Nanoparticle NAD+ formulations and related methods

Abstract

Nano-sized nicotinamide adenine dinucleotide (NAD) containing compositions, dosage forms, and treatment methods are disclosed and described herein. In one example, a composition including a therapeutically effective amount of nano-sized NAD in combination with a pharmaceutically acceptable carrier, is presented. In another example, a method of treating a condition responsive to nano-sized NAD therapy is presented.

Description

[0001] NANOPARTICLE NAD+ FORMULATIONS AND RELATED METHODS

[0002] PRIORITY DATA

[0003] This application claims the benefit of United States Provisional Patent Application Serial No. 63 / 717,257, filed on November 6, 2024, which is incorporated herein by reference.

[0004] TECHNOLOGY FIELD

[0005] The present disclosure involves Nicotinamide adenine dinucleotide (NAD+) containing compositions and methods for the therapeutic use and manufacture thereof. Accordingly, this disclosure involves the fields of chemistry and health science.

[0006] BACKGROUND

[0007] Nicotinamide adenine dinucleotide (NAD) is a coenzyme that is central to metabolism. NAD consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other, nicotinamide, exists in two forms, namely an oxidized form (NAD+) and a reduced form (NADH) as shown below.

[0008] NAD+ nucleobase

[0009]

[0010] Adenine nucleobase

[0011] Accordingly, NAD+ permits hydrogen transport in oxidation-reduction reactions through its ability to acquire two electrons and form NADH. The C4 carbon of the nicotinamide nucleobase is prochiral and the nicotinamide ring of the NAD+ positioned either above or below the plane of the planar C4 carbon acts as a hydride donor as shown above.

[0012] NAD functions as a redox carrier in metabolic processes including glycolysis, tricarboxylic acid (TCA) cycle (i.e. Kreb’s cycle), oxidative phosphorylation, fatty acid oxidation, and alcohol metabolism. In addition, NAD+ acts as a co-substrate for various NAD+ consuming enzymes involved in tumorigenesis, genome stability, metabolism, cell growth, cell death, redox homeostasis, and immune responses; serves as a nucleotide analog in DNA ligation and RNA capping; acts as a metabolite with inflammatory signaling; and acts as an extracellular signaling molecule involved in cell-to-cell communication. In short, NAD is a coenzyme that is central to metabolism.

[0013] BRIEF DESCRIPTION OF THE DRAWINGS

[0014] For a fuller understanding of the nature and advantage of the present invention, reference is being made to the following detailed description and in connection with the accompanying drawings, in which:

[0015] FIG. 1 illustrates a dynamic light scanning (DLS) analysis of an exemplary NAD+ solution containing NAD+ and water in one example embodiment.

[0016] DETAILED DESCRIPTION

[0017] Before particular embodiments of the present invention are disclosed and described, it is to be understood that this invention is not limited to the particular process and materials disclosed herein as such may vary to some degree. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, as the scope of the present invention will be defined only by the appended claims and equivalents thereof.

[0018] Definitions

[0019] In describing and claiming the present invention, the following terminology will be used.

[0020] The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an emollient” includes reference to one or more of such emollients.

[0021] As used herein, the term “about” is used to provide flexibility to numerical values and / or numerical range endpoints by providing that a given value may be “a little above” or “a little below” the endpoint. For example, for the sake of convenience and brevity, a numerical range of “about 50 wt.% to about 80 wt.%” should also be understood to include ranges slightly above or below these end points. A value of “about 50” also includes values slightly above or below 50. Additionally, it is to be understood that in this written description, occurrences of the word “about” in connection with an element to which the term is applied also provide express support for the item itself as though the term “about” were not used. In the case of numerical values for example, the phrase “about 85 wt.%” includes express support for “85 wt ° / o ’ or “exactly 85 wt.%” (e.g. 85 wt.% per se). Additionally, the phrase “about 50 wt.% to about 80 wt.%” includes the range of exactly 50 wt.% to 80 wt.%.

[0022] In this application, “comprises,” “comprising,” “containing,” and “having” and the like have the meaning ascribed to them in U. S. Patent law and mean “includes,” “including.” and the like, and are generally interpreted to be open ended terms. The terms “consisting of’ or “consists of’ are closed terms, and include only the components, structures, steps, or the like specifically listed in conjunction with such terms, as well as that which is in accordance with U. S. Patent law. “Consisting essentially of’ or “consists essentially of’ have the meaning generally ascribed to them by U. S. Patent law. In particular, such terms are generally closed terms, with the exception of allowing inclusion of additional items, materials, components, steps, or elements, that do not materially affect the basic and novel characteristics or function of the item(s) used in connection therewith. For example, trace elements present in a composition, but not affecting the compositions nature or characteristics would be permissible if present under the “consisting essentially of’ language, even though not expressly recited in a list of items following such terminology. When using an open-ended term in this written description, like “comprising” or “including,” it is understood that direct support should be afforded also to “consisting essentially of’ language as well as “consisting of’ language as if stated explicitly and vice versa.

[0023] The term “NAD” as used herein refers to Nicotinamide adenine dinucleotide (NAD). As used in this written description, NAD refers to both the oxidized form (NAD+) and the reduced form (NADH). Thus, when “NAD” is used, it provides support for NAD+, NADH, and a combination of NAD+ and NADH. Additionally, the term "NAD” provides support for both NAD in its nano-sized form as well as NAD in its larger forms.

[0024] The term “subject” as used herein includes all members of the animal kingdom, including mammals, and suitably refers to humans.

[0025] The term “pain” refers to any and all types of physical pain regardless of the pathogenesis or cause. The pain may from a pathophysiological condition or disease, aging, trauma, a wound or injury, surgery or other procedure, or exercise. The pain can be acute or chronic, neuropathic, nociceptive, and / or radicular pain, or a combination thereof.

[0026] As used herein, the term “nano-sized” and “nano” can be used interchangeably and refer to a compound, molecule, or substance that is less than 1 pm in size. For example, nanosized NAD refers to NAD+ or NADH that is less than 1 pm in size. Additionally, “nano-sized NAD” and “nano NAD” can be used interchangeably and also include NAD in its molecular form (e.g. a single molecule of NAD.

[0027] As used herein, an “active agent” or a “drug” may be used interchangeably and refer to a compound, molecule, or substance that exerts or imparts a medicinal physiological effect on a subject. Active agents can be identified in some cases by their mechanism of action or specific treatment effects. For example, active agents which are effective against pain are known as analgesics. In one embodiment, an active agent can be NAD, its related products (e.g. degradation products, metabolites, etc.), or a combination thereof.

[0028] As used herein, “pH modulator” and “pH adjustor” can be used interchangeably and refer to an ingredient that is operable to modulate or adjust a pH of a solution, composition, or an environment. Numerous ingredients which can modulate solutions, compositions, and environments to become either acidic or basic are known and often described by their pH properties, such as “acids” or “bases.”. As such, these terms along with their related terms such as “acidic,” “basic,” “alkaline,” etc. can be used herein to describe the pH properties of a composition or environment (e.g. a treatment site or situs). The pH scale is logarithmic and inversely indicates the activity of hydrogen ions. pH is measured on a scale of 1 to 14 with 1 representing the most acidic, 14 representing the most basic, and 7 representing neutral. Thus, acids and bases can be further articulated in terms of the pH that they impart to a solution, composition, or environment, and can be further categorized into “strong acids,” “w eak acids,” “strong bases,” or “weak bases” depending on the location of the pH scale on which they fall.

[0029] As used herein, a “carrier” refers to an element, molecule, vehicle, substance, or composition with which an active agent can be combined in order to create a therapeutic composition. In some embodiments, such ingredients or combinations of ingredients can preserve the form and / or function of the active agent or its properties. In other embodiments, such ingredients or combinations of ingredients can alter, attenuate, or modulate, the form and / or active agent or its properties. In yet other embodiments, such ingredients or combinations of ingredients can facilitate or improve the handling and / or application / administration of that active agent to a subject. A wide range of ingredients can be combined with an active agent in order to provide a therapeutic composition or formulation, including without limitation, solvents, pH modulators, etc.

[0030] The term “proximate” when referring to an existing pain is a location on a skin surface, particularly as it relates to the location of the existing pain, directly over (in part or fully covering) or immediately adjacent to tissue from which the pain is present. ■‘Skin” refers to animal (e.g. human) skin including the various epidermis, dermis, and hypodermis layers and also mucosal surfaces that are usually at least partially exposed to air such as lips, genital and anal mucosa, and nasal and oral mucosa. In some examples, skin can be intact, or broken, including by a wound, damaged or diseased (e.g. with an ulcer, such as a diabetic ulcer). It is to be understood that as used in this written description, “skin” includes express support for each of the various skin layers as though such layer was expressly recited and vice versa.

[0031] As used herein, the term “medical skin condition” refers to any pathophysiological condition that affects the integumentary system. The term encompasses all medical conditions that have a negative pathophysiological impact on the skin, rather than simply a cosmetic issue.

[0032] As used herein, “mucosa,” “mucosa layer,” “mucosa” “mucus membrane,” “mucosal layer” and the like can be used interchangeably and refer to a lubricating membrane lining an internal cavity, such as a cavity that is periodically exposed, or at lest partially exposed to air, such as the oral, nasal, ear, anal, or vaginal cavities. Mucosa typically includes the following membranes or layers: epithelium, lamina propria and muscularis mucosae. It is to be understood that as used in this written description, the above recited terms such as “mucosa” provide express support for each of the various mucus membrane layers and vice versa.

[0033] As used herein, the term “skin contact region” refers to an area wherein the topical formulation contacts the skin.

