Nicotinamide adenine dinucleotide (NAD) compositions, methods for making them, and methods for using them

Abstract

Disclosed herein are compositions comprising liposomally encapsulated nicotinamide adenine dinucleotide (NAD), its precursors, its derivatives, or mixtures thereof, which exhibit enhanced chemical, physical, and / or microbial storage stability at various storage temperatures. In certain embodiments, the compositions are stable and have positive permeability and aging results. Methods for preparing such compositions and methods for using such compositions are also disclosed herein.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 183,174, filed May 4, 2021, the contents of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates to compositions comprising nicotinamide adenine dinucleotide, its derivatives, its precursors, or combinations thereof. In certain embodiments, the compositions are stable and have positive permeability and aging results. The present disclosure also relates to methods of preparing such compositions and methods of using such compositions. [Background technology]

[0003] The oxidized form of extracellular β-nicotinamide adenine dinucleotide (NAD+) is a crucial cofactor for many redox reactions in living cells and a substrate for numerous enzymes. 1 ( 1Kim UH, Han MK, Park BH, Kim HR, An NH: Function of NAD glycohydrolase in ADP-ribose uptake from NAD by human erythrocytes. Biochim Biophys Acta 1993;1178:121-126, Lee HC, Aarhus R: ADP-ribosyl cyclase: an enzyme that catalyzes NAD+into a calciummobilizing metabolite. Cell Regul 1991;2:203-209, Travo P, Muller H, Shuber F: Calf spleen NAD glycohydrolase. Comparison of the catalytic properties of the membrane-bound and the hydrosoluble forms of the enzyme. Eur J. Biochem 1979;96:141-149). Thus, NAD+ may have potentially beneficial properties in alleviating a variety of conditions.

[0004] Notwithstanding the above, the use of NAD+, its precursors, and / or its derivatives is limited due to their limited stability. For example, NAD+ is known to be relatively unstable. 2 ( 2 Ganti T, Fodor J: Studies on the kinetics of NAD-decomposition. Acta Physiol Acad Sci Hung 1965;26:199-205, Lawry OH, Passonneau JV, Rock MK: The stability of pyridine nucleotides. J Biol Chem 1961;236:2756-2759). Various efforts have been made to stabilize NAD+. 3 ( 3A. Wozniacka, P. Szajerski, J. Adamus, J. Gebicki, A. Sysa-Jedrzejowska: In Search of New Antipsoriatic Agents: NAD + Topical Composition. Skin Pharmacol. Physiol. 2007;20:37-42.), long-term stability outside refrigerated conditions remains a challenge.

[0005] Thus, identifying compositions that contain NAD+, its precursors, and / or its derivatives and that maintain long-term storage stability (e.g., one or more of chemical, physical, and / or microbial stability) under a variety of storage conditions (e.g., various temperatures) is an ongoing endeavor. Summary of the Invention

[0006] In certain embodiments, the present disclosure is directed to a composition comprising a liposome and an active agent encapsulated in the liposome, the active agent comprising nicotinamide adenine dinucleotide (NAD+), a precursor thereof, a derivative thereof, or a combination thereof.

[0007] In certain embodiments, the composition maintains greater than about 90% by weight, greater than about 92% by weight, greater than about 94% by weight, greater than about 96% by weight, greater than about 98% by weight, greater than about 99% by weight, or about 100% by weight of NAD+, its precursors, derivatives, or mixtures thereof, relative to the weight of NAD+, its precursors, derivatives, or mixtures thereof in the composition prior to storage (t=0) after storage for about 1 month, about 3 months, about 6 months, or about 12 months at a temperature of about 2° C. to about 8° C., about 20° C. to about 30° C., or about 35° C. to about 45° C.

[0008] In certain embodiments, the active agent in the composition is selected from nicotinic acid (NA), nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), nicotinamide adenine dinucleotide + hydrogen (NADH), nicotinamide adenine dinucleotide phosphate (NADP), nicotinic acid adenine dinucleotide phosphate (NAADP), nicotinamide adenine dinucleotide phosphate (NADPH), nicotinamide adenine dinucleotide (NAD+), or mixtures thereof.In one embodiment, the active agent comprises NAD+.

[0009] In certain embodiments, the liposome in the composition comprises a vesicle-forming lipid, which may be selected from phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidic acid (PA), phosphatidylinositol (PI), sphingomyelin (SM), polyvinylpyrrolidone, polyvinylmethylether, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyloxazoline, polyhydroxypropylmethacrylamide, polymethacrylamide, polydimethylacrylamide, polyhydroxypropylmethacrylate, polyhydroxyethylacrylate, hydroxymethylcellulose, hydroxyethylcellulose, polyethyleneglycol, polyaspartamide, lecithin, dipalmitoyllecithin, distearoylphosphatidylcholine, or mixtures thereof.In one embodiment, the vesicle-forming lipid comprises lecithin.

[0010] In certain embodiments, the composition further comprises one or more additional excipients.

[0011] In certain embodiments, the one or more additional excipients include a solvent, such as, but not limited to, alcohol, water, or a mixture thereof. In certain embodiments, the solvent includes an alcohol selected from ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl, monobutyl ether, propylene glycol monomethyl, propylene glycol monoethyl ether, propylene glycol monobutyl ether, diethylene glycol monomethyl, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, butylene glycol, pentylene glycol, sorbitol, or a mixture thereof. In one embodiment, the solvent includes water, glycerol, and pentylene glycol.

[0012] In certain embodiments, the one or more additional excipients include a pH adjuster, which may be selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, sulfuric acid, phosphoric acid, nitric acid, sodium citrate, sodium acetate, magnesium hydroxide, citric acid, hydrochloric acid, or mixtures thereof. In certain embodiments, the pH adjuster is present in the composition in an amount effective to adjust the pH of the composition to a range of about 5 to about 9, about 5.5 to about 8.5, or about 6 to about 7.

[0013] In certain embodiments, the compositions may include one or more additional excipients such as, but not limited to, carbohydrates, antioxidants, chelating agents, low molecular weight proteins, high molecular weight polymers, gel formers, stabilizers, additives, wetting agents, emulsifiers, surfactants and / or dispersing agents, alkalizing agents, colorants, synthetic dyes, fillers, diluents, mineral oxides, preservatives, or mixtures thereof.

[0014] In certain embodiments, the compositions are suitable for topical, oral, or parenteral administration.

[0015] In certain embodiments, the present disclosure may be directed to methods for stabilizing an active agent, including nicotinamide adenine dinucleotide (NAD+), a precursor thereof, a derivative thereof, or a combination thereof, by encapsulating the active agent in a liposome.

[0016] In certain embodiments, the present disclosure may relate to a method for preparing any of the compositions described herein.For example, this method may include forming a solution that includes an active agent, such as nicotinamide adenine dinucleotide (NAD+), its precursor, its derivative, or a combination thereof, and a solvent.In certain embodiments, this method may further include combining the active agent solution with vesicle-forming lipids.In certain embodiments, this method may further include combining the active agent solution and vesicle-forming lipids with one or more additional excipients to form, for example, an oral composition, a topical composition, or a parenteral composition.

[0017] In certain embodiments, the present disclosure is directed to a method of treating a condition by administering any of the compositions described herein to a subject in need thereof. In certain embodiments, administration can be topical, oral, or parenteral.

[0018] In certain embodiments, a subject may be treated for one or more of loss of skin firmness, decreased skin thickness, fine lines, wrinkles, loss of elasticity, sagging, dryness, age spots, decreased turnover rate, abnormal desquamation, decreased density and disorganization of the extracellular matrix in the dermis and other histological changes, roughness of the skin, skin smoothness, brightness, radiance, UV damage, free radical damage, radiation damage, pollution damage, damage from environmental toxins or irritants or allergens, skin tone, sunburned appearance, yellowing, reduced visibility of skin pores, pigmentation, scarring, irregularities in the skin surface, rosacea, extrinsic eczema, acne, psoriasis, skin renewal and regeneration processes, redness, ichthyosis, lack of tactile smoothness, lack of visual smoothness, lack of softness, lack of brightness, lack of radiance, skin texture, crow's feet wrinkles, nasolabial folds, pigmentation disorders, crepe paper-like skin texture, decreased skin elasticity, and other damaging skin conditions.

[0019] In certain embodiments, a subject may be treated for one or more of fatigue (e.g., chronic fatigue syndrome), neurocognitive disorders, sleep disorders, post-exercise fatigue, headaches, muscle weakness, joint pain, muscle pain, allergies, swollen and tender lymph nodes, depression, and other stress-related conditions or conditions that may benefit from modulation of cellular energy metabolism.

[0020] In certain embodiments, the compositions disclosed herein are utilized in methods for slowing the aging of the skin.

[0021] In certain embodiments, the compositions disclosed herein are utilized in methods of improving skin microcirculation.

[0022] In certain embodiments, the compositions disclosed herein are utilized in methods to reduce skin tropism.

[0023] In certain embodiments, the compositions disclosed herein are utilized in methods for improving skin tone.

