane (e.g, oral, nasal, vaginal, urethral mucous membrane), a cheek, a nose and/or an eye, and/or under the tongue of a subject (e.g, to skin, a mucous membrane, a cheek or an eye or under a tongue of the subject). Other suitable routes of administration include those routes of administration described herein with respect to formulation bases. [00116] A formulation base or formulation can be administered (e.g, applied) to a subject, in accordance with any of the aforementioned methods and embodiments thereof, once or repeatedly, for example, as directed by a healthcare professional. For example, administration can be 1, 2, 3, 4, 5, 6, etc. times per day.

[00117] 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

[00118] In some embodiments, a method of making a 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. In some embodiments, the method comprises forming a first mixture of lecithin liposomes e.g, according to any of the embodiments or combinations of embodiments described herein) and a first fraction of hyaluronic acid (e.g, according to any of the embodiments or combinations of embodiments described herein), or a pharmaceutically acceptable salt thereof; adding a second fraction of hyaluronic acid (e.g, according to any of the embodiments or combinations of embodiments described herein), or a pharmaceutically acceptable salt thereof, to the first mixture, thereby forming a second mixture; and inducing gelation of the second mixture. Without wishing to be bound by any particular theory, it is believed that gelation of a mixture of lecithin liposomes and hyaluronic acid, or a pharmaceutically acceptable salt thereof, results in formation of a hyaluronic acid- based nanogel having within it (e.g, dispersed or uniformly dispersed within it) the lecithin liposomes.

[00119] 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 active substances (e.g, any of the active substances described herein) and hyaluronic acid (e.g, 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. In some embodiments, the method comprises forming a first mixture of lecithin liposomes e.g, according to any of the embodiments or combinations of embodiments described herein), one or more active substances (e.g, any of the active substances described herein) and a first fraction of hyaluronic acid (e.g, according to any of the embodiments or combinations of embodiments described herein), or a pharmaceutically acceptable salt thereof; adding a second fraction of hyaluronic acid (e.g, according to any of the embodiments or combinations of embodiments described herein), or a pharmaceutically acceptable salt thereof, to the first mixture, thereby forming a second mixture; and inducing gelation of the second mixture. Without wishing to be bound by any particular theory, it is believed that gelation of such mixtures 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 one or more active substances (e.g., the one or more nutraceuticals, such as one or more nutraceuticals that support the immune system).

[00120] For example, 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 nutraceuticals (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. In some embodiments, the method comprises forming a first mixture of lecithin liposomes e.g, according to any of the embodiments or combinations of embodiments described herein), one or more nutraceuticals (e.g, according to any of the embodiments or combinations of embodiments described herein) and a first fraction of hyaluronic acid (e.g, according to any of the embodiments or combinations of embodiments described herein), or a pharmaceutically acceptable salt thereof; adding a second fraction of hyaluronic acid (e.g, according to any of the embodiments or combinations of embodiments described herein), or a pharmaceutically acceptable salt thereof, to the first mixture, thereby forming a second mixture; and inducing gelation of the second mixture.

[00121] In some embodiments, the methods of making further comprise forming the lecithin liposomes. By forming the lecithin liposomes in the presence of one or more active substances (e.g, nutraceuticals, such as vitamin C, N-acetyl-L-cysteine, glutathione, zinc, citrulline, or a pharmaceutically acceptable salt of the foregoing), lecithin liposomes encapsulating one or more active substances can be produced. Accordingly, in some embodiments, forming the lecithin liposomes includes combining one or more active substances and lecithin under conditions suitable to form lecithin liposomes encapsulating the one or more active substances (e.g, nutraceuticals, such as nutraceuticals that support the immune system, nutraceuticals that support sports performance).

[00122] In some embodiments, inducing gelation comprises adding a gelling agent (e.g, according to any of the embodiments or combinations of embodiments described herein) to the mixture or second 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). [00123] Methods of making the formulation bases and formulations described herein are further described in the Exemplification.

NUMBERED EMBODIMENTS

[00124] The following numbered embodiments relate to formulation bases, and formulations thereof, as well as methods of making and using the foregoing.

A1. A formulation base 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; and lecithin liposomes within the nanogel, the 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.

A2. The formulation base of embodiment Al, for topical administration.

A3. The formulation base of embodiment Al or A2, for transdermal, transmucosal, sublingual, buccal, nasal or ocular administration.

A4. The formulation base of any one of embodiments Al-3, in the form of an emulsion.

A5. The formulation base of any one of embodiments A 1-4, in the form of a gel, cream, foam, lotion, ointment, paste, spray or drop.

A6. The formulation base of any one of embodiments Al-5, wherein the hyaluronic acid of the first fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight of greater than about 750 kilodaltons.

A7. The formulation base of embodiment A6, 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.