[0034] The term “topical” refers to a t pe of administration and / or therapeutic effect primarily occurring at or in the skin. For example, a “topical formulation,” refers to a formulation containing an active agent that may be applied to a skin surface. Further, “topical administration” is used in its conventional sense to mean delivery of a substance, such as an active agent, to a region of the skin. For example, to broken or unbroken skin. A “topical effect” refers to a local therapeutic effect in the skin or also to regional therapeutic effect to areas surrounding a skin administration site, and beneath the skin, which occur as a result of topical administration of a topical formulation to a skin administration site. “Topical” does not include (e.g. excludes) “transdermal”

[0035] As used herein, the term “transdermal” refers to administration of an active agent through substantially unbroken skin using a device, mechanism, or composition that is sufficient to transmit the active agent through a subject’s skin and into the circulatory system in order to provide systemic exposure of a therapeutically effective amount of the active agent and achieve a therapeutic effect that is distal from a skin administration site. Examples of transdermal products can include compositions / formulations and patches, such a liquid reservoir patches, matrix patches, and iontophoretic devices.

[0036] As used herein, “parenteral” refers to a route of administration of an active agent (e.g. NAD+) to a subject that is through a route that is other than through the gastrointestinal (G. I) tract. Examples of parenteral administration can include transdermal administration, intravenous (i.v.) administration, injection (e g. intramuscular and / or subcutaneous injection), and others.

[0037] As used herein, “enteral” refers to a route of administration of an active agent, such as NAD+ which is through the G. I. tract. An example of an enteral administration is oral administration with a dosage form that is swallowed and exposed to absorption through the portions of the G. I. tract past the oral cavity. It should be noted that some formulations that are held in the oral cavity and also swallowed, can provide delivery through both enteral and parenteral administration routes. Specifically, any amount of the active agent (e.g. NAD+) that is absorbed through the mucosa of the oral cavity is delivered parenterally, while any amount of the active agent that is swallowed and absorbed through the stomach or small intestines is delivered enterally. Examples of formulations that may provide such dual delivery7include without limitation, solutions (e.g. in the form of a beverage, spray, rinse, liquid suspension, etc.) lozenges, tablets, confections, such as a medicinal or comestible chew, soft gels, gum, gummies, lollipops, and the like.

[0038] The term “treating” or “treatment” as used herein and as is well understood in the art, means an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilizing (i.e. not worsening) the state of disease, delaying or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission (whether partial or total), whether detectable or undetectable. “Treating” and “treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. In addition to being useful as methods of treatment, the methods described herein may be useful for the prevention or prophylaxis of disease.

[0039] As used herein, the terms “treatment site,” “treatment situs,” and like terms refer to an area, a region, or a location on, the skin of a subject. Treatment sites can include nearly any area of skin, mucosa, or keratin, whether normal or abnormal (i.e. diseased, afflicted, infected, wounded, etc.). In some examples, a treatment site can be a location or area of tissue that is afflicted with a disease, illness, condition, or symptom.

[0040] The term “water” as used herein as an ingredient in the compositions of the application refers to pharmaceutically acceptable water (e.g. deionized water, deoxygenated water, etc.).

[0041] As used herein, a plurality of items, structural elements, compositional elements, and / or materials may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary. Moreover, the inclusion of an item in a list or otherwise in this written description also provides express support for exclusion of the item. For example, recitation of specific pharmaceutically acceptable carrier or its ingredients, either alone or in a group, provides express support for exclusion of the specific pharmaceutically acceptable carrier or its ingredients from compositions of formulations generally, or from a list of other pharmaceutically acceptable carriers or ingredients.

[0042] As used herein, the term “substantially” refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result. For example, an object that is “substantially” enclosed would mean that the object is either completely enclosed or nearly completely enclosed. The exact allowable degree of deviation from absolute completeness may in some cases depend on the specific context. However, generally speaking the nearness of completion will be so as to have the same overall result as if absolute and total completion were obtained. The use of “substantially” is equally applicable when used in a negative connotation to refer to the complete or near complete lack of an action, characteristic, property, state, structure, item, or result. For example, a composition that is “substantially free of’ particles would either completely lack particles, or so nearly completely lack particles that the effect would be the same as if it completely lacked particles. In other words, a composition that is “substantially free of’ an ingredient or element may still actually contain such item as long as there is no measurable effect thereof. Moreover, as used in this written description it is to be understood that terms use in connection with or otherwise modified by the term “substantially” shall provide express support for the exact term as if recited without being accompanied by “substantially” and vice versa. For example, an item recited as “substantially enclosed” also provides express support for the item being totally or completely enclosed, and an item that is recited simply as ‘’enclosed” provides express support for the item being “substantially enclosed”.

[0043] As used herein, comparative terms such as “increased,” “decreased,” “better,” “worse,” “higher," “lower,” “enhanced,” “maximized," “minimized,” and the like refer to a property’ of a compositions, components, methods, or activity that is measurably different from other compositions, components, methods, or activities, or as compared to the known state of the art. For example, an “increased” healing response can refer to a degree or timing of healing that surpasses or exceeds healing achieved to a comparable injury' or condition without treatment or without a similar or like treatment. Likewise, an “increased” recovery can refer to a degree or timing of recovery^ that surpasses or exceeds a recovery achieved in the absence of treatment, or a similar or like treatment. An “enhanced” therapeutic effect can refer to a degree or a timing of the therapeutic effect which is advantageous for the subject as compared to a therapeutic effect achieved to a similar but at least slightly different treatment. For example, a composition that includes a therapeutic enhancing agent can provide a more efficacious therapy to a subject as compared to the same composition without the therapeutic enhancing agent.

[0044] As used herein, the term “at least one of’ is intended to be synonymous with “one or more of.” For example, “at least one of A, B, and C” and “at least one of A, B, or C” explicitly include only A, only B, only C, or combinations of each.

[0045] Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity' and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. As an illustration, a numerical range of “about 1 nm to 100 nm” should be interpreted to include not only the explicitly recited values of about 1 nm and about 100 nm, but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 5 nm, 25 nm. 50 nm. 75 nm, and sub-ranges such as from 1 nm to 20 nm, from 15 nm to 45 nm, or from 50 nm to 80 nm etc. Furthermore, such an interpretation should apply regardless of the breadth of the range or the characteristics being described. Additionally, it is noted that all percentages are in weight, unless specified otherwise. Additionally, in some cases, amounts of ingredients or other elements can be recited in terms of percentage (i.e. %). It is to be understood that in this written description, the occurrence of “percent,” “percentage,” “%,” and the like provide express support for any relevant type of percentage (e.g. area percent, such as skin area percent, height or depth percent, weight percent, mass percent, mol percent, atomic percent, volume percent, etc.) unless the reasonable context dictates otherwise and clearly lends itself to a specific percentage type. Moreover, recitation of one specific percentage type in this written description also provides express support for other percentage types (e.g. wt% for vol% and vice versa).

[0046] Reference will now be made to the exemplary embodiments illustrated, and specific language will be used herein to describe the same. It will nevertheless be understood that no limitation of the scope of the technology is thereby intended. Additional features and advantages of the technology will be apparent from the detailed description which follows, taken in conjunction with the accompanying drawings, which together illustrate, by way of example, features of the technology.

[0047] Exemplary Embodiments

[0048] With this background in mind nicotinamide adenine dinucleotide (NAD) containing compositions, local, topical, enteral and parenteral NAD dosage forms, and treatment methods utilizing NAD as an active agent are presented herein. As previously noted. NAD has multiple forms, including NAD+ with the chemical formula C21H29N7O14P2. and NADH which has the chemical formula C21H27N7O14P2 among others. As used in this written description, “NAD” refers to any form of NAD, including without limitation NAD+ and NADH. Additionally, it is to be understood that as used in this written description, the recitation of NAD provides express support for either NAD+ or NADH. Furthermore, the recitation in this written description ofNAD+ provides express support for NADH and vice versa, unless the context or accepted chemical processes and principles dictate otherwise.

[0049] In some embodiments, NAD can be present in its molecular form (e.g. individual separate molecules (including folded, unfolded, etc.) having a size in the nanometer or even angstrom range, typically between about 10 and about 15 angstroms). In other embodiments, NAD can be micron-sized in size or less, including nano-sized (in the case of molecule aggregation, clustering, precipitation, crystalizing, agglomeration, etc.). Incorporating and maintaining NAD in nano-sized form can permit the NAD to move more easily past a body’s natural barriers and increase accessibility and therapeutic efficacy. For example, nano-sized particles can more readily pass into and through layers of the skin and enter into cells. Moreover nano-sized particles allow for higher loading capacity when combined with a carrier. Described herein are therapeutic compositions that include a pharmaceutically acceptable carrier and a therapeutically effective amount of nano-sized NAD. The NAD can be dispersed or dissolved in a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can include water, sterilized water, phosphate-buffered saline (PBS) Dulbecco’s PBS, Alsever’s solution, Tris-buffered saline (TBS), balanced salt solutions (BSS), such as Hank’s BSS, Earle’s BSS, Grey’s BSS, Puck’s BSS, Simm’s BSS, Tyrode’s BSS, BSS Plus, Ringer’s lactate solution, normal saline (i.e. 0.9% saline), ½ normal saline, glycerin, ethyl alcohol, propylene glycol, propylparaben, hydrogel, the like, or a combination thereof. In some examples, the pharmaceutically acceptable carrier can consist essentially of water, or otherwise include substantially no other ingredients, or no other ingredients than water. The NAD present in the composition can include one or more of molecular-sized NAD (e.g. a single molecule), nano-sized particle (e.g. nanoparticles or nanoparticulate) NAD, and micron-sized particles (e.g. microparticles or microparticulate) NAD, or a combination thereof. In some examples, the NAD can be at least one of NAD+, NADH, or a combination of both NAD+ and NADH. In other examples, the NAD can include or consist essentially of NAD+, while in further examples, the NAD can include or consist essentially of NADH. In yet further examples, the NAD can be a combination of NAD+ and NADH. In such examples the NAD+ and NADH can be present in a ratio of from about 1: 100 to about 100: 1. In some embodiments, a "nano-NAD” composition or formulation can have at least about 50% of the NAD content in the form of nanoparticles or smaller. In another embodiment, at least 30% to about 100% of the NAD content can be in the form of nanoparticles or smaller. In a further embodiment, at least about 55%. 60%. 65%. 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the NAD content can be in the form of nanoparticles or smaller. Additionally, in other embodiments, the composition or formulation can have from about 0.1% to about 99% of the NAD in molecular form. In other examples, at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the NAD can be in molecular form.