[0024] The present disclosure is illustrated by way of example, and not by way of limitation, in the figures of the accompanying drawings, in which: [Brief description of the drawings]

[0025] [Figure 1] FIG. 1 shows how explants for the permeability study were divided into six parts for analysis. [Diagram 2] FTIR spectra of formulations P1 and P2. [Diagram 3] FTIR chemical images showing the variation of AUC of the band at about 1030 cm for batches TJ1, P1J1 and P2J1. [Figure 4] FTIR chemical images showing the variation of the 2930 / 2960 cm −1 ratio. [Diagram 5] The NCLS scores of the active ingredient signature contributions in each batch are shown. [Figure 6] Also shown are the NCLS scores of different batches. [Figure 7] 1 is a graph showing cell survival results in human aortic endothelial cells (HAEC). [Figure 8] 1 is a graph showing cellular senescence results in human aortic endothelial cells (HAEC). [Figure 9] 1 is a graph showing cellular senescence results in human epidermal keratinocytes (HEKa).

[0026] definition As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to an "active agent" includes a single active agent as well as mixtures of two or more different active agents, reference to an "excipient" includes a single excipient as well as mixtures of two or more different excipients, and so forth.

[0027] As used herein, the term "about" in reference to a measured quantity refers to normal variations in that measured quantity that would be expected by one of ordinary skill in the art making the measurement and exercising a level of care commensurate with the purpose of the measurement and the precision of the measurement device. In certain embodiments, the term "about" includes the recited number ±10%, so that "about 10" would include 9-11.

[0028] As used herein, the terms "active agent," "active ingredient," and "active pharmaceutical ingredient" refer to any material intended to produce a therapeutic, prophylactic, or other intended effect, whether or not approved by a government agency for that purpose. These terms, with respect to specific agents, include all pharma- ceutically active agents, all pharma- ceutically acceptable salts, complexes, stereoisomers, crystalline forms, cocrystals, ethers, esters, hydrates, solvates, and mixtures thereof, which form is pharma- ceutically active.

[0029] As used herein, the term "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with one or more chiral centers that are not mirror images of one another (diastereomers).

[0030] The term "enantiomer" or "enantiomeric" refers to a molecule that is non-superimposable on its mirror image and therefore optically active, where an enantiomer rotates the plane of polarized light to some extent in one direction and its mirror image rotates the plane of polarized light to the same extent but in the opposite direction.

[0031] The term "chiral center" refers to a carbon atom to which four different groups are attached.

[0032] The term "patient" refers to a subject, animal, or human who exhibits clinical symptoms of a particular symptom or symptoms indicating the need for treatment, who is being treated preventatively or prophylactically for a condition, or who has been diagnosed with a condition to be treated. The term "subject" encompasses the definition of the term "patient" and does not exclude otherwise healthy individuals.

[0033] "Pharmaceutically acceptable salts" include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, etc.; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate, etc.; sulfonate salts such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.; amino acid salts such as alginate, aspartate, glutamate, etc.; metal salts such as sodium salt, potassium salt, cesium salt, etc.; alkaline earth metal salts such as calcium salt, magnesium salt, etc.; and organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.

[0034] The term "condition" or "conditions" refers to a medical or cosmetic condition that can be treated or prevented by administration to a subject of an effective amount of an active agent.

[0035] The terms "treatment of" and "treating" include the reduction or cessation of the severity of a condition, or the reduction or cessation of the severity of the symptoms of a condition.

[0036] The terms "prevention" and "preventing" include the avoidance of the onset of a condition.

[0037] In certain embodiments, the term "treatment" or "treating" refers to administration with the intent of providing a pharmacodynamic effect, regardless of outcome. In certain embodiments, "treatment" or "treating" refers to "having a positive effect on a condition," and includes reducing the severity of a condition, reducing and / or alleviating at least one symptom of a condition, reducing, improving, and / or alleviating the severity of a condition, delaying, preventing, or inhibiting the progression of a condition, or a perceived improvement or benefit as a result of treatment. As used herein, treatment does not require a complete cure of a condition. In certain embodiments, the compositions of the present disclosure may provide an improvement in the quality of life of a patient, or may delay, prevent, inhibit the onset of one or more symptoms of a condition, or provide a perceived benefit. As used herein, these terms also include, for example, aesthetic improvements to the skin upon application of the disclosed active agent containing compositions.

[0038] The term "therapeutically effective amount" is intended to include an amount of an active agent, or an amount of a combination of active agents, for example, to treat or prevent a condition, or to treat a symptom of a condition, in a subject.

[0039] The term "effective amount" is intended to include an amount of a component, or an amount of a combination of components, to achieve a particular result or property, e.g., an effective amount of a pH adjuster to achieve a pH of 6.0 is intended to include the amount of one or more pH adjusters to reach a pH of 6.0.

[0040] The terms "application," "apply," and "applying" with respect to the disclosed topical compositions or methods of using the disclosed topical compositions refer to any method of administering a topical composition to a patient's skin in medical or cosmetic practice that delivers the composition to the patient's skin surface. As used herein, smearing, rubbing, spreading, spraying the disclosed topical compositions onto a patient's skin, with or without the aid of a suitable device, are all included within the scope of the term "application." The terms "topical" or "topically," with respect to administration or application of the disclosed formulations, refer to epidermal administration or application, or administration to the skin.

[0041] As used herein, "oral delivery" or "oral administration" refers to a route of administration in which the composition is ingested through the mouth. Oral administration is a part of enteral administration, and also includes buccal administration (dissolved inside the cheek), sublabial administration (dissolved under the lip), and sublingual administration (dissolved under the tongue). In certain embodiments, oral administration includes a route of administration in which the composition is ingested. In certain embodiments, oral administration includes a route of administration in which the composition is inhaled.

[0042] As used herein, "parenteral administration" refers to a route of administration whereby a pharmaceutical dosage form is injected, for example, into a muscle (intramuscular administration), into a vein (intravenous administration), or under the skin (subcutaneous administration).

[0043] The phrase "pharmacologically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0044] The term "sustained release" refers to an active agent that is released over a period of time, for example to provide a once-daily or twice-daily dosage form.

[0045] The term "immediate release" refers to a composition that dissolves an active agent in the gastrointestinal tract without intending to delay or prolong dissolution or absorption of the active agent, e.g., release of at least 85%, at least 90%, or at least 95% of the active agent in about 5 minutes, about 15 minutes, about 30 minutes, about 45 minutes, or about 60 minutes as measured by in vitro dissolution in USP Apparatus 1 (#40 mesh basket), USP Apparatus 2 (paddle), or USP Apparatus 3 (reciprocating cylinder) at room temperature in aqueous medium (pH 1-8).

[0046] The recitation of ranges of values ​​herein is intended to serve merely as a shorthand method of individually referring to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually recited herein. All methods described herein may be performed in any suitable order, unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") presented herein is intended merely to facilitate understanding of certain materials and methods, and does not limit the scope of the claims. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosed materials and methods. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0047] composition In certain embodiments, the present disclosure is directed to a stable composition comprising an active agent encapsulated in a liposome, the active agent comprising nicotinamide adenine dinucleotide (NAD+), a precursor thereof, a derivative thereof, or a combination thereof.

[0048] Nicotinamide adenine dinucleotide (NAD) comprises two nucleotides joined via their phosphate groups. One nucleotide contains an adenine nucleobase and the other nicotinamide. The oxidized form of NAD is abbreviated as NAD+ and the reduced form of NAD is abbreviated as NADH. The oxidized form of NAD is also sometimes referred to as "β-nicotinamide adenine dinucleotide" and "free acid (NAD)".

[0049] NAD also has various precursors and derivatives, including, but not limited to, nicotinic acid (NA), nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), nicotinamide adenine dinucleotide phosphate (NADP), nicotinic acid adenine dinucleotide phosphate (NAADP), nicotinamide adenine dinucleotide phosphate (NADPH), and nicotinamide adenine dinucleotide (NAD+).

[0050] In certain embodiments, the active agent encapsulated in liposome in any of the compositions described herein can be selected from nicotinic acid (NA), nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), nicotinamide adenine dinucleotide + hydrogen (NADH), nicotinamide adenine dinucleotide phosphate (NADP), nicotinic acid adenine dinucleotide phosphate (NAADP), nicotinamide adenine dinucleotide phosphate (NADPH), nicotinamide adenine dinucleotide (NAD+), or mixtures thereof.In one embodiment, the active agent encapsulated in liposome in any of the compositions described herein can be NAD+.

[0051] In certain embodiments, the active agent (e.g., nicotinamide adenine dinucleotide (NAD+), its precursor, its derivative, or a combination thereof) in any of the compositions described herein may be present in an amount ranging from greater than 0% to about 20% by weight, from about 0.5% to about 15% by weight, or from about 1% to about 10% by weight, based on the total weight of the composition, or any subrange or single value therein. In certain embodiments, NAD+ may be present in the composition in an amount ranging from greater than 0% to about 20% by weight, from about 0.5% to about 15% by weight, or from about 1% to about 10% by weight, based on the total weight of the composition, or any subrange or single value therein. In certain embodiments, these concentrations refer to the amount of active agent in a composition comprising (comprising, consisting of, or consisting essentially of) the active agent, liposomes, and one or more additional excipients suitable for forming a homogenous, single-phase liquid composition of the active agent encapsulated in the liposomes. The present disclosure also encompasses compositions that may include additional pharma- ceutically acceptable excipients to form, for example, oral, topical, or parenteral compositions, in which the concentration of the active agent may or may not fall within these ranges in various embodiments.