A8. The formulation base of any one of embodiments A 1-7, wherein the hyaluronic acid of the second fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight of less than about 10 kilodaltons. A9. The formulation base of any one of embodiments Al-8, 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.

A10. The formulation base of embodiment A9, 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.

A11. The formulation base of any one of embodiments Al-10, wherein the lecithin liposomes having a d₇₅ of from about 30 nm to about 150 nm.

A12. The formulation base of any one of embodiments Al-11, further comprising a gelling agent.

A13. The formulation base of embodiment A12, wherein the gelling agent is poly(acrylic acid), or a salt thereof.

A14. The formulation base of embodiment A12 or A13, wherein the gelling agent is a carbomer.

A15. A method of making the formulation base of any one of embodiments 1-14, comprising forming a mixture of the lecithin liposomes and the first and second fractions of hyaluronic acid, or a pharmaceutically acceptable salt thereof; and inducing gelation of the mixture.

A16. A formulation comprising the formulation base of any one of embodiments Al-14 and one or more active substances.

A17. The formulation of embodiment A16, wherein the one or more active substances are selected from a neutraceutical, a cosmeceutical or a pharmaceutical.

A18. The formulation of embodiment A16 or A17, wherein the formulation is a nutraceutical formulation.

A19. The formulation of any one of embodiments A16-18, wherein the one or more active substances comprise a neutraceutical.

A20. The formulation of any one of embodiments A16-19, wherein the formulation is a cosmetic formulation.

A21. The formulation of any one of embodiments A16-20, wherein the one or more active substances comprise a cosmeceutical.

A22. The formulation of any one of embodiments A16-21, wherein the formulation is a pharmaceutical formulation. A23. The formulation of any one of embodiments A16-22, wherein the one or more active substances comprises a pharmaceutical.

A24. A method of administering one or more active substances to a subject, comprising applying a formulation of any one of embodiments A16-23 to skin, a mucous membrane, a cheek or an eye or under a tongue of the subject.

A25. A method of treating a subject in need of one or more active substances, comprising administering an effective amount of a formulation of any one of embodiments A16- 23 comprising the one or more active substances to the subject.

A26. A method of treating a subject having a disease, disorder or condition that would benefit from administration of one or more active substances, comprising administering an effective amount of a formulation of any one of embodiments A16- 23 comprising the one or more active substances to the subject.

A27. The method of embodiment A25 or A26, wherein administering an effective amount of the formulation comprises applying an effective amount of the formulation to skin, a mucous membrane, a cheek or an eye or under a tongue of the subject.

[00125] The following numbered embodiments relate to formulations to support the immune system, and methods of making and using the same.

B 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 nutraceuticals that support the immune system.

B2. The formulation of embodiment Bl, wherein the one or more nutraceuticals are selected from glutathione, N-acetyl-L-cysteine, coenzyme Q10 (CoQ-10), vitamin A, a B vitamin, vitamin D3, vitamin C, vitamin E, a probiotic, echnicacea, garlic, astragalus, a beta-glucan, docosahexaenoic acid, colostrum, ginseng, a thymic extract, zinc, selenium, iron, folic acid or alpha-lipoic acid, or a pharmaceutically acceptable salt of any of the foregoing.

B3. The formulation of embodiment B2, wherein the one or more nutraceuticals are selected from glutathione, N-acetyl-L-cysteine, CoQ-10, vitamin D3, vitamin C, zinc or alpha-lipoic acid, or a pharmaceutically acceptable salt of any of the foregoing.

B4. The formulation of any one of embodiments Bl-3, wherein at least one of the one or more nutraceuticals is encapsulated within the lecithin liposomes.

B5. 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 the following nutraceuticals: alpha-lipoic acid, or a pharmaceutically acceptable salt thereof; glutathione, or a pharmaceutically acceptable salt thereof; N-acetyl-L-cysteine, or a pharmaceutically acceptable salt thereof; coenzyme Q10; vitamin D3, or a pharmaceutically acceptable salt thereof; vitamin C, or a pharmaceutically acceptable salt thereof; and zinc oxide.

B6. The formulation of embodiment B5 comprising: about 2.2% by weight of the first fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof; about 0.4% by weight of the second fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof; about 0.2% by weight of the lecithin liposomes; about 0.2% by weight alpha-lipoic acid, or a pharmaceutically acceptable salt thereof; about 1.1% by weight glutathione, or a pharmaceutically acceptable salt thereof; about 0.2% by weight N-acetyl-L-cysteine, or a pharmaceutically acceptable salt thereof; about 0.4% by weight coenzyme Q10; about 0.4% by weight vitamin D3, or a pharmaceutically acceptable salt thereof; about 0.4% by weight vitamin C, or a pharmaceutically acceptable salt thereof; and about 0.4% by weight zinc oxide.