[0050] In some embodiments, the composition can consist essentially of water and nano-sized NAD. For example, the composition can have no other ingredients than nano-sized NAD and water. In some examples, the water can be USP pharmaceutical grade and can be sterile and / or bacteriostatic. In another example, the pharmaceutically acceptable carrier can include water and propylene glycol. The pharmaceutically acceptable carrier can be present at an amount ranging from about 50 wt% to about 95 wt%. In yet other examples, a pharmaceutically acceptable carrier can be present in compositions at from about 50 wt% to about 80 wt%, from about 55 wt% to about 75 wt%, from about 60 wt% to about 95 wt%, or from about 75 wt% to about 95 wt%. Whereas NAD can be present in compositions from about 5 wt% to about 99 wt%, from about 5 wt% to about 50 wt%, from about 10 wt% to about 70 wt%, from about 25 wt% to about 85 wt%, from about 5 wt% to about 65 wt%, or from about 30 wt% to about 90 wt%. Additionally, the weight ratio of NAD to pharmaceutically acceptable carrier can be from about 0.001:100 to about 100:0.001, from about 0.01:100 to about 100:0.01, from about 0.1:100 to about 100:0.1, from about 1:100 to about 100:1, from about 10:100 to about 100:10, from about 1:1, or from about 0.5:9.5 to about 2:8.

[0051] The nano NAD can remain relatively stable in the composition over time. In some examples, from about 5% to about 95% of the total NAD in the composition can remain nanosized NAD when stored at a temperature of about 40 degrees Fahrenheit or below for a period of from about 30 days to about 1 year. In other examples, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% o 95% of the total NAD in the composition can remain nano-sized NAD when stored at a temperature of about 40 degrees Fahrenheit or below for a period of from about 30 days to about 1 year. Additionally, at least 75%, 80%, 85%, 90%, or 95% of an initial amount of NAD in the composition can remain when the composition is stored at a temperature below 40 degrees Fahrenheit for a period of a year.

[0052] Compositions presented herein may, in some embodiments, further include additives such as a pH adjustor (e g. buffer), such as an acid or base, to reach a desired pH. Acidifying pH adjustors can be selected from acetic acid, citric acid, hydrochloric acid, malic acid, orthophosphoric acid, or the like. Alkalizing pH adjusters can be selected from ammonia, potassium hydroxide, sodium carbonate, sodium hydroxide, triethanolamine, or the like. A pH adjustor can be added to a composition to adjust a pH to from about 3 to about 6 or from about 4 to about 5. Despite the acidic nature of the compositions herein, NAD is stable in the compositions. In some embodiments, the pH of the aqueous solution can be about 5.5.

[0053] Compositions herein can be formulated as a topical formulation, a parenteral formulation, or an enteral formulation (e.g. oral) formulation. In some examples, the composition can be a topical formulation. Topical formulations may deliver NAD topically or transdermally. The ability of nano-sized NAD to penetrate skin depends on size, charge, and material. Generally, particles pass through skin in one of three pathways: intracellularly through comeocytes, intercellularly around comeocytes, or via dermal structures like hair follicles. Topical formulations may include nano-sized NAD and a size of the NAD can assist topical ortransdermal delivery thereof. In one example, compositions herein can be formulated for administration as a liquid, cream, gel, paste, lotion, solution, suspension, ointment, or the like. A viscosity of a topical formulation can range from about 1 cps to about 10 cps, from about 10 cps to about 50 cps, from about 50 cps to about 150 cps, from about 150 cps to about 300 cps, from about 300 cps to about 600, or from about 500 cps to about 1000 cps. In some examples when the composition is formulated as a cream, gel, paste, lotion, solution, suspension, or the like, the pharmaceutically acceptable carrier can further include at least one of an emollient, thickening agent, surfactant, viscosity modifier, pH adjustor, or preservative among other ingredients.

[0054] In examples when an emollient is included, exemplary emollients include without limitation almond oil, aluminum stearate, caprylic / capric triglyceride, canola oil, castor oil, ceratonia extract, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cholesterol, cocos nucifera (coconut oil), cottonseed oil, cyclomethicone, decyl glycoside, dibutyl sebacate, dimethicone, ethylene glycol palmitostearate, glycerin, glycerin monostearate, glycerin monooleate, glyceryl stearate, isopropyl myristate, isopropyl palmitate, lanolin, lanolin alcohols, lecithin, medium-chain triglycerides, mineral oil, myristyl alcohol, octyldodecanol, oleyl alcohol, petrolatum, safflower glycerides, safflower oil, sodium lauryl sulphate, soybean oil, stearyl alcohol, sunflower oil, tricaprylin, triolein, xylitol, zinc acetate, or any combinations thereof.

[0055] In examples where a thickening agent is included, exemplary thickening agents include without limitation, acacia gum, alginate, bentonite, carbomer, calcium carbonate, calcium lactate, calcium phosphate, calcium silicate, calcium sulfate, carrageenan, cellulose, cetearyl alcohol, chitosan, dextran, dextrose, ethyl cellulose, fructose, gelatin, glyceryl, guar gum, hydroxyethylcellulose, magnesium aluminum silicate, magnesium carbonate, magnesium oxide, maltodextrin, maltose, pectin, silica, sodium alginate, starch, stearic acid, stearyl alcohol, talc, xanthum gum, xylitol, and any combinations thereof.

[0056] In examples where a surfactant is included, exemplar}’ surfactants can include without limitation, dimethicone, ethylene, ethoxylates, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, propylene oxide, sodium lauryl sulfate, sorbitan esters, sorbitan monooleate, sorbitan monolaurate, sulphates, and any combinations thereof.

[0057] In examples where a viscosity modifier is included, exemplary viscosity modifiers can include without limitation cyclopentasiloxane, dimethicone, hemisqualane, phenyl trimethicone, vinyl dimethicone crosspolymer, hydroxyethyl acrylate, sodium acryloyl dimethyl taurate copolymer, olefin copolymer, ethylene-propylene oligomer, polyethylene glycol 12 dimethicone, styrene olefin copolymer, polybutylene copolymer, poly isobutylene, polyalphaolefin, polymethacrylate, or a combination thereof.

[0058] In examples where a pH adjustor is included, exemplary pH adjustors can include without limitation acetic acid, citric acid, hydrochloric acid, malic acid, ortho-phosphoric acid, ammonia, potassium hydroxide, sodium carbonate, sodium hydroxide, or triethanolamine.

[0059] In examples where a preservative is included, exemplary preservative can include without limitation, benzyl alcohol, butylparaben, caprylyl glycol, diazolidinyl urea, ethyl hexyl glycerin, methylisothiazolinone, methylparaben, paraben, phenoxyethanol, potassium sorbate, propylparaben, sodium benzoate, urea, and any combinations thereof. In an example, the preservative can include phenoxyethanol, ethyl hexyl glycerin, phenoxyethanol, caprylyl glycol, or a combination thereof.

[0060] In another example, compositions presented herein can be formulated for administration as a spray. The spray can be a skin spray, oral or throat spray, ear spray, anal spray, or nasal spray. In such examples, the pharmaceutically acceptable carrier can further include at least one of a buffering agent, tonicity adjustor, stabilizer, or preservative. In examples where a buffering agent is included, exemplary buffering agents can include without limitation, phosphate buffer, citrate buffer, acetate buffer, histidine buffer, bicarbonate buffer, glycine buffer, succinate buffer, maleate buffer, or combinations thereof.

[0061] In examples where a tonicity adjustor is included, exemplary tonicity adjustors or adjusting agents can include without limitation, sodium chloride, potassium chloride, dextrose, mannitol, glycerin, sorbitol, sodium acetate, calcium chloride, magnesium chloride, sodium lactate, or combinations thereof.

[0062] In examples where a stabilizer is included, exemplary stabilizers or stabilizing agents can include without limitation, ascorbic acid, sodium metabisulfite, tocopherol, glutathione, cysteine, disodium edetate, or combinations thereof.

[0063] In examples where a preservative is included, exemplary preservatives can include without limitation, benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, phenoxyethanol, chlorobutanol, sorbic acid, benzoic acid, dehydroacetic acid, or combinations thereof.

[0064] In another example, compositions presented herein can be in the form of a parenteral formulation. Parenteral formulations can include transmucosal, transdermal, infusion, and injection (e.g. subcutaneous, intravenous (IV), intrathecal, and / or intramuscular) routes of administration. In examples such as these, the pharmaceutically acceptable carrier can further include at least one of a buffering agent, tonicity adjustor, stabilizer, preservative, or surfactant. In examples where a buffering agent is included, the buffering agent is selected from phosphate buffer, citrate buffer, acetate buffer, histidine buffer, bicarbonate buffer, glycine buffer, succinate buffer, maleate buffer, or combinations thereof.

[0065] In examples where a tonicity adjustor is included, exemplary tonicity adjusters can include without limitation, sodium chloride, potassium chloride, dextrose, mannitol, glycerin, sorbitol, sodium acetate, calcium chloride, magnesium chloride, sodium lactate, or combinations thereof.