[0052] In certain embodiments, the active agent (e.g., nicotinamide adenine dinucleotide (NAD+), its precursor, its derivative, or a combination thereof) in any of the compositions described herein may be present in an amount ranging from any of greater than 0% by weight, about 0.5% by weight, about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, or about 9% by weight to any of about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, or about 20% by weight, or any subrange or single value therein, based on the total weight of the composition. In certain embodiments, these concentrations refer to the amount of active agent in a composition comprising (comprising, consisting of, or consisting essentially of) the active agent, liposomes, and one or more additional excipients suitable for forming a homogenous, single-phase liquid composition of the active agent encapsulated in the liposome. The present disclosure also encompasses compositions that may include additional pharma- ceutically acceptable excipients to form, for example, oral, topical, or parenteral compositions, in which the concentration of the active agent may or may not fall within these ranges in various embodiments.

[0053] In certain embodiments, NAD+ may be present in any of the compositions described herein in an amount ranging from greater than 0%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, or about 9% to about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% by weight, based on the total weight of the composition, or any subrange or single value therein. In certain embodiments, these concentrations refer to the amount of NAD+ in a composition that comprises (comprises, consists of, or consists essentially of) an active agent, liposomes, and one or more additional excipients suitable for forming a homogenous, single-phase liquid composition of NAD+ encapsulated in the liposomes. The present disclosure also encompasses compositions that may include additional pharma- ceutically acceptable excipients to form, for example, oral, topical, or parenteral compositions in which the concentration of NAD+ may or may not fall within these ranges in various embodiments.

[0054] Liposomes are formed when vesicle-forming lipids (such as phospholipids and their derivatives) are dispersed in an aqueous solvent (such as water). When dispersed in an aqueous medium, the vesicle-forming lipids form closed vesicles called "liposomes," which are characterized by a lipid bilayer that encapsulates an aqueous core.

[0055] In certain embodiments, the liposome of any of the compositions described herein may comprise vesicle-forming lipid.In certain embodiments, the vesicle-forming lipid may be selected from phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidic acid (PA), phosphatidylinositol (PI), sphingomyelin (SM), phosphatidylserine, phosphatidylglycerol, polyvinylpyrrolidone, polyvinylmethylether, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyloxazoline, polyhydroxypropylmethacrylamide, polymethacrylamide, polydimethylacrylamide, polyhydroxypropylmethacrylate, polyhydroxyethylacrylate, hydroxymethylcellulose, hydroxyethylcellulose, polyethyleneglycol, polyaspartamide, lecithin, dipalmitoyllecithin, distearoylphosphatidylcholine, or mixture thereof.In one embodiment, the vesicle-forming lipid comprises lecithin.

[0056] In certain embodiments, the vesicle-forming liquid in any of the compositions described herein may be present in an amount ranging from greater than 0% to about 20% by weight, from about 0.5% to about 15% by weight, or from about 1% to about 10% by weight, based on the total weight of the composition, or any subrange or value therein. In certain embodiments, the lecithin may be present in the composition in an amount ranging from greater than 0% to about 20% by weight, from about 0.5% to about 15% by weight, or from about 1% to about 10% by weight, based on the total weight of the composition, or any subrange or value therein. In certain embodiments, these concentrations refer to the amount of vesicle-forming agent in a composition that comprises (comprises, consists of, or consists essentially of) an active agent, liposomes, and one or more additional excipients suitable for forming a homogenous, single-phase liquid composition of the active agent encapsulated in the liposomes. The present disclosure also encompasses compositions that may include additional pharma- ceutically acceptable excipients to form, for example, oral, topical, or parenteral compositions, in which the concentration of vesicle-forming lipids may or may not fall within these ranges in various embodiments.

[0057] In certain embodiments, the vesicle-forming lipid in any of the compositions described herein may be present in an amount ranging from greater than 0% by weight, about 0.5% by weight, about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, or about 9% by weight to about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, or about 20% by weight, or any subrange or single value therein. In certain embodiments, these concentrations refer to the amount of vesicle-forming lipid in a composition that comprises (comprises, consists of, or consists essentially of) an active agent, liposomes, and one or more additional excipients suitable for forming a homogenous single-phase liquid composition of the active agent encapsulated in the liposomes. The present disclosure also encompasses compositions that may include additional pharma- ceutically acceptable excipients to form, for example, oral, topical, or parenteral compositions, in which the concentration of vesicle-forming lipids may or may not fall within these ranges in various embodiments.

[0058] In certain embodiments, lecithin may be present in any of the compositions described herein in an amount ranging from greater than 0%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, or about 9% to about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% by weight, based on the total weight of the composition, or any subrange or single value therein. In certain embodiments, these concentrations refer to the amount of lecithin in a composition that comprises (comprises, consists of, or consists essentially of) an active agent, liposomes, and one or more additional excipients suitable for forming a homogenous single-phase liquid composition of the active agent encapsulated in the liposomes. The present disclosure also encompasses compositions that may include additional pharma- ceutically acceptable excipients to form, for example, oral, topical, or parenteral compositions, in which the concentration of lecithin may or may not fall within these ranges in various embodiments.

[0059] In certain embodiments, the weight to weight ratio of active agent to vesicle-forming lipid is in the range of about 10:1 to about 1:10, about 8:1 to about 1:8, about 5:1 to about 1:5, about 3:1 to about 1:3, about 2:1 to about 1:2, about 1:1 to about 1:10, about 1:1 to about 1:8, about 1:1 to about 1:5, about 1:1 to about 1:3, or about 1:1 to about 1:2, or any subrange or single value therein. In certain embodiments, the minimum amount of active agent in the composition is a therapeutically effective amount. In certain embodiments, the maximum amount of active agent in the composition is an effective amount to maintain a homogeneous single liquid phase. In certain embodiments, the active agent is not added to the composition in an amount that would cause phase separation.

[0060] In certain embodiments, the composition further comprises one or more additional excipients.

[0061] In certain embodiments, the one or more additional excipients include a solvent, such as, but not limited to, alcohol, water, or a mixture thereof. In certain embodiments, the solvent includes an alcohol selected from ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl, monobutyl ether, propylene glycol monomethyl, propylene glycol monoethyl ether, propylene glycol monobutyl ether, diethylene glycol monomethyl, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, butylene glycol, pentylene glycol, sorbitol, or a mixture thereof.

[0062] In certain embodiments, the solvent in any of the compositions described herein may be present in an amount ranging from about 70% to about 98%, about 80% to about 95%, or about 85% to about 92% by weight, based on the total weight of the composition, or any subrange or single value therein. In certain embodiments, the solvent in any of the compositions described herein may be present in an amount ranging from about 70%, about 72%, about 74%, about 76%, about 78%, about 80%, about 82%, about 84%, about 85%, or about 86% by weight, based on the total weight of the composition, to about 88%, about 90%, about 92%, about 94%, about 95%, about 96%, or about 98% by weight, or any subrange or single value therein. In certain embodiments, these concentrations refer to the amount of solvent in a composition comprising (comprising, consisting of, or consisting essentially of) an active agent, liposomes, and one or more additional excipients suitable for forming a homogenous, single-phase liquid composition of the active agent encapsulated in the liposome. The present disclosure also encompasses compositions that may include additional pharma- ceutically acceptable excipients, for example, to form oral, topical, or parenteral compositions, in which the concentration of the solvent may or may not fall within these ranges in various embodiments.

[0063] In one embodiment, the solvent comprises water, glycerol, and pentylene glycol.

[0064] In certain embodiments, water in any of the compositions described herein may be present in an amount ranging from greater than 0% to about 50%, from about 5% to about 40%, or from about 10% to about 30%, or any subrange or single value therein, based on the total weight of the composition. In certain embodiments, water in any of the compositions described herein may be present in an amount ranging from greater than 0%, from about 5%, from about 10%, from about 15%, from about 20%, or from about 25% to about 30%, from about 35%, from about 40%, from about 45%, or from about 50%, based on the total weight of the composition, or any subrange or single value therein. In certain embodiments, these concentrations refer to the amount of water in a composition comprising (comprising, consisting of, or consisting essentially of) an active agent, liposomes, and one or more additional excipients suitable for forming a homogenous single-phase liquid composition of the active agent encapsulated in the liposomes. The present disclosure also encompasses compositions that may include additional pharma- ceutically acceptable excipients to form, for example, oral, topical, or parenteral compositions, in which the concentration of water may or may not fall within these ranges in various embodiments.

[0065] In certain embodiments, glycerol in any of the compositions described herein may be present in an amount ranging from greater than 0% to about 90%, from about 30% to about 80%, or from about 50% to about 70% by weight, based on the total weight of the composition, or any subrange or single value therein. In certain embodiments, glycerol in any of the compositions described herein may be present in an amount ranging from greater than 0%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% by weight, based on the total weight of the composition, to about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% by weight, based on the total weight of the composition, or any subrange or single value therein. In certain embodiments, these concentrations refer to the amount of glycerol in a composition comprising (comprising, consisting of, or consisting essentially of) an active agent, liposomes, and one or more additional excipients suitable for forming a homogenous, single-phase liquid composition of the active agent encapsulated in the liposome. The present disclosure also encompasses compositions that may include additional pharma- ceutically acceptable excipients, for example, to form oral, topical, or parenteral compositions, in which the concentration of glycerol may or may not fall within these ranges in various embodiments.