B7. The formulation of embodiment B5 or B6, further comprising water.

B8. The formulation of embodiment B7, comprising about 91% by weight water.

B9. The formulation of any one of embodiments B5-8, wherein at least one of the nutraceuticals is encapsulated within the lecithin liposomes.

B10. The formulation of embodiment B9, wherein the glutathione, or a pharmaceutically acceptable salt thereof; N-acetyl-L-cysteine, or a pharmaceutically acceptable salt thereof; vitamin D3, or a pharmaceutically acceptable salt thereof; and zinc oxide are encapsulated within the lecithin liposomes.

B11. The formulation of any one of embodiments B5-10, 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 nutraceuticals.

B12. The formulation of any one of embodiments Bl-11, for topical administration.

B13. The formulation of any one of embodiments B 1-12, for transdermal, transmucosal, sublingual, buccal, nasal or ocular administration.

B14. The formulation of any one of embodiments Bl-13, in the form of an emulsion.

B15. The formulation of any one of embodiments B 1-14, in the form of a gel, cream, foam, lotion, ointment, paste, spray or drop.

B16. The formulation of any one of embodiments Bl-15, wherein the hyaluronic acid of the first fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight of greater than about 750 kilodaltons.

B17. The formulation of embodiment B 16, 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. B18. The formulation of any one of embodiments Bl-17, wherein the hyaluronic acid of the second fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight of less than about 10 kilodaltons.

B19. The formulation of any one of embodiments Bl-18, 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.

B20. The formulation of embodiment B 19, 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.

B21. The formulation of any one of embodiments Bl-20, wherein the lecithin liposomes have a d₇₅ of from about 30 nm to about 150 nm.

B22. The formulation of any one of embodiments Bl-21, wherein the formulation is a nutraceutical formulation.

B23. The formulation of any one of embodiments Bl-22, wherein the formulation is a cosmetic formulation.

B24. The formulation of any one of embodiments Bl-23, wherein the formulation is a pharmaceutical formulation.

B25. The formulation base of any one of embodiments B 1-24, further comprising a gelling agent.

B26. The formulation base of embodiment B25, wherein the gelling agent is poly(acrylic acid), or a salt thereof.

B27. The formulation base of embodiment B25 or B26, wherein the gelling agent is a carbomer.

B28. A method of making the formulation of any one of embodiments Bl-27, comprising forming a mixture of the lecithin liposomes, the nutraceuticals and the hyaluronic acid, or a pharmaceutically acceptable salt thereof; and inducing gelation of the mixture.

B29. A method of supporting the immune system of a subject, comprising administering to the subject a formulation of any one of embodiments Bl-27.

B30. The method of embodiment B29, wherein the immune system is the native immune system. B31. The method of embodiment B29, wherein the immune system is the adaptive immune system.

B32. A method of inhibiting viral replication in a subject, comprising administering to the subject a formulation of any one of embodiments Bl-27.

B33. A method of inhibiting inflammation in a subject, comprising administering to the subject a formulation of any one of embodiments Bl-27.

B34. A method of treating a viral infection in a subject, comprising administering to the subject an effective amount of a formulation of any one of embodiments Bl-27.

B35. The method of embodiment B34, wherein the viral infection is COVID-19, severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS).

B36. The method of any one of embodiments B29-35, wherein administering the formulation comprises applying a formulation described herein to the skin, a mucous membrane, a cheek or an eye or under a tongue of the subject.

[00126] The following numbered embodiments relate to formulations to support sports performance, and methods of making and using the same.

Cl. 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 nutraceuticals that support sports performance.

C2. The formulation of embodiment Cl, wherein the one or more nutraceuticals comprise a nitric oxide booster.

C3. The formulation of embodiment C2, wherein the nitric oxide booster is citrulline, or a pharmaceutically acceptable salt thereof, beetroot, potassium nitrate or coenzyme Q- 10 (CoQ-10).

C4. The formulation of any one of embodiments Cl-3, wherein the one or more nutraceuticals comprise an adenosine triphosphate (ATP) booster. C5. The formulation of embodiment C4, wherein the ATP booster is ATP, or a pharmaceutically acceptable salt thereof, or ribose, or a pharmaceutically acceptable salt thereof.

C6. The formulation of any one of embodiments Cl -5, wherein the one or more nutraceuticals comprise a carnosine booster.

C7. The formulation of embodiment C6, wherein the carnosine booster is magnesium orotate.

C8. The formulation of embodiment Cl, wherein the one or more nutraceuticals are selected from ATP, ribose, citrulline, orotate, beetroot, nitrate, caffeine or CoQ-10, or a pharmaceutically acceptable salt of any of the foregoing.

C9. The formulation of any one of embodiments Cl -8, wherein at least one of the one or more nutraceuticals is encapsulated within the lecithin liposomes.