[0066] In examples where a stabilizer is included, the stabilizer is selected from ascorbic acid, sodium metabisulfite, tocopherol, glutathione, cysteine, disodium edetate, or combinations thereof.

[0067] In examples where a preservative is included, exemplary preservatives can include without limitation, benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, phenoxyethanol, chlorobutanol, sorbic acid, benzoic acid, dehydroacetic acid, or combinations thereof.

[0068] In examples where a surfactant is included, exemplary surfactants can include without limitation, dimethicone, ethylene, ethoxylates, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, propylene oxide, sodium lauryl sulfate, sorbitan esters, sorbitan monooleate, sorbitan monolaurate, sulphates, or combinations thereof.

[0069] In further examples, compositions herein can be oral formulations. Oral formulations can be absorbable through the oral cavity or enterally by swallowing. Oral formulations can include solutions, a capsule, dissolvable strips, sachet, tablet, soft gel, lozenges, powder suspension, gel, liquid, syrups, beverages, and the like, including appropriate combinations thereof. In one example, an oral formulation can be in the form of a capsule or tablet. In another example, the formulation can be in the form of a dissolvable strip. In yet another example, the formulation can be a solution or liquid.

[0070] Also described herein, are topical NAD dosage forms. In some examples, a dosage form can include any composition previously described and a dose indicating mechanism. A dose indicating mechanism can be any container or housing for the composition that dispenses a specified and consistent amount of the composition every time. Thus, a person using the NAD topical dosage form can consistently apply a specified dose without worry about applying too small or too large a dose. In one example, the dose indicating mechanism is a bottle with a volume-specific pump, where one pump dispenses a consistent and specified amount of composition. In another example, the dose indicating mechanism is a bottle having a cap sized to allow the user to fill the cap with the composition, with a full cap equating to one dose. Additionally, any mechanism that allows for the dispensing of a specified and consistent amount of composition is contemplated. In some examples, NAD is present in an amount of from about 5 wt% to about 50 wt%, from about 5 wt% to about 15 wt%, from about 10 wt% to about 30 wt%, from about 25 wt% to about 50 wt%, from about 5 wt% to about 25 wt%, or from about 30 wt% to about 50 wt%.

[0071] In some examples, a dosage regimen is further included. The dosage regimen can include applying a dose of any composition previously described in an amount of from about.1 mL to about 2 mL, from about 1 mL to about 5 mL, from about 2 mL to about 8 mL. from about 1 mL to about 15 mL, or from about 2 mL to about 20 mL. In some examples, the dosage regimen can further include applying a dose at an interval from about 30 min to about 3 hours, from about 45 minutes to about 2 hours, from about 1 hour to about 5 hours, from about 2 hours to about 8 hours, from about 1 hour to about 15 hours, or from about 2 hours to about 24 hours.

[0072] In one embodiment, the composition is in the form of a spray housed in a bottle. The bottle has a volume-specific pump, connected with a tube that runs down into the bottle containing the spray. Spray is dispensed by pressing down on the pump with a finger. The pump creates suction, causing spray to be drawn up through the tube. The spray is dispensed through the nozzle of the pump, dispensing a consistent and specified amount of spray per activation of the pump. One spray can contain a specific dose or amount of NAD and multiple sprays can be used to achieve a larger total dosage amount.

[0073] Additionally, presented herein, are methods of treating a condition responsive to nicotinamide adenine dinucleotide (NAD) therapy in a subject, including administering a therapeutically effective amount of nano-sized NAD to the subject. In some examples, the condition can be pain. The pain may be acute or chronic. The methods herein can be used for treating musculoskeletal pain, e.g., joint pain, muscle pain, inflammation, etc. In some embodiments the pain can be joint pain, muscle pain, osteoarthritis pain, peripheral vascular-ischemia-induced claudication pain. In some embodiments, the methods can also be used to treat neuropathic pain, or any other pain from nerve-related issues or pathologies. In some examples, the methods can result in the pain being reduced by at least 20%, 30%, 40%, 50%, 60%, 70%. 80%, or 90%. Additionally, the methods can also be used to treat cognitive or neurological disorders, such as Generalized Anxiety Disorder (GAD), Major Depression Disorder, Attention Deficit Disorder, Attention-Deficit Hyperactivity Disorder, Normal Age Related Cognitive Decline, Alzheimer’s Disease, Small Vessel Disease, Dementia, Parkinson’s Disease, Multiple Sclerosis, Systemic Lupus Erythematosus, Traumatic Brain Injury, Migraines, Substance Use Disorder, or Substance Withdrawal, as well as other conditions such as heart disease, metabolic syndrome, cerebrovascular disease, and non-insulin dependent diabetes mellitus.

[0074] Several mechanisms could avail NAD in treating pain. First, for treating pain caused by musculoskeletal inflammation, it is important to understand the role of sirtuins (SIRTs). SIRTs are a family of class III histone deacety lases whose biological functions depend on NAD. SIRT1 facilitates the generation of multiple antioxidants, such as superoxide dismutase, glutathione, and others. Glutathione is a major anti-inflammatory agent through free radical reduction and other anti-oxidation mechanisms. Glutathione can act directly as an antioxidant to protect cells against free radicals and pro-oxidants, and as a cofactor for antioxidant and detoxification enzy mes, such as glutathione peroxidases, glutathione S-transferases, and glyoxalases. Glutathione peroxidases detoxify peroxides by a reaction that is coupled to glutathione oxidation to glutathione disulfide (GSSG). GSSG is converted back to glutathione by glutathione reductase and cofactor NADPH. To do this, glutathione must be in its reduced form which is reduced by NADPH, which in turn relies on NAD+ to supply its H, as well as for its own formation through a phosphate group transfer to NAD from ATP. Therefore, it can be seen that glutathione in its active form is dependent on adequate NAD levels to create it. With more glutathione made possible by more NAD, musculoskeletal inflammation goes down, resulting in a decrease in pain.

[0075] Second, for treating neuropathic pain, it is important to understand the role of poly ADP-ribose polymerase (PARP). In various neuropathies, increased PART expression is commonly seen. When combined with NAD, PARP forms a complex which scans DNA for errors and initiates the error codons removal and replacement mechanism. This results in PARP being an anti-mutational agent. However, when NAD is below adequate levels to combine with PARP, the unopposed PARP drives mechanisms that produce axonal damage in peripheral neuropathies. Therefore, when PARP levels are unopposed, it results in ATP depletion, inflammatory pathway activation, and cell death. On the contrary, with NAD supplementation, PARP is no longer unopposed and instead combines with NAD, thus diverting them from peripheral neuropathy mechanisms and instead becoming anti-mutational agents. In terms of pain, these PARPs are no longer available to induce the mechanism needed for neuropathic pain. Furthermore, the method can be used to treat a medical skin condition, such as shingles, inflammation, itchy skin, a hyper-proliferation disorder (e.g. psoriasis, eczema, keratosis pilaris, pachyonychia congenita, skin hyperkeratosis, dermatitis, including atopic dermatitis, non-melanoma skin cancers, etc.), acne, or the like. In some examples, the methods can result in the medical skin condition being reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. The methods can also be used to treat mucosal disorders, such as candidiasis, canker sores, and the like. Additionally, the methods can be used to treat vaginal, anal and rectal disorders, such as anal or rectal abscesses, anal fissures, hemorrhoids, and the like.

[0076] In some examples of the methods, administration can include locally applying the therapeutically effective amount of nano-sized NAD at the location of manifestation of the condition, or a location proximal thereto. In other examples, the administration can include systemically administering the therapeutically effective amount of nano-sized NAD. The therapeutically effective amount of NAD can be from about 200 mg to about 800 mg. In other examples, the therapeutically effective amount of NAD can be at least 200 mg, 300 mg, 400 mg, 400 mg, 500 mg, 600 mg, or 700 mg.

[0077] Also presented herein are methods of treating a condition responsive to nicotinamide adenine dinucleotide (NAD) therapy in a subject, including administering a therapeutic composition as previously described. Further presented herein, are methods of manufacturing a NAD composition or formulation, such as a nanoparticle NAD composition (e.g. a topical composition) as recited herein. Such a method of manufacture can include preparing an aqueous NAD solution. Preparing an aqueous NAD solution includes providing an amount of NAD and agitating the NAD with a pharmaceutically acceptable carrier at a weight ratio of NAD to carrier ranging from about 0.5:9.5 to about 3:7. from about 0.5:9.5 to about 2:8, from about 1:9 to about 2:8, or from about 2:8 to about 3:7. In some examples, the amount of NAD can be from about 200 mg to about 800 mg. In other examples, the amount of NAD can be at least 200 mg. 300 mg, 400 mg, 500 mg, 600 mg, or 700 mg. At this point, the pharmaceutically acceptable carrier can include only water. Agitating can occur by a suitable agitation process or mechanism Examples can include laboratory mixers, magnetic mixer and stir bar, homogenizer pump, rockers, rotor blades, shakers, shear mixers, stirrers, or the like. Agitation can occur for a period time that permits dispersion and / or dissolving of the NAD in the carrier. Preparing the aqueous NAD solution can further include the addition of a pH adjustor to bring the solution to the desired pH. In some examples, the desired pH is a from about 3 to about 6, or about 4 to about 5. In some examples, the pH is about 5.5, In some examples, preparing an aqueous NAD or nano NAD solution can include subjecting the solution to shear forces. Examples of equipment typically able to exert or impart sheer force can include laboratory mixers, magnetic mixer and stir bar, homogenizer pump, rockers, rotor blades, shakers, shear mixers, stirrers, or the like. Exposure to shear forces can occur at from about 1,000 rpms to about 20,000 rpms for a period of time ranging from about 1 minute to about 120 minutes. In other examples, exposure can occur from about 1,000 rpms to about 10,000 rpms, from about 3,000 rpms to about 6,000 rpms, from about 5,000 rpms to about 15,000 rpms, or from about 15,000 rpms to about 20,000 rpms. Exposure to shear forces can occur for a period time that permits the NAD in the solution to transform into nano-NAD. Mixing speed and time period are directly related. At higher mixing speeds a period of time necessary to permit transformation to nano-NAD can be less. At lower mixing speeds a period of time necessary to permit transformation can be more. For example, the same level of transformation may occur at 20,000 rpms for one minute as may occur at 1,000 rpms for one hour. Accordingly, the period of time can range from about 1 minute to about 120 minutes, from about 1 minute to about 45 minutes, from about 1 minute to about 60 minutes, from about 30 minutes to about 90 minutes, or from about 60 minutes to about 120 minutes and can vary with exposure speed. In one example, exposure can occur at from about 3,000 rpms to about 6,000 rpms for a period of time ranging from about 1 minute to about 45 minutes.