[0066] In certain embodiments, pentylene glycol in any of the compositions described herein may be present in an amount ranging from greater than 0% to about 20%, from about 0.5% to about 15%, or from about 1% to about 10% by weight, based on the total weight of the composition, or any subrange or single value therein. In certain embodiments, pentylene glycol in any of the compositions described herein may be present in an amount ranging from greater than 0%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, or about 9% by weight, based on the total weight of the composition, to about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% by weight, based on the total weight of the composition, or any subrange or single value therein. In certain embodiments, these concentrations refer to the amount of pentylene glycol in a composition comprising (comprising, consisting of, or consisting essentially of) an active agent, liposomes, and one or more additional excipients suitable for forming a homogenous, single-phase liquid composition of the active agent encapsulated in the liposome. The present disclosure also encompasses compositions that may include additional pharma- ceutically acceptable excipients to form, for example, oral, topical, or parenteral compositions, in which the concentration of pentylene glycol may or may not fall within these ranges in various embodiments.

[0067] In certain embodiments, other inorganic solvents may be suitably used instead of or in addition to pentylene glycol. Exemplary suitable solvents include, but are not limited to, alcohols selected from ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl, monobutyl ether, propylene glycol monomethyl, propylene glycol monoethyl ether, propylene glycol monobutyl ether, diethylene glycol monomethyl, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, butylene glycol, pentylene glycol, sorbitol, or mixtures thereof. Any of these solvents or other suitable solvents may be included in concentrations similar to those described above for pentylene glycol.

[0068] In certain embodiments, the aqueous solvent utilized with vesicle-forming lipids to form liposomes is mainly glycerol.Glycerol is self-preserving and exhibits microbial stability without necessarily including preservatives or storage agents.In certain embodiments, the composition has less than about 20% by weight, less than about 15% by weight, less than about 10% by weight, less than about 8% by weight, less than about 5% by weight, less than about 3% by weight, less than about 1% by weight, less than about 0.5% by weight, less than about 0.1% by weight of preservatives and / or preservatives or does not contain them (e.g., 0% by weight).

[0069] In certain embodiments, the weight to weight ratio of glycerol to other solvents (e.g., water and / or pentylene glycol, individually or cumulatively together) in the composition is in the range of about 15:1 to about 1:5, about 10:1 to about 1:5, about 8:1 to about 1:3, about 5:1 to about 1:1, or about 3:1 to about 1:5:1, or any subrange or single value therein.

[0070] In certain embodiments, the one or more additional excipients include a pH adjuster, which may be selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, sulfuric acid, phosphoric acid, nitric acid, sodium citrate, sodium acetate, magnesium hydroxide, citric acid, hydrochloric acid, or mixtures thereof. In one embodiment, the pH adjuster is sodium hydroxide. In certain embodiments, the pH adjuster is present in the composition in an amount effective to adjust the pH of the composition to a range of about 4 to about 9, about 5.5 to about 8.5, or about 6 to about 7.

[0071] In certain embodiments, the pH adjusting agent (e.g., sodium hydroxide) in any of the compositions described herein may be present in an amount of up to 5% by weight, up to about 4% by weight, up to about 3% by weight, up to about 2% by weight, or up to about 1% by weight, based on the total weight of the composition, or any subrange or single value therein. In certain embodiments, these concentrations refer to the amount of pH adjusting agent in a composition that comprises (comprises, consists of, or consists essentially of) an active agent, liposomes, and one or more additional excipients suitable for forming a homogenous single-phase liquid composition of the active agent encapsulated in the liposome. The present disclosure also encompasses compositions that may include additional pharma- ceutically acceptable excipients, for example, to form oral, topical, or parenteral compositions, in which the concentration of the pH adjusting agent and / or the final pH of the composition may or may not fall within these ranges in various embodiments.

[0072] In certain embodiments, the compositions described herein have a pH in the range of about 4, about 4.3, about 4.5, about 4.7, about 5, about 5.3, about 5.5, about 5.8, about 6.0, about 6.2, about 6.5, about 6.8, or about 7 to about 7.3, about 7.5, about 7.7, about 8.0, about 8.3, about 8.5, about 8.7, or about 9.0, or any subrange or single value therein.

[0073] In certain embodiments, the compositions may include one or more additional excipients such as, but not limited to, carbohydrates, antioxidants, chelating agents, low molecular weight proteins, high molecular weight polymers, gel formers, stabilizers, additives, wetting agents, emulsifiers, surfactants and / or dispersing agents, alkalizing agents, colorants, synthetic dyes, fillers, diluents, mineral oxides, preservatives, or mixtures thereof.

[0074] In certain embodiments, the composition further comprises an antioxidant. In certain embodiments, the antioxidant may include, for example, trivalent phosphorus such as phosphites, phenolic antioxidants, hydroxylamines, lactones such as substituted benzofuranones, etc. While hindered phenols, thiosynergists and / or hindered amines are useful for long-term stability of the polymer, the following antioxidants are suitable for use in situations where the active is oxidized: acids (ascorbic acid, erythorbic acid, etidronic acid, gallic acid, low phosphoric acid, nordihydroguaiaretic acid, propionic acid, etc.), phenols (e.g., BHA, BHT, t-butylhydroquinone, dodecyl gallate, octyl gallate, 1,3,5-trihydroxybenzene), organic and inorganic salts (calcium ascorbate, ascorbic acid, etc.), and the like. Sodium, sodium bisulfite, sodium metabisulfite, potassium bisulfite, potassium metabisulfite), esters (calcium ascorbate, dilauryl thiodipropionate, dimyristyl thioidopropionate), pyranones (maltol), and vitamin E (tocopherol, D-α-tocopherol, DL-α-tocopherol, tocopherol acetate, d-α-tocopherol acetate, dl-α-tocopheryl acetate. However, other antioxidants known in the art may be used in accordance with the present invention.