CIO. 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 the following nutraceuticals:

ATP, or a pharmaceutically acceptable salt thereof; ribose, or a pharmaceutically acceptable salt thereof; citrulline, or a pharmaceutically acceptable salt thereof; magnesium orotate; beetroot; potassium nitrate; caffeine, or a pharmaceutically acceptable salt thereof; and coenzyme Q10.

Cl 1. The formulation of embodiment CIO, comprising: about 0.1% by weight of the first fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof; about 1.2% by weight of the second fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof; about 0.4% by weight of the lecithin liposomes; about 1.8% by weight ATP, or a pharmaceutically acceptable salt thereof; about 0.2% by weight ribose, or a pharmaceutically acceptable salt thereof; about 0.1% by weight citrulline, or a pharmaceutically acceptable salt thereof; about 0.4% by weight magnesium orotate; about 0.4% by weight beet root powder; about 0.2% by weight potassium nitrate; about 10% by weight caffeine, or a pharmaceutically acceptable salt thereof; and about 0.2% by weight coenzyme Q10.

C12. The formulation of embodiment CIO or Cl 1, further comprising water.

C13. The formulation of embodiment C12, comprising about 84% by weight water.

C14. The formulation of any one of embodiments CIO-13, wherein at least one of the nutraceuticals is encapsulated within the lecithin liposomes.

C15. The formulation of embodiment C14, wherein the magnesium orotate is encapsulated within the lecithin liposomes.

Cl 6. The formulation of any one of embodiments Cl 0-15, 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 nutraceuticals.

Cl 7. The formulation of any one of embodiments Cl-16, for topical administration.

Cl 8. The formulation of any one of embodiments Cl-17, for transdermal, transmucosal, sublingual, buccal, nasal or ocular administration.

Cl 9. The formulation of any one of embodiments Cl-18, in the form of an emulsion.

C20. The formulation of any one of embodiments Cl-19, in the form of a gel, cream, foam, lotion, ointment, paste, spray or drop.

C21. The formulation of any one of embodiments Cl -20, wherein the hyaluronic acid of the first fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight of greater than about 750 kilodaltons.

C22. The formulation of embodiment C21, 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. C23. The formulation of any one of embodiments Cl -22, wherein the hyaluronic acid of the second fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight of less than about 10 kilodaltons.

C24. The formulation of any one of embodiments Cl-23, 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 : 15 to about 1:10.

C25. The formulation of embodiment C24, 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 1:12.

C26. The formulation of any one of embodiments Cl -25, wherein the lecithin liposomes have a d₇₅ of from about 30 nm to about 150 nm.

C27. The formulation of any one of embodiments Cl -26, wherein the formulation is a nutraceutical formulation.

C28. The formulation of any one of embodiments Cl-27, wherein the formulation is a cosmetic formulation.

C29. The formulation of any one of embodiments Cl -28, wherein the formulation is a pharmaceutical formulation.

C30. The formulation base of any one of embodiments Cl-29, further comprising a gelling agent.

C31. The formulation base of embodiment C30, wherein the gelling agent is poly(acrylic acid), or a salt thereof.

C32. The formulation base of embodiment C30 or C31, wherein the gelling agent is a carbomer.

C33. A method of making the formulation of any one of embodiments Cl-32, comprising forming a mixture of the lecithin liposomes, the nutraceuticals and the hyaluronic acid, or a pharmaceutically acceptable salt thereof; and inducing gelation of the mixture.

C34. A method of supporting the sports performance of a subject, comprising administering to the subject a formulation of any one of embodiments Cl-32.

C35. A method of inhibiting delayed onset muscle soreness in a subject, comprising administering to the subject a formulation of any one of embodiments Cl-32. C36. A method of inhibiting inflammation in a subject, comprising administering to the subject a formulation of any one of embodiments Cl -32.

C37. A method of increasing blood oxygen level in a subject, comprising administering to the subject a formulation of any one of embodiments Cl -32.

C38. A method of decreasing oxidative stress in a subject, comprising administering to the subject a formulation of any one of embodiments Cl -32.

C39. A method of increasing strength, stamina or endurance in a subject, comprising administering to the subject a formulation of any one of embodiments Cl -32.

C40. A method of increasing nitric oxide level in a subject, comprising administering to the subject a formulation of any one of embodiments Cl -32.

C41. A method of reducing exercise-induced fatigue in a subject, comprising administering to the subject a formulation of any one of embodiments Cl -32.

C42. The method of any one of embodiments C34-41, wherein the formulation is administered to the subject prior to a workout.

C43. The method of any one of embodiments C34-42, 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.