[0078] For example, one method of manufacturing a nano NAD composition to form a solution can include combining an amount of NAD with water and agitating or otherwise subjecting the combination to sufficiently high shear forces to create a nano NAD solution. pH adjustors, such as sodium hydroxide can be included to provide the NAD nanoparticle solution with a desired pH.

[0079] In some embodiments, the resultant solution can be used in a method of treating a subject for various conditions, such as pain or medical skin conditions. The solution can be administered as a spray, or can be administered as rub, such as by applying the liquid solution in appropriate amounts to the subject’s skin. In other embodiments, the solution can be administered as a wipe using a substrate, such as a fabric that is loaded with an appropriate amount of the aqueous NAD solution. In some embodiments, the amount of NAD solution in the wipe can be pre-loaded and standardized to a specific NAD or nanoparticle NAD concentration.

[0080] In some examples, the methods can include parenteral administration, where the composition is administered as a subcutaneous or intravenous injection or drip, in an amount sufficient to allow the delivery of NAD. In some examples, the subcutaneous or intravenous injection or drip can include nano-sized NAD.

[0081] In other examples, the methods can include oral mucosal administration, where the composition is administered in the subject’s mouth, in an amount sufficient to allow the delivery of NAD. In some examples, the oral composition can include nano-sized NAD. The nano-sized NAD can be delivered topically and / or transdermally. In some examples, the composition of the oral mucosal administration can be in the form of a solution (e.g. rinse) or mouth spray.

[0082] EXAMPLES

[0083] The following examples illustrate embodiments of the disclosure. However, it is to be understood that the following are only exemplary or illustrative of the application of the principles of the present disclosure. Numerous modifications and alternative compositions, methods, and systems may be devised by those skilled in the art without departing from the spirit and scope of the present disclosure. The appended claims are intended to cover such modifications and arrangements. Thus, while the present disclosure has been described above with particularity, the following examples provide further detail in connection with what are presently deemed to be the most practical embodiments of the disclosure.

[0084] Example 1: Preparation of Aqueous NAD+ Solution

[0085] Nicotinamide adenine dinucleotide (NAD) raw material was obtained from Oriental Yeast and was determined to have the following properties:

[0086] Purity: 98.3%

[0087] NAD+ contents: 95.7%

[0088] Water Contents: 2.7%

[0089] The raw material was combined with bacteriostatic water to form a solution, with the amounts indicated in Table 1, below: Table 1: Nano-sized NAD+ Containing Composition

[0090]

[0091] *Based on the total weight of the solution

[0092] The solution was subjected to high shear forces of up to 5000 rpm using a high-speed homogenizer for 25 minutes. This entire process was conducted at a temperature between 33 and 38 degrees Fahrenheit.

[0093] The resultant nano-NAD solution was subjected to Dynamic Light Scattering (DLS) analysis as show in FIG. 1. As can be seen, NAD particle size distribution ranged between 1 nm and 10 nm.

[0094]

[0095] An aqueous nano-NAD solution was prepared according to Example 1. Before the solution was subjected to high shear forces, the solution was buffered with NaOH until the pH reached 5.5. The following composition was the result:

[0096] Table 2: Solution

[0097]

[0098] *Based on the total weight of the solution

[0099]

[0100] An aqueous nano-NAD solution was prepared according to Example 1, with the exception of using distilled water instead of bacteriostatic water. Before the solution was subjected to high shear forces, the solution was buffered with ammonia until the pH reached 5.1. The following composition was the result: Table 3: Solution II

[0101]

[0102] *Based on the total weight of the solution

[0103] Example 4: Solution III

[0104] An aqueous nano-NAD solution was prepared according to Example 1, with the exception of using glycerin instead of bacteriostatic water. The following composition was the result:

[0105] Table 4: Solution III

[0106]

[0107] *Based on the total weight of the solution

[0108] Example 5: Solution IV

[0109] An aqueous nano-NAD solution was prepared according to Example 1, with the exception of using ethyl alcohol instead of bacteriostatic water. Before the solution was subjected to high shear forces, the solution was buffered with citric acid until the pH reached 4.8. The following composition was the result:

[0110] Table 5: Solution IV

[0111]

[0112] *Based on the total weight of the solution Example 6: Case Study 1

[0113] The patient was a 50-year old with PTSD, GAD, Panic Disorder, Traumatic Brain Injury, CBE who suffered from dizziness, poor concentration, fatigue, insomnia, anxiety, panic attacks, flashbacks, and intrusive thoughts. Previous medications were unsuccessful. The patient received three consecutive days of the nano-NAD composition in the form of an IV (lOOOmg / lOOOcc Normal Saline) over a 6hr period in clinic. The patient reported over the following 2 weeks improvements in sleep, concentration, memory', mental endurance, and physical energy. The patient also reported the ability to work on her farm without anxiety or panic attacks.

[0114] Example 7: Case Study 2

[0115] The patient was a 47-year old with bilateral tinnitus from multiple blast injuries from combat. The patient was treated with NAD nasal spray with no improvement. The patient was then treated with nano NAD nasal spray (400mg / cc, 0.18cc per spray) bilaterally. Within 5 minutes of treatment, patient reported a 90% decrease in ringing. The patient continued daily use and reported complete removal of symptoms.

[0116] Example 8: Case Study 3

[0117] The patient was a 49-year old with testicular cancer with unilateral nephrectomy and unilateral orchiectomy. The patient complained of fatigue, poor concentration, insomnia and was previously treated with three consecutive days of NAD via IV (1000 mg / lOOOcc Normal Saline for two hours) without improvement. The patient was then treated with three consecutive days of nano NAD composition via IV (300mg / cc / 1000cc Normal Saline for two hours). The patient reported that within 24 hours, improvement in energy, concentration, mental endurance, and sleep, with a 1 month follow up appointment showing continued improvement.

[0118] Example 9: Case Study 4

[0119] The patient was a 72-year old with poor memory', confusion, fatigue, drooling, bilateral tremor to the extent they were not able to use utensils and inability’ to write. The patient was on medication for symptoms as well as treated with 5 separate sessions of NAD via IV (800mg / cc / 1000cc Normal Saline) yvith only slight improvement of energy. The patient was then treated with three consecutive days of nano NAD composition via IV (400mg / cc / 1000 Normal Saline over 4 hours). After 30 minutes, tremors decrease by 50%, the patient showed better facial expression, increased energy and mental clarity. The patient continued to report improved symptoms over the following month.

[0120] Example 10: Case Study 5

[0121] The patient was an 81 -year old with 25 years of chronic muscle and joint pain, with the pain producing chronic insomnia and fatigue. The pain also decreased range of motion of neck down to approximately 10% of normal. Patient was treated with nano NAD solution (500mg / cc 0.5cc) which was rubbed on the back of the neck for 2 minutes. Within 5 minutes, the patient reported diminished pain (from a 9 to a 3 on a self-reported scale) and exhibited a dramatic increase of range of motion in the neck, with flexion and extension approximately 75% and 90%, respectively. The patient continued to use the nano NAD solution and reported continued pain relief and increased mobility, with improved sleep and energy.

[0122] Example 11: Potency Testing

[0123] Three samples of 400 mg / mL NAD solution were sent for potency testing. Testing was done using High-Performance Liquid Chromatography (HPLC), with the samples being stored at a temperature between 2 and 8 degrees Celsius for 8 months. The results are shown in the table below.

[0124]

[0125] As shown from the results, all three samples fell within the acceptable range for potency.

[0126] EXAMPLE EMBODIMENTS

[0127] The following examples pertain to specific embodiments and point out specific features, elements, or steps that may be used or otherwise combined in achieving such embodiments. In a first example there is provided a therapeutic composition comprising a therapeutically effective amount of nano-sized nicotinamide adenine dinucleotide (NAD) in combination with a pharmaceutically acceptable carrier.

[0128] In a second example, the NAD of the first example is at least one of NAD+. NADH, or a combination thereof.

[0129] In a third example of a composition, the NAD of any preceding example includes or consists essentially of NAD+.

[0130] In a fourth example of a composition, the NAD of any preceding example includes or consists essentially of NADH.

[0131] In a fifth example of a composition, the NAD of any preceding example is a combination of NAD+ and NADH.

[0132] In a sixth example of a composition, the NAD+ and NADH of any preceding example are present in a ratio of from about 1: 100 to about 100: 1.

[0133] In a seventh example of a composition, the NAD of any preceding example has an average particle size of less than 100 nm, less than 50 nm, less than 25 nm, or less than 10 nm.

[0134] In an eighth example of a composition, substantially all the NAD of any preceding example in the composition is nano-sized NAD.

[0135] In a ninth example of a composition in any preceding example, from about 0.1% to about 99% of the NAD is in molecular form.

[0136] In a tenth example of a composition, at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the NAD of any preceding example is in molecular form.