[0075] In certain embodiments, suitable antioxidants include, but are not limited to, sterically hindered phenols, arylamines, thioureas, thiocarbamates, phosphites, thioether esters, and combinations of the foregoing. Other suitable examples of antioxidants include alkylated monophenols (including, but not limited to, 2,6-di-tert-butyl-4-methylphenol, 2-tert-butyl-4,6-di-methylphenol, 2,6-di-tert-butyl-4-ethylphenol, 2,6-di-tert-butyl-4-n-butylphenol, 2,6-di-tert-butyl-4-isobutylphenol, 2,6-dicyclopentyl-4-methylphenol, 2-(α-methylcyclohexyl) -4,6-dimethylphenol, 2,6-dioctadecyl-4-methylphenol, 2,4,6-tricyclohexylphenol, 2,6-di-tert-butyl-4-methoxymethylphenol, nonylphenols which are linear or branched in the side chain, such as 2,6-di-nonyl-4-methylphenol, 2,4-dimethyl-6-(1'-methylundec-1'-yl)phenol, 2,4-dimethyl-6-(1'-methylheptadece-1'-yl)phenol. , 2,4-dimethyl-6-(1'-methyltridec-1-yl)phenol and mixtures thereof), alkylthiomethylphenols (including but not limited to 2,4-dioctylthiomethyl-6-tert-butylphenol, 2,4-dioctylthiomethyl-6-methylphenol, 2,4-diethylthiomethyl-6-ethylphenol, 2,6-di-dodecylthiomethyl-4-nonylphenol), hydroquinone and alkylated hydroquinones (including but not limited to 2,4-dioctylthiomethyl-6-tert-butylphenol, 2,4-dioctylthiomethyl-6-methylphenol, 2,4-diethylthiomethyl-6-ethylphenol, 2,6-di-dodecylthiomethyl-4-nonylphenol), , 2,6-di-tert-butyl-4-methoxyphenol, 2,5-di-tert-butylhydroquinone, 2,5-di-tort-amylhydroquinone, 2,6-diphenyl-4-octadecyloxyphenol, 2,6-di-tert-butylhydroquinone, 2,5-di-tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxyphenyl stearate, bis(3,Tocopherols (including but not limited to α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol and mixtures thereof (vitamin E)), hydroxylated thiodiphenyl ethers (including but not limited to 2,2′-thiobis(6-tert-butyl-4-methylphenol), 2,2′-thiobis(4-ethylphenol), 4,4′-thiobis(6-tert-butyl-3-methylphenol), 4,4′-thiobis(6-tert-butyl-4-hydroxyphenyl)adipate, 4,4'-bis(2,6-dimethyl-4-hydroxyphenyl)-disulfide), alkylidene bisphenols (including but not limited to 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 2,2'-methylenebis(6-tert-butyl-4-ethylphenol), 2,2'-methylenebis[4-methyl-6-(α-methylcyclohexyl)-phenol], 2,2'-methylenebis(4-methyl-6-cyclohexyl)-phenol), 2,2'-methylenebis(6-nonyl-4-methylphenol), 2,2'-methylenebis(4,6-di-tert-butylphenol), 2,2'-ethylidenebis(4,6-di-tert-butylphenol), 2,2'-ethylidenebis(6-tert-butyl-4-isobutylphenol), 2,2'-methylenebis[6-(α-methylbenzyl)-4-nonylphenol], 2,2'-methylenebis[6-(α,α-dimethylbenzyl)-4-nonylphenol], 4,4'-methylenebis(2,6-di-tert- butylphenol), 4,4′-methylenebis(6-tert-butyl-2-methylphenol), 1,1-bis(5-tert-butyl-4-hydroxy-2-methylphenyl)butane, 2,6-bis(3-test-butyl-5-methyl-2-hydroxybenzyl)-4-methylphenol, 1,1,3-tris(5-tert-butyl-4-hydroxy-2-methylphenyl)butane, 1,1-bis(5-tert-butyl-4-hydroxy-2-methylphenyl)-3-n-dodecylmercaptobutane, ethylene glycol bis[3,3-bis(3′-tert-butyl-4′-hydroxyphenyl)butyrate], bis(3-tert-butyl-4-hydroxy-5-methyl-phenyl)dicyclopentadiene, bis[2-(3′-tert-butyl-2′-hydroxy-5′-methylbenzyl)-6-tert-butyl-4-methylphenyl]terephthalate, 1,1-bis-(3,5-dimethyl-2-hydroxyphenyl)butane, 2,2-bis(3,5-di-tert-butyl-4-hydroxyphenyl)propane, 2,2-bis(5-tert-butyl-4-hydroxy-2-methylphenyl)propane, 1,5,5-tetra-(5-tert-butyl-4-hydroxy-2-methylphenyl)pentane), O-, N- and S-benzyl compounds (including but not limited to 3,5,3′,5′-tetra-tert-butyl-4,4′-dihydroxydibenzyl ether, octadecyl-4-hydroxy-3,5-dimethylbenzyl mercaptoacetate, tridecyl-4-hydroxy-3,5-di-tert-butylbenzyl mercaptoacetate, tris(3,5-di-tert-butyl-4-hydroxyphenyl)-4-hydroxyphenyl ether ... benzyl)amine, bis(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)dithioterephthalate, bis(3,5-di-tert-butyl-4-hydroxybenzyl)sulfide, isooctyl-3,5-di-tert-butyl-4-hydroxybenzyl mercaptoacetate), hydroxybenzylated malonates (including but not limited to dioctadecyl-2,2-bis(3,5-di-tert-butyl-2-hydroxybenzyl)malonate, di-octadecyl-2-(3-tert-butyl-4-hydroxy-5-methylbenzyl 1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl)-2,4,6-trimethylbenzene, 1,4-bis(3,5-di-tert-butyl-4-hydroxybenzyl)-2,4,6-trimethylbenzene, 1,4-bis(3,5-di-tert-butyl-4-hydroxybenzyl)-2,5,6-trimethylbenzene, 1,4-bis(3,5-di-tert-butyl-4-hydroxybenzyl)-2 ...3,5,6-tetramethylbenzene, 2,4,6-tris(3,5-di-tert-butyl-4-hydroxybenzyl)phenol), triazine compounds (including but not limited to 2,4-bis(octylmercapto)-6-(3,5-di-tert-butyl-4-hydroxyanilino)-1,3,5-triazine, 2-octylmercapto-4,6-bis(3,5-di-tert-butyl-4-hydroxyanilino)-1,3,5-triazine, 2-octylmercapto-4,6-bis(3,5-di-tert-butyl-4-hydroxyphenoxy)- 1,3,5-triazine, 2,4,6-tris-(3,5-di-tert-butyl-4-hydroxyphenoxy)-1,2,3-triazine, 1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl)isocyanurate, 1,3,5-tris(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)isocyanurate, 2,4,6-tris-(3,5-di-tert-butyl-4-hydroxyphenylethyl)-1,3,5-triazine, 1,3,5-tris(3,5-di-tert-butyl-4-hydroxy-f 1,3,5-tris(3,5-dicyclohexyl-4-hydroxybenzyl)iso-cyanurate), benzyl phosphonates (including but not limited to dimethyl-2,5-di-tert-butyl-4-hydroxybenzylphosphonate, diethyl-3,5-di-tert-butyl-4-hydroxybenzylphosphonate, dioctadecyl 3,5-di-tert-butyl-4-hydroxybenzylphosphonate, dioctadecyl-5-tert-butyl-4-hydroxy-3-methylbenzyl arylphosphonates, including the calcium salt of the monoethyl ester of 3,5-di-tert-butyl-4-hydroxybenzylphosphonic acid; acylaminophenols (including, but not limited to, 4-hydroxylauranilide, 4-hydroxystearanilide, octyl N-(3,5-di-tert-butyl-4-hydroxyphenyl)carbamate); monohydric or polyhydric alcohols, such as methanol, ethanol, n-octanol, i-octanol, octadecanol, 1,6-Hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N′-bis(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, esters of 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane with β-(5-tert-butyl-4-hydroxy-3-methylphenyl)propionic acid, mono- or polyhydric alcohols, e.g. methanol, ethanol, n-octanol, i-octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N′-bis(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, esters of 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane with β-(5-tert-butyl-4-hydroxy-3-methylphenyl)propionic acid, Esters with 3,9-bis[2-{3-(3-tert-butyl-4-hydroxy-5-methylphenyl)propionyloxy}-1,1-dimethylethyl]-2,4,8,10-tetraoxadioxane; 3-thiaundecanol; 3-thiapentadecanol; trimethylhexanediol; trimethylolpropane; 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane; 3,9-bis[2-{3-(3-tert-butyl-4-hydroxy-5-methylphenyl)propionyloxy}-1,1-dimethylethyl]-2,4,8,10-tetraoxadioxane; Suspiro[5.5]-undecane, 6-(3,5-d-dicyclohexyl-4-hydroxyphenyl)propionic acid, mono- or polyhydric alcohols, such as methanol, ethanol, octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N'-bis(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, esters of 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane, 3,5-di-tert-butyl-4-hydroxyphenylacetic acid with mono- or polyhydric alcohols, e.g., methanol, ethanol, octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, tri, Ethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N′-bis(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, esters with 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane, 6-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid, e.g., N,N′-bis(3,5-di- tert-Butyl A-hydroxyphenylpropionyl)hexamethylenediamide, N,N'-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)trimethylenediamide, N,N'-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)hydrazide, N,N'-bis[2-(3-[3,5-di-tert-butyl-4-hydroxyphenyl]propionyloxy)ethyl]oxamide (Naugard® XL-1, Uni Ascorbic Acid (Vitamin C), Amine Antioxidants (including but not limited to N,N'-Di-isopropyl-p-phenylenediamine, N,N'-Di-sec-butyl-p-phenylenediamine, N,N'-Bis(1,4-dimethylpentyl)-p-phenylenediamine, N,N'-Bis(1-ethyl-3-methylpentyl)-p-phenylenediamine, N,N'-Bis(1-methylheptyl)-p-phenylenediamine, N,N'-Dicyclohexyl ... N,N'-diphenyl-p-phenylenediamine, N,N'-bis(2-naphthyl)-p-phenylenediamine, N-isopropyl-N'-phenyl-p-phenylenediamine, N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine, N-(1-methylheptyl)-N'-phenyl-p-phenylenediamine, N-cyclohexyl-N'-phenyl-p-phenylenediamine, 4-(p-toluenesulfamoyl)diphenylamine, N,N'-dimethyl-N,N'-di-sec-butyl-p-phenylenediamine, diphenylamine, N-allyldiphenylamine, 4-isopropoxydiphenylamine, N-phenyl-1-naphthylamine, N-(4-tert-octylphenyl)-1-naphthylamine, N-phenyl-2-naphthylamine), octylated diphenylamines (including but not limited to p,p'-di-tert-octyldiphenylamine, 4-n-butylaminophenol, 4-butyrylaminophenol, 4-nonanoylaminophenol, Phenol, 4-dodecanoylaminophenol, 4-octadecanoylaminophenol, bis(4-methoxyphenyl)amine, 2,6-di-tert-butyl-4-dimethylaminomethylphenol, 2,4′-diaminodiphenylmethane, 4,4′-diaminodiphenylmethane, N,N,N′,N′-tetramethyl-4,4′-diaminodiphenylmethane, 1,2-bis[(2-methylphenyl)amino]ethane, 1,2-bis(phenylamino)propane, (o-tolyl)biguanide, bi tert-octylated N-phenyl-1-naphthylamine), mixtures of mono- and di-alkylated tert-butyl / tert-octyldiphenylamines, mixtures of mono- and di-alkylated nonyldiphenylamines, mixtures of mono- and di-alkylated dodecyldiphenylamines, mixtures of mono- and di-alkylated isopropyl / isohexyldiphenylamines, mixtures of mono- and di-alkylated The alkylated tert-butyl diphenylamines include, but are not limited to, mixtures of mono- and dialkylated tert-butyl / tert-octyl phenothiazines, mixtures of mono- and dialkylated tert-octyl-phenothiazines, N-allyl phenothiazine, N,N,N',N'-tetraphenyl-1,4-diaminobut-2-ene, and combinations of the foregoing.

[0076] In one embodiment, the antioxidant comprises tocopherol. In certain embodiments, the antioxidant (e.g., tocopherol) in any of the compositions described herein may be present in an amount of up to about 0.5% by weight, up to about 0.4% by weight, up to about 0.3% by weight, up to about 0.2% by weight, or up to about 0.1% by weight, based on the total weight of the composition, or any subrange or single value therein. In certain embodiments, these concentrations refer to the amount of antioxidant in a composition that comprises (comprises, consists of, or consists essentially of) an active agent, liposomes, and one or more additional excipients suitable for forming a homogeneous single-phase liquid composition of the active agent encapsulated in the liposome. The present disclosure also encompasses compositions that may include additional pharma- ceutically acceptable excipients, for example, to form oral, topical, or parenteral compositions, in which the concentration of the antioxidant in the composition may or may not fall within these ranges in various embodiments.

[0077] In certain embodiments, the present disclosure is directed to a composition comprising NAD+ encapsulated in a liposome. In one embodiment, the liposome comprises a vesicle-forming lipid that is lecithin. In one embodiment, the composition comprises water and one or more of an inorganic alcohol, such as glycerol and / or pentylene glycol. In one embodiment, the composition comprises a pH adjuster, such as sodium hydroxide. In one embodiment, the composition comprises an antioxidant, such as tocopherol.