EXEMPLIFICATION

Example 1. Fabrication of Lecithin Liposomes Encapsulating Vitamin D3

[00127] The following materials were used to prepare lecithin liposomes encapsulating vitamin D3 :

• 88 grams organic sunflower lecithin powder

• 27 grams vitamin D3

• One litre of steam-distilled water

• One 2 litre flat-bottomed borosilicate glass flask

• One 1 litre flat-bottomed borosilicate glass flask

• Two 200 millilitre flat-bottomed borosilicate glass flasks

• Glass rod or glass spoon

• Small Pyrex glass saucepan

• Electric hand whisk or a food blender with a glass mixing bowl

• Ultrasonic cleaner 2 litre capacity

• A 1 litre glass bottle. [00128] Lecithin liposomes encapsulating vitamin D3 were prepared using the following process:

1. Poured 900 millilitres steam-distilled water into the 2 litre borosilicate glass flask.

2. Weighed 88 grams of sunflower lecithin, added it to the water from step (1) and stirred with glass spoon or glass rod.

3. Poured 100 millilitres steam-distilled water into a glass saucepan and brought water to near boiling.

4. Weighed 27 grams vitamin d3 and placed it into a 200-millilitre borosilicate glass flask. When the water in step (3) was near boiling, poured it over the vitamin D3 and swirled until the vitamin D3 dissolved. (This happens very quickly when using very hot water.)

5. Then, partly filled the saucepan with cold water and placed the 200ml borosilicate glass flask with dissolved vitamin D3 into the saucepan to cool. When it was sufficiently cool or cold, poured the vitamin D3 fluid into the 2-litre borosilicate glass flask and stirred with the glass rod or glass spoon. Put a saucer or plate on top and allowed it to stand for several hours or overnight.

6. Used the electric hand food whisk for five minutes to blend the lecithin and vitamin D3 mix.

7. Poured the now thoroughly blended lecithin and vitamin d3 into the 1 litre flat bottomed borosilicate glass flask and placed it into the ultrasonic unit.

8. Filled the steel well of the ultrasonic unit with water to its maximum level and switched on, and let it run it for a total of 100 minutes. Periodically stirred the solution with the glass spoon or glass rod.

9. Poured liposomal vitamin D3 into 1 litre glass bottle and placed it into the fridge. Drew down as needed.

Example 2. Manufacture of Formulation Comprising Formulation Base [00129] Deionized or distilled water having a pH of 7 and a temperature of 68 °C is mixed on medium speed (moderate agitation) while 1/3 of the long chain hyaluronic acid is slowly feathered in. The resulting mixture was blended for 6 minutes. One or more active substances are added individually, and the resulting mixture is blended for 2 minutes after the addition of each, individual substance. Lecithin liposomes encapsulating vitamin D3 from Example 1 are added, and the resulting mixture is blended for 2 minutes. The remaining 2/3 of the long chain HA and all of the ultra-short chain HA are added, and the resulting mixture is blended for 4 minutes. Carbomer 940 is added, and the resulting mixture is blended for 2 minutes. The formulation gels rapidly, and is, therefore, packaged immediately.

[00130] The formulation can be applied to clean, dry skin topically to effect transdermal administration. Application may be repeated, as desired or recommended by a healthcare professional.

Example 3. Formulation and Manufacture of Immune Gel

[00131] 1.0 Kilogram of an immune gel having the following formula was prepared according to the procedure described below:

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

2. Added vitamin C slowly into vortex while mixing using a propeller lOO-lOOOrpm until completely dissolved.

3. Added N-acetyl-L-cysteine slowly into vortex while mixing until completely dissolved.

4. Added glutathione (GSH) slowly into vortex while mixing until completely dissolved.

5. Added zinc oxide slowly into vortex while mixing until completely dispersed and uniform. 6. Added organic sunflower lecithin slowly into vortex while mixing until completely dissolved.

7. Added vegetable glycerin slowly into vortex while mixing until completely dispersed and uniform.

8. Added alpha lipoic acid slowly into vortex while mixing until uniformly dispersed.

9. Added coenzyme Q10 slowly into vortex while mixing until uniformly dispersed.

10. Added vitamin D3 (cholecalciferol) slowly into vortex while mixing until uniformly dispersed.

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

12. Switched the steam off, added hyaluronic acid (sodium hyaluronate 0.80-1.50 million daltons) to the mixing kettle.

13. Kept mixing for 10 minutes until the sodium hyaluronate was dispersed uniformly.

14. Added hyaluronic acid (sodium hyaluronate <10,000 daltons) to the mixing kettle. Kept mixing for 15 minutes.

15. Added the preservative (SUTTOCIDE™ A) to the mixing kettle, and mixed for 10 minutes.

16. Added the orange oil to the mixing kettle, and mixed for 10 minutes.

17. Added the carbomer 940 to the mixing kettle, and mixed for 1 minute.

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

[00132] The immune gel 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.