[0137] In an eleventh example of a composition, the amount of NAD in any preceding example is from about 5 wt% to about 99 wt% of the composition.

[0138] In a twelfth example of a composition, the amount of NAD in any preceding example is at least about 1 wt%, 10 wt%, 20 wt%, 30 wt%, 40 wt%, 50 wt%, 60 wt%, 70 wt%, 80 wt%, or 90 wt% of the composition.

[0139] In a thirteenth example of a composition, in any preceding example from about 5% to about 95% of the total NAD in the composition remains nano-sized NAD when stored at a temperature of about 40 degrees Fahrenheit or below for a period of from about 30 days to about lyear.

[0140] In a fourteenth example of a composition, in any preceding example at least 10%. 20% 30% 40% 50%, 60%, 70%, 80%, 90%, or 95% of the total NAD in the composition is maintained as nano-sized NAD when stored at a temperature of about 40 degrees Fahrenheit or below for a period of from about 30 days to about 1 year.

[0141] In a fifteenth example of a composition, in any preceding example at least 75%, 80%, 85%, 90%, or 95% of an initial amount of NAD in the composition remains when the composition is stored at a temperature below 40 degrees Fahrenheit for a period of a year.

[0142] In a sixteenth example of a composition, in any preceding example the pharmaceutically acceptable carrier comprises water, sterilized water, phosphate-buffered saline (PBS) Dulbecco’s PBS, Alsever's solution, Tris-buffered saline (TBS), balanced salt solutions (BSS), such as Hank’s BSS, Earle’s BSS, Grey’s BSS, Puck’s BSS, Simm’s BSS, Tyrode’s BSS, BSS Plus, Ringer’s lactate solution, normal saline (i.e. 0.9% saline), 'A normal saline, glycerin, ethyl alcohol, propylene glycol, propylparaben, hydrogel, or a combination thereof.

[0143] In a seventeenth example of a composition, in any preceding example the pharmaceutically acceptable carrier includes or consists essentially of water.

[0144] In an eighteenth example of a composition, in any preceding example the weight ratio of NAD to pharmaceutically acceptable carrier is from about 0.001:100 to about 100:0.001, from about 0.01:100 to about 100:0.01, from about 0.1: 100 to about 100:0.1, from about 1:100 to about 100:1, from about 10:100 to about 100:10, from about 1:1, or from about 0.5:9.5 to about 2:8.

[0145] In a nineteenth example of a composition, in any preceding example the composition further comprising a pH adjuster.

[0146] In a twentieth example of a composition, in any preceding example the pH adjuster is selected from the group consisting of acetic acid, citric acid, hydrochloric acid, malic acid, ortho-phosphoric acid, ammonia, potassium hydroxide, sodium carbonate, sodium hydroxide, or triethanolamine.

[0147] In a twenty first example of a composition, in any preceding example the pH of the composition is from about 3 to 6.

[0148] In a twenty second example of a composition, in any preceding example the composition is formulated for administration as an intravenous (IV) therapy.

[0149] In a twenty third example of a composition, in any preceding example the pharmaceutically acceptable carrier further comprises at least one of a buffering agent, tonicity adjuster, or stabilizer. In a twenty fourth example of a composition, in any preceding example the buffering agent is selected from phosphate buffer, citrate buffer, acetate buffer, histidine buffer, bicarbonate buffer, glycine buffer, succinate buffer, maleate buffer, or combinations thereof.

[0150] In a twenty fifth example of a composition, in any preceding example the tonicity adjuster is selected from sodium chloride, potassium chloride, dextrose, mannitol, glycerin, sorbitol, sodium acetate, calcium chloride, magnesium chloride, sodium lactate, or combinations thereof.

[0151] In a twenty sixth example of a composition, in any preceding example the stabilizer is selected from ascorbic acid, sodium metabisulfite, tocopherol, glutathione, cysteine, disodium edetate, or combinations thereof.

[0152] In a twenty seventh example of a composition, in any preceding example the composition is formulated for administration as a spray.

[0153] In a twenty eighth example of a composition, in any preceding example the pharmaceutically acceptable earner further comprises at least one of a buffering agent, tonicity adjuster, stabilizer, or preservative.

[0154] In twenty ninth example of a composition, in any preceding example the buffering agent is selected from phosphate buffer, citrate buffer, acetate buffer, histidine buffer, bicarbonate buffer, glycine buffer, succinate buffer, maleate buffer, or combinations thereof.

[0155] In a thirtieth example of a composition, in any preceding example the tonicity adjuster is selected from sodium chloride, potassium chloride, dextrose, mannitol, glycerin, sorbitol, sodium acetate, calcium chloride, magnesium chloride, sodium lactate, or combinations thereof.

[0156] In a thirty first example of a composition, in any preceding example the stabilizer is selected from ascorbic acid, sodium metabisulfite, tocopherol, glutathione, cysteine, disodium edetate, or combinations thereof.

[0157] In a thirty second example of a composition, in any preceding example the preservative is selected from benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, phenoxyethanol, chlorobutanol, sorbic acid, benzoic acid, dehydroacetic acid, or combinations thereof.

[0158] In a thirty third example of a composition, in any preceding example the composition is formulated for administration as a subcutaneous injection. In a thirty fourth example of a composition, in any preceding example the pharmaceutically acceptable carrier further comprises at least one of a buffering agent, tonicity adjustor, stabilizer, preservative, or surfactant.

[0159] In a thirty fifth example of a composition, in any preceding example the buffering agent is selected from phosphate buffer, citrate buffer, acetate buffer, histidine buffer, bicarbonate buffer, glycine buffer, succinate buffer, maleate buffer, or combinations thereof.

[0160] In a thi rty sixth example of a composition, in any preceding example the tonicity adjustor is selected from sodium chloride, potassium chloride, dextrose, mannitol, glycerin, sorbitol, sodium acetate, calcium chloride, magnesium chloride, sodium lactate, or combinations thereof.

[0161] In a th i rty seventh example of a composition, in any preceding example the stabilizer is selected from ascorbic acid, sodium metabisulfite, tocopherol, glutathione, cysteine, disodium edetate, or combinations thereof.

[0162] In a th i rty eighth example of a composition, in any preceding example the preservative is selected from benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, phenoxyethanol, chlorobutanol, sorbic acid, benzoic acid, dehydroacetic acid, or combinations thereof.

[0163] In a thirty’ ninth example of a composition, in any preceding example the surfactant is selected from dimethicone, ethylene, ethoxylates, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, propylene oxide, sodium lauryl sulfate, sorbitan esters, sorbitan monooleate, sorbitan monolaurate, sulphates, or combinations thereof.

[0164] In a fortieth example of a composition, in any preceding example the composition is formulated for administration as a cream, gel, paste, lotion, solution, or suspension.

[0165] In aforty first example of a composition, in any preceding example the pharmaceutically acceptable carrier further comprises at least one of an emollient, thickening agent, surfactant, viscosity modifier, pH adjustor, or preservative.

[0166] In a forty second example of a composition, in any preceding example the emollient is selected from the group consisting of almond oil, aluminum stearate, caprylic / capric triglyceride, canola oil, castor oil, ceratonia extract, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cholesterol, cocos nucifera (coconut oil), cottonseed oil, cyclomethicone, decyl glycoside, dibutyl sebacate, dimethicone. ethylene glycol palmitostearate. glycerin, glycerin monostearate, glycerin monooleate, glyceryl stearate, isopropyl myristate, isopropyl palmitate, lanolin, lanolin alcohols, lecithin, medium-chain triglycerides, mineral oil, myristyl alcohol, octyldodecanol, oleyl alcohol, petrolatum, safflower glycerides, safflower oil, sodium lauryl sulphate, soybean oil, stearyl alcohol, sunflower oil, tricaprylin, triolein, xylitol, zinc acetate, or any combinations thereof.

[0167] In a forty third example of a composition, in any preceding example the thickening agent is selected from the group consisting of acacia gum, alginate, bentonite, carbomer, calcium carbonate, calcium lactate, calcium phosphate, calcium silicate, calcium sulfate, carrageenan, cellulose, cetearyl alcohol, chitosan, dextran, dextrose, ethyl cellulose, fructose, gelatin, glyceryl, guar gum, hydroxy ethylcellulose, magnesium aluminum silicate, magnesium carbonate, magnesium oxide, maltodextrin, maltose, pectin, silica, sodium alginate, starch, stearic acid, stearyl alcohol, talc, xanthum gum, xylitol, and any combinations thereof.

[0168] In forty fourth example of a composition, in any preceding example the surfactant is selected from the group consisting of dimethicone, ethylene, ethoxylates, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, propylene oxide, sodium lauryl sulfate, sorbitan esters, sorbitan monooleate, sorbitan monolaurate, sulphates, and any combinations thereof.

[0169] In forty fifth example of a composition, in any preceding example the viscosity modifier is selected from the group consisiting of cyclopentasiloxane, dimethicone, hemisqualane, phenyl trimethicone, vinyl dimethicone crosspolymer, hydroxyethyl acrylate, sodium acryloyl dimethyl taurate copolymer, olefin copolymer, ethylene-propylene oligomer, polyethylene glycol 12 dimethicone, styrene olefin copolymer, polybutylene copolymer, polyisobutylene, polyalphaolefin, polymethacrylate, or a combination thereof.

[0170] In forty sixth example of a composition, in any preceding example the pH adjustor is selected from the group consisting of acetic acid, citric acid, hydrochloric acid, malic acid, ortho-phosphoric acid, ammonia, potassium hydroxide, sodium carbonate, sodium hydroxide, or triethanolamine.