[0078] In certain embodiments, the present disclosure provides a) greater than 0% to about 20%, about 0.5% to about 15%, or about 1% to about 10% by weight of NAD+; b) greater than 0% to about 20%, about 0.5% to about 15%, or about 1% to about 10% by weight of vesicle-forming lipids (e.g., lecithin); c) greater than 0% to about 90%, about 30% to about 80%, about 50% to about 70%, or about 55% to about 65% by weight of glycerol; d) 0% to about 50%, about 5% to about 40%, or about 10% to about 30% by weight of water; e) 0% f) up to about 5% by weight, up to about 4% by weight, up to about 3% by weight, up to about 2% by weight, or up to about 1% by weight of a pH adjuster (e.g., sodium hydroxide); and / or g) up to about 0.5% by weight, up to about 0.4% by weight, up to about 0.3% by weight, up to about 0.2% by weight, or up to about 0.1% by weight of an antioxidant (e.g., tocopherol), all weight percentages being based on the total weight of a)-g).

[0079] In certain embodiments, the present disclosure may further be directed to pharmaceutical compositions, cosmetic compositions, beauty compositions, nutraceutical compositions, or nutritional compositions. The term "pharmaceutical composition" refers to a composition manufactured for use for medicinal purposes. The term "cosmetic composition" refers to a cosmetic composition scientifically proven to have medical properties. The term "cosmetic composition" refers to a composition that can maintain, protect, cleanse, add fragrance, change the appearance, etc., without penetrating the skin or altering its function. The term "nutraceutical composition" refers to a composition that can be used for medicinal purposes other than nutrition. The term "nutraceutical composition" refers to a supplement intended to complement a subject's diet by providing additional nutrients.

[0080] In certain embodiments, the present disclosure may be directed to oral compositions suitable for oral administration. In certain embodiments, the present disclosure may be directed to topical compositions suitable for topical administration. In certain embodiments, the present disclosure may be directed to injectable compositions suitable for parenteral administration.

[0081] Any of the pharmaceutical compositions (whether suitable for oral, topical, or parenteral administration), cosmetic compositions, beauty compositions, nutraceutical compositions, nutritional compositions, and the like, may comprise a liposomally encapsulated active agent and a pharma- ceutically acceptable excipient, wherein the active agent is selected from nicotinic acid (NA), nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), nicotinamide adenine dinucleotide + hydrogen (NADH), nicotinamide adenine dinucleotide phosphate (NADP), nicotinic acid adenine dinucleotide phosphate (NAADP), nicotinamide adenine dinucleotide phosphate (NADPH), nicotinamide adenine dinucleotide (NAD+), or mixtures thereof, and preferably the active agent comprises NAD+.

[0082] In certain embodiments, suitable pharma- ceutically acceptable excipients include acrylics, cellulose derivatives, polysaccharides, monosaccharides, gums, natural or synthetic polymers (e.g., polyalkylene oxides (e.g., polymethylene oxide, polyethylene oxide, polypropylene oxide) polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylates, polycaprolactone, polymethacrylate copolymers thereof, and mixtures thereof), liposomes, disintegrants (e.g., polyvinylpyrrolidone, sodium starch glycolate, croscarmellose sodium, or mixtures thereof), glidants, lubricants, absorption enhancers, and the like. The chewable compositions may include any of the following additives: agents, surfactants, binders, softeners, plasticizers (e.g., lecithin, hydrogenated vegetable oils, glycerol esters, lanolin, methyl esters, pentaerythritol esters, rice bran wax, stearic acid, potassium sodium stearate, and the like), waxes, fats, emulsifiers, fillers, antioxidants, flavoring agents, coloring agents, diluents, processing aids (e.g., granulation aids), sweeteners as described above with respect to the chewable compositions, fixatives (e.g., polyols such as, but not limited to, sorbitol, maltitol / isomalt, mannitol, starch, pH adjusters, viscosity adjusters, solubility enhancers or reducers, osmotic agents, solvents, or combinations thereof.

[0083] In certain embodiments, suitable pharma- ceutically acceptable excipients may include polyvinylpyrrolidone, natural and synthetic gums, polyvinyl alcohol, corn starch, hydrophilic and hydrophobic materials such as sustained release polymers, acrylic resins, protein-derived materials, waxes, shellac, and solid or semi-solid oils such as hydrogenated castor oil and hydrogenated vegetable oils. More specifically, the controlled release material can be, for example, alkylcelluloses such as ethylcellulose, acrylic and methacrylic acid polymers and copolymers (e.g., acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymers, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), methyl methacrylate, polymethacrylic acid, poly(methyl methacrylate), poly(methyl methacrylate) copolymers, polyacrylamides, aminoalkyl methacrylate copolymers, poly(methacrylic anhydride), glycidyl methacrylate copolymers, and mixtures of any of the foregoing), and cellulose ethers such as hydroxyl cellulose (e.g., hydroxylmethyl cellulose) and carboxyl alkyl celluloses. Waxes include, for example, natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof (eg, beeswax, carnauba wax, stearic acid and stearyl alcohol).

[0084] In certain embodiments, suitable pharma- ceutically acceptable excipients include gelling agents, including, but not limited to, sugars or sugar-derived alcohols, such as mannitol, sorbitol, and the like, starch and starch derivatives, cellulose derivatives (e.g., microcrystalline cellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester-ethers, cellulose acylates, cellulose diacylates, cellulose triacylates, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropylmethylphthalate, cellulose acetate ... Examples of suitable surfactants include cellulose, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), and mixtures thereof, attapulgite, bentonite, dextrin, algenates, salts such as sodium alginate and potassium alginate, casein, stearic acid, shellac, carrageenan, tragacanth gum, acacia gum, arabic gum, pullulan gum, dextrin, gellan gum, agar gum, tara gum, karaya, guar gum, welan gum, rhamsan gum, locust bean gum, xanthan gum, pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, carbomer and carbopol, polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, surfactants, mixed surfactant / wetting agent systems, emulsifiers, other polymeric materials, and mixtures thereof.

[0085] In certain embodiments, suitable pharma- ceutically acceptable excipients may include hydrophilic excipients, such as, but not limited to, water, low molecular weight polyols, such as polyethylene glycol, polypropylene glycol, or combinations thereof.Other suitable hydrophilic carriers include, but are not limited to, polyoxyethylene derivatives of sorbitan esters, such as sorbitan monolaurate (polysorbate 20), polysorbate 80, polysorbate 60, polyoxyethylene 20 sorbitan trioleate (polysorbate 85), acetic acid, formic acid, other hydrophilic surfactants, and mixtures thereof. Exemplary low molecular weight polyols include, but are not limited to, those having a number average molecular weight of about 200 daltons, about 400 daltons, about 600 daltons, about 800 daltons, or about 1000 daltons to about 2000 daltons, about 3000 daltons, about 4000 daltons, about 5000 daltons, about 6000 Da, or about 7000 Da, or any subrange or single value therein (e.g., polyethylene glycol 400, polyethylene glycol 600, etc.).

[0086] In certain embodiments, suitable pharma- ceutically acceptable excipients include, but are not limited to, plasticizers, such as sugar alcohol plasticizers, such as triacetin, isomalt, maltitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, or mannitol; or polyol plasticizers, such as diglycerin, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene glycols up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, ethanolamines, and mixtures thereof. Other exemplary plasticizers also include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols with aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, single block polymers, citrate ester-type plasticizers, and triacetin. Such plasticizers may include 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate and allyl glycolate, and mixtures thereof.

[0087] In certain embodiments, suitable pharma- ceutically acceptable excipients include plasticizers, such as, but not limited to, phosphate esters; phthalate esters; amides; mineral oils; fatty acids and esters; fatty alcohols, including acetylated hydrogenated cottonseed glycerides and acetylated hydrogenated soybean oil glycerides, vegetable oils and hydrogenated vegetable oils; acetyl tributyl citrate, acetyl triethyl citrate, castor oil, diacetylated monoglycerides, dipropylene glycol salicylate, glycerin, glyceryl cocoate, monoacetylated and diacetylated monoglycerides. Ceride, nitrobenzene, carbon disulfide, fl-naphthyl salicylate, phthalyl glycolate, diosyl phthalate; sorbitol, sorbitol glyceryl tricitrate; sucrose octaacetate; a-tocopheryl polyethylene glycol succinate, phosphate esters; phthalate esters; amides; mineral oils; fatty acids and esters; fatty alcohols; and vegetable oils, fatty alcohols including cetostearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, and myristyl alcohol;Methyl abietate, acetyl tributyl citrate, acetyl triethyl citrate, diisooctyl adipate, amyl oleate, butyl ricinoleate, benzyl benzoate, butyl and glycol esters of fatty acids, butyl diglycol carbonate, butyl oleate, butyl stearate, di(beta-methoxyethyl)adipate, dibutyl sebacate, dibutyl tartrate, diisobutyl adipate, dihexyl adipate, triethylene glycol di(beta-ethylbutyrate), polyethylene glycol di(2-ethylhexoate), diethylene glycol monolaurate, monomeric polyethylene esters, hydrogenated methyl esters of rosin, methoxyethyl oleate, butoxyethyl stearate, beta-(p-tert-amylphenoxy)ethanol, beta-(p-tert-butylphenoxyethyl)ethanol, camphor, Cumar W-1, Cumar MH-1, Cumar May include V-1, diamyl phthalate, (diamylphenoxy)ethanol, diphenyl oxide, technical hydroabietyl alcohol, beccolin, benzene hexahydrochloride, Clorafin 40, Piccolastic A-5, Piccalastic A-25, Flexol B-400, glycerol alpha-methyl alpha-phenyl ether, chlorinated naphthalene, HB-40, monoamyl phthalate, Nevillac 10 o-nitrodiphenyl, and Paracril 26;

[0088] In certain embodiments, suitable pharma- ceutically acceptable excipients may include plasticizers, such as, but not limited to, sugar alcohol plasticizers, such as isomalt, maltitol, sorbitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, or mannitol; or polyol plasticizers, such as glycerin, diglycerin, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene glycols up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, ethanolamines, and mixtures thereof. Other exemplary plasticizers include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols with aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, single block polymers, citrate ester-type plasticizers, and triacetin. Such plasticizers may include 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate, and allyl glycolate, and mixtures thereof.