Example 4. Preparation of Beet Root Powder

[00133] Organic, non-genetically modified organism (GMO) beet root powder (beta vulgaris) was drum dried at 90 °F for 360 minutes. Approximately 2 mg dried beet root powder/serving (approximately 0.2% by weight) was included in a performance gel formulation. Exceeding this inclusion rate resulted in beet-colored markings on skin, where applied. Example 5. Preparation of a Performance Gel Formulation

[00134] 10.96 Kilograms of a performance gel having the following formula was prepared according to the procedure described below:

2. Added caffeine slowly into vortex while mixing using a propeller 100-1000rpm until completely dissolved.

3. Added ATP slowly into vortex while mixing until completely dissolved.

4. Added hyaluronic acid (<10,000 D) slowly into vortex while mixing until completely dissolved.

5. Added SUTTOCIDE™ A slowly into vortex while mixing until completely dispersed and uniform.

6. Added liposomes (organic sunflower lecithin) slowly into vortex while mixing until completely dispersed and uniform.

7. Added beet root powder slowly into vortex while mixing until uniformly dispersed.

8. Added coenzyme Q10 slowly into vortex while mixing until uniformly dispersed.

9. Added ribose slowly into vortex while mixing until uniformly dispersed.

10. Added potassium nitrate until uniformly dispersed. 11. Switched the steam off, and added hyaluronic acid (sodium hyaluronate 0.80-1.50 million Daltons) to the mixing kettle.

12. Kept mixing for 10 minutes until the sodium hyaluronate was dispersed uniformly.

13. Added potassium nitrate. Kept mixing for 15 minutes.

14. Added citrulline until uniformly dispersed.

15. Added magnesium orotate until uniformly dispersed.

16. Added polysorbate 40 until uniformly dispersed.

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

[00135] The resulting gel was light purple in color

[00136] Two to three pumps of the performance gel can be applied to clean, dry skin five minutes before workout. The performance gel can be rubbed on skin until dry, typically for 30 seconds. Application can be repeated to desired dosage or as directed by a healthcare professional.

Example 6. Preparation of Liposomes Encapsulating Magnesium Orotate

[00137] The following materials were used in the preparation of liposomes encapsulating magnesium orotate:

• 40 grams organic sunflower lecithin powder

• 10 grams Mg orotate

• One litre of steam-distilled water

• One 2 litre flat-bottomed borosilicate glass flask

• One 1 litre flat-bottomed borosilicate glass flask

• Two 200 millilitre flat-bottomed borosilicate glass flasks

• Glass rod or glass spoon

• Small Pyrex glass saucepan

• Electric hand whisk or a food blender with a glass mixing bowl

• Ultrasonic cleaner 2 litre capacity

• A 1 litre glass bottle.

[00138] The liposomes were prepared using the following process:

10. Poured 900 millilitres steam-distilled water into the 2-litre borosilicate glass flask.

11. Weighed 40 grams of sunflower lecithin, and added it to the above and stirred with glass spoon or glass rod. 12. Poured 100 millilitres steam-distilled water into a glass saucepan and brought to near boiling.

13. Weighed 10 grams Mg orotate and placed it into a 200-millilitre borosilicate glass flask. When the water in step 3 was near boiling, poured it over the Mg orotate and swirled until dissolved. (This happened very quickly when very hot water was used.)

14. Then, partly filled the saucepan with cold water and placed the 200ml borosilicate glass flask with dissolved Mg orotate into it to cool. When the flask was sufficiently cool or cold, poured the Mg orotate fluid into the 2-litre borosilicate glass flask and stirred with the glass rod or glass spoon. Put a saucer or plate on top and allowed it to stand for several hours or overnight.

15. Used the electric hand food whisk for five minutes to blend the lecithin and Mg orotate mix.

16. Poured the now thoroughly blended lecithin and Mg orotate into the 1 litre flat bottomed borosilicate glass flask and placed it into the ultrasonic unit.

17. Filled the steel well of the ultrasonic unit with water to its maximum level, switched it on, and let it run it for a total of 100 minutes. Periodically stirred the solution with the glass spoon or glass rod.

18. Poured the resulting liposomal Mg orotate into 1 litre glass bottle and placed it into the fridge. Drew down as needed.

[00139] The liposomes encapsulating magnesium orotate were incorporated into the performance gel formulation described in Example 5 by adding liposomes encapsulating magnesium orotate in step 6 of Example 5, and omitting step 15 of Example 5.

[00140] The teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.

[00141] 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 base 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; and lecithin liposomes within the nanogel, the 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.

2. The formulation base of claim 1, wherein the hyaluronic acid of the first fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight of greater than about 750 kilodaltons.

3. The formulation base of claim 2, 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.

4. The formulation base of any one of claims 1-3, wherein the hyaluronic acid of the second fraction, or a pharmaceutically acceptable salt thereof, has a molecular weight of less than about 10 kilodaltons.