[0171] In a forty seventh example of a composition, in any preceding example the preservative is selected from the group consisting of benzyl alcohol, butylparaben, caprylyl glycol, diazolidinyl urea, ethyl hexyl glycerin, methylisothiazolinone, methylparaben, paraben, phenoxyethanol, potassium sorbate, propylparaben, sodium benzoate, urea, and any combinations thereof. In an example, the preservative can include phenoxyethanol, ethyl hexyl glycerin, phenoxyethanol, caprylyl glycol, or a combination thereof. In a forty-eighth example there is provided a method of treating a condition responsive to nicotinamide adenine dinucleotide (NAD) therapy in a subject, comprising: administering a therapeutically effective amount of nano-sized NAD to the subject.

[0172] In a forty ninth example, the method, of example forty-eight the condition is pain. In a fiftieth example of the method of example forty-eight, the pain is one or more of musculoskeletal, joint, muscle, osteoarthritis, peripheral vascular-ischemia-induced claudication, or neuropathic pain.

[0173] In a fifty first example of the method of example forty -eight, the condition is a medical skin condition.

[0174] In a fifty second example of the method of example forty-eight, the medical skin condition is one or more of shingles, inflammation, itchy skin, a hyper-proliferation disorder, acne, or a mucosal disorder.

[0175] In a fifty third example of the method of example forty-eight, the condition is one or more of a cognitive disorder or a neurological disorder.

[0176] In a fifty fourth example of the method of example forty-eight, the cognitive disorder or neurological disorder is one or more of Generalized Anxiety Disorder, Major Depression Disorder, Attention Deficit Disorder, Attention-Deficit Hyperactivity Disorder, Normal Age Related Cognitive Decline, Alzheimer's Disease, Small Vessel Disease, Dementia, Parkinson’s Disease, Multiple Sclerosis, Systemic Lupus Erythematosus, Traumatic Brain Injury, Migraines, Substance Use Disorder, or Substance Withdrawal.

[0177] In a fifty fifth example of the method of any preceding example, the administering comprises locally applying the therapeutically effective amount of nano-sized NAD at the location of a manifestation of the condition, or a location proximal thereto.

[0178] In fifty sixth example of the method of any preceding example, the administration comprises s stemically administering the therapeutically effective amount of nano-sized NAD.

[0179] In fifty seventh example of the method of any preceding example, the pain is reduced by at least 30% for a period of about 2 hours.

[0180] In fifty eighth example of the method of any preceding example, the medical skin condition is reduced by at least 20% for a period of about 2 hours.

[0181] In fifty ninth example of the method of any preceding example, the therapeutically effective amount of nano-sized NAD is from about 200 mg to about 800 mg.

[0182] In sixtieth example of the method of any preceding example, the therapeutically effecti ve amount of nano-sized NAD is at least about 400 mg. In a sixty first example there is provided a method of treating a condition responsive to nicotinamide adenine dinucleotide (NAD) therapy in a subject, comprising administering a therapeutic composition as previously recited, particularly in any of examples one to forty seven to the subject.

[0183] In a sixty second example there is provide a method of manufacturing a nano-sized nicotinamide adenine dinucleotide (NAD) composition, comprising agitating an amount of NAD with a pharmaceutically acceptable carrier to create a solution and subjecting the solution to shear forces sufficient to reduce at least a portion of NAD to nano-sized NAD.

[0184] In a sixty third example of the method the sixty second example, the amount of NAD is from about 200 mg to about 800 mg.

[0185] In a sixty fourth example of the method of any preceding example, agitating occurs via laboratory mixer, magnetic mixer and stir bar, homogenizer pump, rockers, rotor blades, shakers, shear mixers, stirrers, or a combination thereof.

[0186] In a sixty fifth example of the method of any preceding example, agitating occurs until at least one of dispersion or dissolving of the NAD in the pharmaceutically acceptable carrier is complete.

[0187] In a sixty sixth example of the method of any preceding example, the shear forces are from about 1,000 rpras to about 20,000 rpms.

[0188] In sixty seventh example of the method of any preceding example, the solution is subjected to shear forces for about 1 minute to about 120 minutes.

[0189] In sixty eighth example there is provided a composition for the use in treating a condition responsive to nicotinamide adenine dinucleotide (NAD) therapy in a subject, comprising a therapeutically effective amount of nano-sized NAD in combination with a pharmaceutically acceptable carrier.

[0190] In sixty ninth example there is provided a use of a nano-sized nicotinamide adenine dinucleotide (NAD) composition for the manufacture of a medicament for the treatment of a condition m a subject responsive to NAD therapy.

[0191] In a seventieth example there is provided a topical nicotinamide adenine dinucleotide (NAD) dosage form comprising a therapeutic composition as previously recited and a dose indicating mechanism.

[0192] In a seventy first example of the NAD dosage form of example seventy, the dose indicating mechanism is a volume-specific pump. In the seventy7second example of the NAD dosage form of any previous example, the dosage form further comprising a dosage regimen.

[0193] in a seventy7third example of the NAD dosage form of any7previous example, the dosage regimen comprises a dose administered in a volume of from about 1 mL to about 15 mL.

[0194] In seventy- fourth example of the NAD dosage form of any previous example, the dose is administered at an interval of from about 2 hours to about 24 hours.

Claims

1. CLAIMS2.What is claimed is:

1. A therapeutic composition comprising:4.a therapeutically effective amount of nano-sized nicotinamide adenine dinucleotide (NAD) in combination with a pharmaceutically acceptable carrier.

2. The composition of claim 1, wherein the NAD is at least one of NAD+, NADH, or a combination thereof.

3. The composition of claim 1, wherein the NAD includes or consists essentially of NAD+.

4. The composition of claim 1, wherein the NAD includes or consists essentially of NADH.

5. The composition of claim 1, wherein the NAD is a combination of NAD+ and NADH.

6. The composition of claim 5, wherein the NAD+ and NADH are present in a ratio of from about 1: 100 to about 100:1.

7. The composition of claim 1, wherein the NAD has an average particle size of less than 100 nm, less than 50 nm, less than 25 nm, or less than 10 nm.

8. The composition of claim 1, wherein substantially all the NAD in the composition is nano-sized NAD.

9. The composition of claim 1, wherein from about 0.1% to about 99% of the NAD is in molecular form.

10. The composition of claim 1, wherein at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the NAD is in molecular form.

11. The composition of claim 1, wherein the amount of NAD is from about 5 wt% to about 99 wt% of the composition.

12. The composition of claim 1, wherein the amount of NAD is at least about 1 wt%, 10 wt%, 20 wt%, 30 wt%, 40 wt%, 50 wt%, 60 wt%, 70 wt%, 80 wt%, or 90 wt% of the composition.

13. The composition of any preceding claim, wherein from about 5% to about 95% of the total NAD in the composition remains nano-sized NAD when stored at a temperature of about 40 degrees Fahrenheit or below for a period of from about 30 days to about lyear.

14. The composition of any of claims 1-12, wherein at least 10%. 20% 30% 40% 50%.17.60%, 70%, 80%, 90%, or 95% of the total NAD in the composition is maintained as nanosized NAD when stored at a temperature of about 40 degrees Fahrenheit or below for a period of from about 30 days to about 1 year.

15. The composition of any of claims 1-12, wherein at least 75%, 80%, 85%, 90%, or 95% of an initial amount of NAD in the composition remains when the composition is stored at a temperature below 40 degrees Fahrenheit for a period of a year.

16. The composition of claim 1, wherein the pharmaceutically acceptable carrier comprises water, sterilized water, phosphate-buffered saline (PBS) Dulbecco’s PBS, Alsever’s solution, Tris-buffered saline (TBS), balanced salt solutions (BSS), such as Hank’s BSS, Earle’s BSS, Grey's BSS, Puck’s BSS, Simm's BSS, Tyrode’s BSS, BSS Plus, Ringer's lactate solution, normal saline (i.e. 0.9% saline), 'A normal saline, glycerin, ethyl alcohol, propylene glycol, propylparaben, hydrogel, or a combination thereof.

17. The composition of claim 16, wherein the pharmaceutically acceptable carrier includes or consists essentially of water.

18. The composition of claim 1, wherein the weight ratio of NAD to pharmaceutically acceptable carrier is from about 0.001:100 to about 100:0.001, from about 0.01:100 to about100:0.01, from about 0.1:100 to about 100:0.1, from about 1:100 to about 100:1, from about 10:100 to about 100:10, from about 1:1, or from about 0.5:9.5 to about 2:8.

19. The composition of claim 1, further comprising a pH adjuster.

20. The composition of claim 19, wherein the pH adjuster is selected from the group consisting of acetic acid, citric acid, hydrochloric acid, malic acid, ortho-phosphoric acid, ammonia, potassium hydroxide, sodium carbonate, sodium hydroxide, or triethanolamine.

21. The composition of claim 1, wherein the pH of the composition is from about 3 to 6.

22. The composition as recited in any of claims 1-21, wherein the composition is formulated for administration as an intravenous (IV) therapy.

23. The composition of claim 22, wherein the pharmaceutically acceptable carrier further comprises at least one of a buffering agent, tonicity adjuster, or stabilizer.

24. The composition of claim 23, wherein the buffering agent is selected from phosphate buffer, citrate buffer, acetate buffer, histidine buffer, bicarbonate buffer, glycine buffer, succinate buffer, maleate buffer, or combinations thereof.

25. The composition of claim 23, wherein the tonicity adjuster is selected from sodium chloride, potassium chloride, dextrose, mannitol, glycerin, sorbitol, sodium acetate, calcium chloride, magnesium chloride, sodium lactate, or combinations thereof.

26. The composition of claim 23, wherein the stabilizer is selected from ascorbic acid, sodium metabisulfite, tocopherol, glutathione, cysteine, disodium edetate, or combinations thereof.

27. The composition as recited in any of claims 1-21, wherein the composition is formulated for administration as a spray.