[0089] In certain embodiments, suitable pharma- ceutically acceptable excipients may include flavors, such as, but not limited to, natural and / or synthetic flavoring materials. For example, oil-soluble flavoring oils, which may or may not be mixed with water-soluble flavoring oils. Oil-soluble flavoring materials are natural or nature-identical essential oils, such as orange oil, lavender oil, pine oil, eucalyptus oil, lemon oil, clove leaf, peppermint oil, cedarwood oil, rosemary oil, bergamot oil, lavandin oil, patchouli oil, chamomile oil, jasmine oil, spike oil, rose oil, vetiver oil, fennel oil, anise oil, thyme oil, germanium oil, menthol, and marjoram oil. Animal flavors are, for example, musk, castoreum, abel, or zibet. Spagelic essences are also known to those skilled in the art. They are made by fermenting certain herbs, which are then processed into the final product. Synthetic fragrance ingredients are synthetic essential oils composed of a single compound, such as, for example, linalool, terpinol, nerol, citronellal, benzaldehyde, cinnamon aldehyde, vanillin, ethyl vanillin, or methylacetophenone. The fragrance material may also be a synthetic oil-soluble fragrance oil selected from the usual group consisting of fragrance hydrocarbons, alcohols, ketones, aldehydes, ethers, esters, polyene derivatives. Other fragrances that may be used are cataloged and described in reference books and databases such as S. Arctander, Perfume and Flavor Chemicals, Volumes I and II (1960, 1969; reprint 2000), Allured's Flavor and Fragrance Materials (2005), and the database maintained by the Research Institute for Fragrance Materials at www.rifm.org.

[0090] In certain embodiments, suitable pharma- ceutically acceptable excipients may include flavor oils. Suitable flavor oils include mixtures of natural and synthetic flavors. Natural fragrances are extracts from flowers (lily, lavender, rose, jasmine, neroli, ylang-ylang), stems and leaves (geranium, patchouli, petitgrain), fruits (anise, coriander, cumin, juniper), fruit peels (bergamot, lemon, orange), roots (mace, angelica, celery, cardamom, costus, iris, calmus), woods (pinewood, sandalwood, guaiacwood, cedarwood, rosewood), herbs and grasses (tarragon, lemongrass, sage, thyme), needles and branches (spruce, fir, pine, pumila), resins and saps (galbanum, elemi, benzoin, myrrh, olibanum, opoponax). Typical synthetic fragrance compounds are products of the ester, ether, aldehyde, ketone, alcohol, and hydrocarbon types. Fragrance compounds of the ester type are, for example, benzyl acetate, phenoxyethyl isobutyrate, p-tert-butylcyclohexyl acetate, linalyl acetate, dimethylbenzylcarbinyl acetate, phenylethyl acetate, linalyl benzoate, benzyl formate, ethylmethylphenyl glycinate, allyl cyclohexylpropionate, styrallyl propionate, and benzyl salicylate. The ethers include, for example, benzyl ethyl ether; the aldehydes include, for example, the linear alkanals having 8 to 18 carbon atoms, citral, citronellal, citronellyloxyacetaldehyde, cyclamen aldehyde, hydroxycitronellal, lilial and bourgeonal; the ketones include, for example, the ionones, α-isomethylionone and methyl cedryl ketone; the alcohols include anethole, citronellol, eugenol, isoeugenol, geraniol, linalool, phenylethyl alcohol and terpineol; and the hydrocarbons include mainly the terpenes and balsams.

[0091] In certain embodiments, suitable pharma- ceutically acceptable excipients may include essential oils of relatively low volatility that are primarily used as fragrance components, and are also suitable as flavor oils, such as sage oil, chamomile oil, clove oil, melissa oil, mint oil, cinnamon leaf oil, linden blossom oil, juniper berry oil, vetiver oil, olibanum oil, galbanum oil, labranum oil, and lavandin oil. Other suitable oils include bergamot oil, dihydromyrcenol, lilial, lyral, citronellol, phenylethyl alcohol, alpha-hexylcinnamaldehyde, geraniol, benzyl acetone, cyclamen aldehyde, linalool, boisambrene forte, ambroxan, indole, hedione, sandelice, lemon oil, mandarin oil, orange oil, allyl amyl glycolate, cyclovertal, lavandin oil, clary sage oil, beta-damascene, geranium oil bourbon, cyclohexyl salicylate, Vertofix coeur, iso-E-super, Fixolide NP, evernyl, iraldine gamma, phenylacetic acid, geranyl acetate, benzyl acetate, rose oxide, romirat, irotyl, and floramat, either alone or in admixture.

[0092] In certain embodiments, suitable pharma- ceutically acceptable excipients may include preservatives. As used herein, the term "preservative" refers to an agent that extends the shelf life of a dosage form by slowing or preventing deterioration of flavor, odor, color, texture, appearance, therapeutic value, or safety. A preservative need not provide a lethal, irreversible action that results in partial or complete microbial cell destruction or incapacitation. Sterilants, disinfectants, disinfectants, sporicides, virucides, and tuberculocides provide such an irreversible mode of action and are sometimes referred to as "bactericidal" action. In contrast, a preservative can provide a reversible inhibitory or bacteriostatic effect, in that the target microorganism can resume growth if the preservative is removed. The main differences between a preservative and a bactericide include primarily the mode of action (preservatives prevent growth of microorganisms rather than killing them) and the exposure time (preservatives take days to months to act, whereas bactericides take only minutes to act). Suitable preservatives include, but are not limited to, phenoxyethanol, parabens, pentanediol, and sorbic acid solutions, as well as silver complexes.

[0093] In certain embodiments, suitable pharma- ceutically acceptable excipients may include colorants, such as, but not limited to, white, black, yellow, blue, green, pink, red, orange, purple, indigo, and brown.

[0094] In certain embodiments, suitable pharma- ceutically acceptable excipients may include, but are not limited to, "flavor extracts" obtained by extracting a source, e.g., a part of an animal or plant material, often by using a solvent such as ethanol or water, natural essences obtained by extracting essential oils from flowers, fruits, roots, etc., or from whole plants. Additional exemplary flavoring agents of the compositions described herein may include, but are not limited to, menthol, spearmint, and cinnamon, coffee bean, other flavors or fragrances, such as fruit flavors (e.g., cherry, orange, grape, etc.), quaternary ammonium bases, etc. The flavor effect may be enhanced using flavor enhancers such as tartaric acid, citric acid, vanillin, etc.

[0095] In certain embodiments, suitable pharma- ceutically acceptable excipients may include sweeteners, such as, but not limited to, one or more artificial sweeteners, one or more natural sweeteners, or a combination thereof. Artificial sweeteners include, for example, acesulfame and its various salts, such as the potassium salt (available as Sunett®), alitame, aspartame (available as NutraSweet® and Equal®), aspartame-acesulfame salt (available as Twinsweet®), neohesperidin dihydrochalcone, naringin dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate, saccharin and its various salts, such as the sodium salt (available as Sweet'N Low®), stevia, chloro derivatives of sucrose, such as sucralose (available as Kaltame® and Splenda®), and mogrosides. Natural sweeteners include, for example, glucose, dextrose, convert sugar, fructose, sucrose, glycyrrhizin; monoammonium glycyrrhizinate (sold under the trademark MagnaSweet®); natural intense sweeteners such as Stevia rebaudiana (stevioside), Lo Han Kuo, and polyols such as sorbitol, mannitol, xylitol, and erythritol.

[0096] In certain embodiments, suitable pharma- ceutically acceptable excipients may include an alkalizing agent(s), such as, but not limited to, magnesium oxide, ammonium hydroxide, sodium hydroxide, sodium carbonate, sodium citrate, trisodium phosphate, and / or disodium phosphate.

[0097] In certain embodiments, suitable pharma- ceutically acceptable excipients may include lubricant(s) / release agent(s), such as, but not limited to, fatty acids and their salts, fatty alcohols, fatty esters, fatty amines, fatty amine acetates, and fatty amides. Other suitable lubricants may include, but are not limited to, glyceryl behenate (Compritol™ 888), metallic stearates (e.g., magnesium stearate, calcium stearate, and sodium stearate), stearic acid, hydrogenated vegetable oils (e.g., Sterotex™), talc, beeswax and carnauba wax, silica, fumed silica, colloidal silica, calcium stearate, long chain fatty alcohols, boric acid, sodium benzoate and sodium acetate, sodium chloride, DL-leucine, polyethylene glycol (e.g., Carbowax™ 4000 and Carbowax™ 6000), sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, sodium stearyl fumarate (Pruv™), magnesium lauryl sulfate, stearic acid, stearyl alcohol, mineral oil, paraffin, microcrystalline cellulose, glycerin, propylene glycol, and combinations thereof.