5. The formulation base of any one of claims 1-4, 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.

6. The formulation base of claim 5, 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.

7. The formulation base of any one of claims 1-4, 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 : 15 to about 1:10.

8. The formulation base of claim 7, 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 1:12.

9. The formulation base of any one of claims 1-8, wherein the lecithin liposomes have a d of from about 30 nm to about 150 nm.

10. The formulation base of any one of claims 1-9, further comprising a gelling agent.

11. The formulation base of claim 10, wherein the gelling agent is poly(acrylic acid), or a salt thereof.

12. The formulation base of claim 10 or 11, wherein the gelling agent is a carbomer.

13. A formulation comprising the formulation base of any one of claims 1-12 and one or more active substances.

14. The formulation of claim 13, wherein the one or more active substances comprise one or more nutraceuticals.

15. The formulation of claim 13 or 14, wherein the one or more active substances comprise one or more nutraceuticals that support the immune system.

16. The formulation of claim 15, wherein the one or more nutraceuticals are selected from glutathione, N-acetyl-L-cysteine, coenzyme Q10 (CoQ-10), vitamin A, a B vitamin, vitamin D3, vitamin C, vitamin E, a probiotic, echnicacea, garlic, astragalus, a beta- glucan, docosahexaenoic acid, colostrum, ginseng, a thymic extract, zinc, selenium, iron, folic acid or alpha-lipoic acid, or a pharmaceutically acceptable salt of any of the foregoing.

17. The formulation of claim 16, wherein the one or more nutraceuticals are selected from glutathione, N-acetyl-L-cysteine, CoQ-10, vitamin D3, vitamin C, zinc or alpha-lipoic acid, or a pharmaceutically acceptable salt of any of the foregoing.

18. The formulation of claim 13 or 14, wherein the one or more active substances comprise one or more nutraceuticals that support sports performance.

19. The formulation of claim 18, wherein the one or more nutraceuticals comprise a nitric oxide booster.

20. The formulation of claim 19, wherein the nitric oxide booster is citrulline, or a pharmaceutically acceptable salt thereof, beetroot, potassium nitrate or coenzyme Q- 10 (CoQ-10).

21. The formulation of any one of claims 18-20, wherein the one or more nutraceuticals comprise an adenosine triphosphate (ATP) booster.

22. The formulation of claim 21, wherein the ATP booster is ATP, or a pharmaceutically acceptable salt thereof, or ribose, or a pharmaceutically acceptable salt thereof.

23. The formulation of any one of claims 18-22, wherein the one or more nutraceuticals comprise a camosine booster.

24. The formulation of claim 23, wherein the camosine booster is magnesium orotate.

25. The formulation of claim 18, wherein the one or more nutraceuticals are selected from ATP, ribose, citrulline, orotate, beetroot, nitrate, caffeine or CoQ-10, or a pharmaceutically acceptable salt of any of the foregoing.

26. The formulation of any one of claims 13-25, wherein at least one of the one or more active substances is encapsulated within the lecithin liposomes.

27. 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 the following nutraceuticals: alpha-lipoic acid, or a pharmaceutically acceptable salt thereof; glutathione, or a pharmaceutically acceptable salt thereof; N-acetyl-L-cysteine, or a pharmaceutically acceptable salt thereof; coenzyme Q10; vitamin D3, or a pharmaceutically acceptable salt thereof; vitamin C, or a pharmaceutically acceptable salt thereof; and zinc oxide.

28. The formulation of claim 27, comprising: about 2.2% by weight of the first fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof; about 0.4% by weight of the second fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof; about 0.2% by weight of the lecithin liposomes; about 0.2% by weight alpha-lipoic acid, or a pharmaceutically acceptable salt thereof; about 1.1% by weight glutathione, or a pharmaceutically acceptable salt thereof; about 0.2% by weight N-acetyl-L-cysteine, or a pharmaceutically acceptable salt thereof; about 0.4% by weight coenzyme Q10; about 0.4% by weight vitamin D3, or a pharmaceutically acceptable salt thereof; about 0.4% by weight vitamin C, or a pharmaceutically acceptable salt thereof; and about 0.4% by weight zinc oxide.

29. The formulation of claim 27 or 28, further comprising water.

30. The formulation of claim 29, comprising about 91% by weight water.

31. The formulation of any one of claims 27-30, wherein at least one of the nutraceuticals is encapsulated within the lecithin liposomes.

32. The formulation of claim 31, wherein the glutathione, or a pharmaceutically acceptable salt thereof; N-acetyl-L-cysteine, or a pharmaceutically acceptable salt thereof; vitamin D3, or a pharmaceutically acceptable salt thereof; and zinc oxide are encapsulated within the lecithin liposomes.