28. The composition of claim 27, wherein the pharmaceutically acceptable carrier further comprises at least one of a buffering agent, tonicity adjuster, stabilizer, or preservative.

28. The composition of claim 28, wherein the buffering agent is selected from phosphate buffer, citrate buffer, acetate buffer, histidine buffer, bicarbonate buffer, glycine buffer, succinate buffer, maleate buffer, or combinations thereof.

29. The composition of claim 28, wherein the tonicity adjuster is selected from sodium chloride, potassium chloride, dextrose, mannitol, glycerin, sorbitol, sodium acetate, calcium chloride, magnesium chloride, sodium lactate, or combinations thereof.

30. The composition of claim 28, wherein the stabilizer is selected from ascorbic acid, sodium metabisulfite, tocopherol, glutathione, cysteine, disodium edetate, or combinations thereof.

31. The composition of claim 28, wherein the preservative is selected from benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, phenoxyethanol, chlorobutanol, sorbic acid, benzoic acid, dehydroacetic acid, or combinations thereof.

32. The composition as recited in any of claim 1-21, wherein the composition is formulated for administration as a subcutaneous injection.

33. The composition of claim 32, wherein the pharmaceutically acceptable carrier further comprises at least one of a buffering agent, tonicity adjustor, stabilizer, preservative, or surfactant.

34. The composition of claim 33, wherein the buffering agent is selected from phosphate buffer, citrate buffer, acetate buffer, histidine buffer, bicarbonate buffer, glycine buffer, succinate buffer, maleate buffer, or combinations thereof.

35. The composition of claim 33, wherein the tonicity adjustor is selected from sodium chloride, potassium chloride, dextrose, mannitol, glycerin, sorbitol, sodium acetate, calcium chloride, magnesium chloride, sodium lactate, or combinations thereof.

36. The composition of claim 33, wherein the stabilizer is selected from ascorbic acid, sodium metabisulfite, tocopherol, glutathione, cysteine, disodium edetate, or combinations thereof.

37. The composition of claim 33, wherein the preservative is selected from benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, phenoxyethanol, chlorobutanol, sorbic acid, benzoic acid, dehydroacetic acid, or combinations thereof.

38. The composition of claim 33, wherein the surfactant is selected from dimethicone, ethylene, ethoxylates, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, propylene oxide, sodium lauryl sulfate, sorbitan esters, sorbitan monooleate, sorbitan monolaurate, sulphates, or combinations thereof.

39. The composition as recited in any of claims 1-21, wherein the composition is formulated for administration as a cream, gel, paste, lotion, solution, or suspension.

40. The composition of claim 39, wherein the pharmaceutically acceptable carrier further comprises at least one of an emollient, thickening agent, surfactant, viscosity modifier, pH adjustor, or preservative.

41. The composition of claim 40, wherein the emollient is selected from the group consisting of almond oil, aluminum stearate, caprylic / capric triglyceride, canola oil, castor oil, ceratonia extract, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cholesterol, cocos nucifera (coconut oil), cottonseed oil, cyclomethicone, decyl glycoside, dibutyl sebacate, dimethicone, ethylene glycol palmitostearate, glycerin, glycerin monostearate, glycerin monooleate, glyceryl stearate, isopropyl myristate, isopropyl palmitate, lanolin, lanolin alcohols, lecithin, medium-chain triglycerides, mineral oil, myristyl alcohol, octyldodecanol, oleyl alcohol, petrolatum, safflower glycerides, safflower oil, sodium lauryl sulphate, soybean oil, stearyl alcohol, sunflower oil, tricaprylin, triolein, xylitol, zinc acetate, or any combinations thereof.

42. The composition of claim 40, wherein the thickening agent is selected from the group consisting of acacia gum, alginate, bentonite, carbomer, calcium carbonate, calcium lactate, calcium phosphate, calcium silicate, calcium sulfate, carrageenan, cellulose, cetearyl alcohol, chitosan, dextran, dextrose, ethyl cellulose, fructose, gelatin, glyceryl, guar gum, hydroxy ethylcellulose, magnesium aluminum silicate, magnesium carbonate, magnesium oxide, maltodextrin, maltose, pectin, silica, sodium alginate, starch, stearic acid, stearyl alcohol, talc, xanthum gum, xylitol, and any combinations thereof.

43. The composition of claim 40, wherein the surfactant is selected from the group consisting of dimethicone, ethylene, ethoxylates, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, propylene oxide, sodium lauryl sulfate, sorbitan esters, sorbitan monooleate, sorbitan monolaurate, sulphates, and any combinations thereof.

44. The composition of claim 40, wherein the viscosity modifier is selected from the group consisiting of cyclopentasiloxane, dimethicone, hemisqualane, phenyl trimethicone, vinyl dimethicone crosspolymer, hydroxyethyl acrylate, sodium acryloyl dimethyl taurate copolymer, olefin copolymer, ethylene-propylene oligomer, polyethylene glycol 12 dimethicone, styrene olefin copolymer, polybutylene copolymer, polyisobutylene, polyalphaolefin, polymethacrylate, or a combination thereof.

45. The composition of claim 40, wherein the pH adjustor is selected from the group consisting of acetic acid, citric acid, hydrochloric acid, malic acid, ortho-phosphoric acid, ammonia, potassium hydroxide, sodium carbonate, sodium hydroxide, or triethanolamine.

46. The composition of claim 40, wherein the preservative is selected from the group consisting of benzyl alcohol, butylparaben, caprylyl glycol, diazolidinyl urea, ethyl hexyl glycerin, methylisothiazolinone. methylparaben, paraben, phenoxyethanol, potassium sorbate, propylparaben, sodium benzoate, urea, and any combinations thereof. In an example, the preservative can include phenoxyethanol, ethyl hexyl glycerin, phenoxyethanol, caprylyl glycol, or a combination thereof.

47. A method of treating a condition responsive to nicotinamide adenine dinucleotide (NAD) therapy in a subject, comprising:administering a therapeutically effective amount of nano-sized NAD to the subject.

48. The method of claim 47, wherein the condition is pain.

49. The method of claim 48, wherein the pain is one or more of musculoskeletal, joint, muscle, osteoarthritis, peripheral vascular-ischemia-induced claudication, or neuropathic pain,50. The method of claim 47, wherein the condition is a medical skin condition.

51. The method of claim 50, wherein the medical skin condition is one or more of shingles, inflammation, itchy skin, a hyper-proliferation disorder, acne, or a mucosal disorder.

52. The method of claim 48, wherein the condition is one or more of a cognitive disorder or a neurological disorder.

53. The method of claim 52, wherein the cognitive disorder or neurological disorder is one or more of Generalized Anxiety Disorder, Major Depression Disorder, Attention Deficit Disorder, Attention-Deficit Hyperactivity Disorder, Normal Age Related Cognitive Decline, Alzheimer's Disease, Small Vessel Disease, Dementia, Parkinson's Disease, Multiple Sclerosis. Systemic Lupus Erythematosus, Traumatic Brain Injury, Migraines, Substance Use Disorder, or Substance Withdrawal.

54. The method of claim 47, wherein the administering comprises locally applying the therapeutically effective amount of nano-sized NAD at the location of a manifestation of the condition, or a location proximal thereto.

55. The method of claim 47, wherein the administration comprises systemically administering the therapeutically effective amount of nano-sized NAD,56. The method of claim 48, wherein the pain is reduced by at least 30% for a period of about 2 hours.

57. The method of claim 50, wherein the medical skin condition is reduced by at least 20% for a period of about 2 hours.

58. The method of claim 47, wherein the therapeutically effective amount of nano-sized NAD is from about 200 mg to about 800 mg.

59. The method of claim 47, wherein the therapeutically effective amount of nano-sized NAD is at least about 400 mg.

60. A method of treating a condition responsive to nicotinamide adenine dinucleotide (NAD) therapy in a subject, comprising:61.administering a therapeutic composition as recited in any of claims 1-46 to the subject.

61. A method of manufacturing a nano-sized nicotinamide adenine dinucleotide (NAD) composition, comprising:63.agitating an amount of NAD with a pharmaceutically acceptable carrier to create a solution; and64.subjecting the solution to shear forces sufficient to reduce at least a portion of NAD to nano-sized NAD.

62. The method of claim 61, wherein the amount of NAD is from about 200 mg to about 800 mg.

64. The method of claim 61, wherein agitating occurs via laboratory mixer, magnetic mixer and stir bar, homogenizer pump, rockers, rotor blades, shakers, shear mixers, stirrers, or a combination thereof.67.65, The method of claim 61, wherein agitating occurs until at least one of dispersion or dissolving of the NAD in the pharmaceutically acceptable carrier is complete.

66. The method of claim 61. wherein the shear forces are from about 1,000 rpms to about 20,000 rpms.

67. The method of claim 61, wherein the solution is subjected to shear forces for about 1 minute to about 120 minutes.

68. A composition for the use in treating a condition responsive to nicotinamide adenine dinucleotide (NAD) therapy in a subject, comprising:70.a therapeutically effective amount of nano-sized NAD in combination with a pharmaceutically acceptable carrier.

69. Use of a nano-sized nicotinamide adenine dinucleotide (NAD) composition for the manufacture of a medicament for the treatment of a condition in a subject responsive to NAD therapy.

70. A topical nicotinamide adenine dinucleotide (NAD) dosage form comprising:73.a therapeutic composition as recited in any of claims 1-46; and a dose indicating mechanism.

71. The dosage form of claim 70, wherein the dose indicating mechanism is a volumespecific pump.

72. The dosage form of claim 70, further comprising a dosage regimen.

73. The dosage form of claim 72, wherein the dosage regimen comprises a dose administered in a volume of from about 1 mL to about 15 mL.

74. The dosage form of claim 73, wherein the dose is administered at an interval of from about 2 hours to about 24 hours.

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