33. 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 the following nutraceuticals:

34. The formulation of claim 33, comprising: about 0.1% by weight of the first fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof; about 1.2% by weight of the second fraction of hyaluronic acid, or a pharmaceutically acceptable salt thereof; about 0.4% by weight of the lecithin liposomes; about 1.8% by weight ATP, or a pharmaceutically acceptable salt thereof; about 0.2% by weight ribose, or a pharmaceutically acceptable salt thereof; about 0.1% by weight citrulline, or a pharmaceutically acceptable salt thereof; about 0.4% by weight magnesium orotate; about 0.4% by weight beet root powder; about 0.2% by weight potassium nitrate; about 10% by weight caffeine, or a pharmaceutically acceptable salt thereof; and about 0.2% by weight coenzyme Q10.

35. The formulation of claim 33 or 34, further comprising water.

36. The formulation of claim 35, comprising about 84% by weight water.

37. The formulation of any one of claims 33-36, wherein at least one of the nutraceuticals is encapsulated within the lecithin liposomes.

38. The formulation of claim 37, wherein the magnesium orotate is encapsulated within the lecithin liposomes.

39. The formulation of any one of claims 27-38, 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 nutraceuticals.

40. The formulation base of any one of claims 1-12 or the formulation of any one of claims 13-39, for topical administration.

41. The formulation base of any one of claims 1-12 and 40, or the formulation of any one of claims 13-40, for transdermal, transmucosal, sublingual, buccal, nasal or ocular administration.

42. The formulation base of any one of claims 1-12, 40 and 41, or the formulation of any one of claims 13-41, in the form of an emulsion.

43. The formulation base of any one of claims 1-12 and 40-42, or the formulation of any one of claims 13-42, in the form of a gel, cream, foam, lotion, ointment, paste, spray or drop.

44. A method of making the formulation base of any one of claims 1-12 and 40-43, comprising forming a mixture of the lecithin liposomes and the first and second fractions of hyaluronic acid, or a pharmaceutically acceptable salt thereof; and inducing gelation of the mixture.

45. A method of making the formulation of any one of claims 13-43, comprising forming a mixture of the lecithin liposomes, the one or more active substances or nutraceuticals, and the hyaluronic acid, or a pharmaceutically acceptable salt thereof; and inducing gelation of the mixture.

46. A method of administering a formulation base or formulation to a subject, comprising applying a formulation base of any one of claims 1-12 and 40-43, or a formulation of any one of claims 13-43 to skin, a mucous membrane, a cheek, a nose or an eye, or under a tongue of the subject.

47. A method of treating a subject in need of a formulation base of any one of claims 1-12 and 40-43, or a formulation of any one of claims 13-43, comprising administering an effective amount of the formulation base of any one of claims 1-12 and 40-43, or the formulation of any one of claims 13-43 to the subject.

48. A method of treating a subject having a disease, disorder or condition that would benefit from administration of a formulation base of any one of claims 1-12 and 40- 43, or a formulation of any one of claims 13-43, comprising administering an effective amount of the formulation base of any one of claims 1-12 and 40-43, or the formulation of any one of claims 13-43 to the subject.

49. A method of inhibiting inflammation in a subject, comprising administering a formulation base of any one of claims 1-12 and 40-43, or a formulation of any one of claims 13-43 to the subject.

50. A method of treating inflammation in a subject in need thereof, comprising administering an effective amount of a formulation base of any one of claims 1-12 and 40-43, or a formulation of any one of claims 13-43 to the subject.

51. The method of claim 49 or 50, wherein the inflammation is inflammation of the skin.

52. The method of any one of claims 49-51, wherein the inflammation is a result of a bug bite or sunburn.

53. The method of any one of claims 49-52, comprising administering an effective amount of the formulation base of any one of claims 1-12 and 40-43 to the subject.

54. The method of any one of claims 49-52, comprising administering an effective amount of the formulation of any one of claims 13-43 to the subject.

55. A method of administering one or more active substances or nutraceuticals to a subject, comprising applying a formulation of any one of claims 13-43 comprising the one or more active substances or nutraceuticals to skin, a mucous membrane, a cheek, a nose or an eye, or under a tongue of the subject.

56. A method of treating a subject in need of one or more active substances or nutraceuticals, comprising administering an effective amount of a formulation of any one of claims 13-43 comprising the one or more active substances or nutraceuticals to the subject.

57. A method of treating a subject having a disease, disorder or condition that would benefit from administration of one or more active substances or nutraceuticals, comprising administering an effective amount of a formulation of any one of claims 13-43 comprising the one or more active substances or nutraceuticals to the subject.

58. The method of any one of claims 47-54, 56 and 57, wherein administering the formulation base or the formulation comprises applying an effective amount of the formulation to skin, a mucous membrane, a cheek, a nose or an eye, or under a tongue of the subject.