[0098] In certain embodiments, suitable pharma- ceutically acceptable excipients may include diluents, such as, but not limited to, lactose USP, lactose USP (anhydrous), lactose USP (spray dried), starch USP, direct compression starch, mannitol USP, sorbitol, dextrose monohydrate, microcrystalline cellulose NF, dibasic calcium phosphate dihydrate NF, sucrose-based diluents, confectioners' sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate NF, calcium lactate trihydrate granules NF, dextrates NF (e.g., Emdex™), dextrose (e.g., Cerelose™), inositol, hydrolyzed grain solids such as Maltrons™ and Mor-Rex™, amylose, powdered cellulose (e.g., Elcema™), calcium carbonate, glycine, bentonite, polyvinylpyrrolidone, and the like.

[0099] In certain embodiments, suitable pharma- ceutically acceptable excipients may include oils and fats, such as, but not limited to, almond oil, argan oil, avocado oil, canola oil, cashew oil, castor oil, cocoa butter, coconut oil, colza oil, corn oil, cottonseed oil, grapeseed oil, hazelnut oil, hemp oil, hydroxylated lecithin, lecithin, linseed oil, macadamia oil, mango butter, manila oil, mongongo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, rice bran oil, safflower oil, sesame oil, shea butter, soybean oil, sunflower oil, walnut oil, watermelon seed oil. Other oils and fats that may be in the filling of the PVA shell may include, but are not limited to, fish oil (omega-3), krill oil, animal or vegetable fats (e.g., hydrogenated forms thereof), monoglycerides, diglycerides, and triglycerides having C12-, C14-, C16-, C18-, C20-, and C22-fatty acids.

[0100] In certain embodiments, suitable pharma- ceutically acceptable excipients include sunflower protein, soy protein, cottonseed protein, peanut protein, grapeseed protein, whey protein, whey protein isolate, blood protein, egg protein, acrylated proteins, water soluble polysaccharides such as alginates, carrageenan, guar gum, agar, xanthan gum, gellan gum, gum arabic and related gums (gum ghatti, gum karaya, gum tragacanth), pectin, water soluble derivatives of cellulose: alkylcelluloses hydroxyalkylcelluloses and hydroxylalkylalkylcelluloses such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxylbutylmethylcellulose, cellulose esters, and hydroxylalkylcellulose esters such as cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose (HPMC); carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters such as carboxymethylcellulose and their derivatives. Alkali metal salts; water-soluble synthetic polymers such as polyacrylic acid, polyacrylamide, and polyacrylic acid esters, polymethacrylic acid, polymethacrylamide, and polymethacrylic acid esters, polyvinyl acetate, polyvinyl alcohol, polyvinyl acetate phthalate (PVAP), polyvinylpyrrolidone (PVP), PVY / vinyl acetate copolymers, and polycrotonic acid; also suitable are phthalated gelatin, succinic gelatin, crosslinked gelatin, shellac, water-soluble chemical derivatives of starch, cationically modified acrylates, and methacrylates having tertiary or quaternary amino groups, such as diethylaminoethyl groups, which may be quaternized if desired; and other similar polymers; inorganic fillers such as oxides of magnesium aluminum, silicone, titanium, and the like.

[0101] In certain embodiments, suitable pharma- ceutically acceptable excipients include, but are not limited to, digestible long chain (C8-C 50, especially C 12 ~C 40 The hydrophobic materials may include hydrophobic materials including glyceryl ether, ...

[0102] In certain embodiments, suitable pharma- ceutically acceptable excipients may include polyvinyl alcohol, polyvinylpyrrolidone, polyalkylene oxides, polyacrylic acid, cellulose, cellulose ethers, cellulose esters, cellulose amides, polyvinyl acetate, polycarboxylic acids and salts, acetic acid, caprylic acid, oleic acid, polyamino acids or peptides, polyamides, polyacrylamides, maleic acid / acrylic acid copolymers, polysaccharides including starch and gelatin, natural gums such as xanthan, and carrageenan. For example, the polymer can be selected from polyacrylates and water soluble acrylate copolymers, methylcellulose, sodium carboxymethylcellulose, dextrin, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, maltodextrin, polymethacrylates, and combinations thereof, or from polyvinyl alcohol, polyvinyl alcohol copolymers and hydroxypropylmethylcellulose (HPMC), methacrylic acid / methyl methacrylate, methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl acrylate / methyl methacrylate copolymer, shellac, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose trimellitate, cellulose acetate phthalate, polyvinyl acetate phthalate, PEG-35 castor oil, caprylocaproyl polyoxy-8 glyceride, glyceryl distearate, and combinations thereof.

[0103] In certain embodiments, suitable pharma- ceutically acceptable excipients may include high HLB surfactants, such as, but not limited to, polysorbate 80-polyoxyethylene (20) sorbitan monooleate, polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, caprylocaproyl macrogol glycerides, and combinations thereof.

[0104] In certain embodiments, suitable pharma- ceutically acceptable excipients can include fillers, such as, but not limited to, lactose, microcrystalline cellulose, and combinations thereof.

[0105] In certain embodiments, suitable pharma- ceutically acceptable excipients may include natural gums (e.g., natural vegetable gums).Suitable natural gums include, but are not limited to, guar gum, carob gum, konjac gum, xanthan gum, sclerotium gum, acacia gum, cellulose gum (whether modified or not), or combinations thereof.

[0106] In certain embodiments, suitable pharma- ceutically acceptable excipients include emulsifiers, such as, but not limited to, PEG-30 dipolyhydroxystearate, PEG-4 dilaurate, PEG-8 dioleate, PEG-40 sorbitan peroleate, PEG-7 glyceryl cocoate, PEG-20 almond glycerides, PEG-25 hydrogenated castor oil, glyceryl stearate (and) PEG-100 stearate, PEG-7 olivoyl fatty acid, PEG-8 oleate, PEG-8 laurate, PEG-60 almond glycerides, PEG-20 methyl glucose sesquistearate, PEG-40 stearate, PEG-100 stearate, PEG-80 sorbitan laureate, PEG-80 sorbitan laurate ... glyceryl stearate citrate, glyceryl stearate SE (self-emulsifying), stearic acid, salts of stearic acid, polyglyceryl-3-methylglycose distearate, or combinations thereof.

[0107] Further suitable emulsifiers are phosphoric acid esters and their salts, such as cetyl phosphate (Amphisol® A), cetyl diethanolamine phosphate (Amphisol® DEA), potassium cetyl phosphate (Amphisol® K), sodium cetearyl sulfate, sodium glyceryl oleate, sodium glyceryl oleate phosphate, hydrogenated vegetable glyceride phosphates, and mixtures thereof. Further suitable emulsifiers are sorbitan oleate, sorbitan sesquioleate, sorbitan isostearate, sorbitan trioleate, cetearyl glucoside, lauryl glucoside, decyl glucoside, sodium stearoyl glutamate, sucrose polystearate, and hydrated polyisobutene. Furthermore, one or more synthetic polymers may be used as emulsifiers. For example, PVP eicosene copolymer, acrylate / C 10~30 Alkyl acrylate crosspolymer, acrylates / steareth-20 methacrylate copolymer, PEG-22 / dodecyl glycol copolymer, PEG-45 / dodecyl glycol copolymer, and mixtures thereof.

[0108] In certain embodiments, suitable pharma- ceutically acceptable excipients may include chelating agents, such as, but not limited to, disodium ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), N-(hydroxyethyl)-ethylenediaminetriacetic acid (HEDTA), and nitrilotriacetic acid (NTA).

[0109] In certain embodiments, suitable pharma- ceutically acceptable excipients may include fatty alcohols such as Guerbet alcohols based on fatty alcohols having 6-18, preferably 8-10, carbon atoms, including, but not limited to, cetyl alcohol, stearyl alcohol, cetearyl alcohol, oleyl alcohol, octyldodecanol, benzoates of C12-C15 alcohols, acetylated lanolin alcohol, and the like.

[0110] In certain embodiments, suitable pharma- ceutically acceptable excipients include esters of fatty acids, such as, but not limited to, linear C6-C 24 Linear C3-C fatty acids 24 Esters with alcohols, branched C6-C 13 Linear C6-C carboxylic acids 24 Esters with fatty alcohols, linear C6-C 24 Esters of fatty acids with branched alcohols, especially 2-ethylhexanol, and linear or branched C6-C hydroxycarboxylic acids 22Esters of fatty acids, in particular dioctyl malate, esters of linear and / or branched fatty acids with polyhydric alcohols (e.g. propylene glycol, dimer diol or trimer triol) and / or Guerbet alcohols, such as caproic acid, caprylic acid, 2-ethylhexanoic acid, capric acid, lauric acid, isotridecanoic acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, isostearic acid, oleic acid, eleic acid, petroselinic acid, linoleic acid, eleostearic acid, arachidic acid, gadoleic acid, behenic acid and erucic acid, and alcohols, such as isopropyl alcohol, caproic alcohol. , capryl alcohol, 2-ethylhexyl alcohol, capryl alcohol, lauryl alcohol, isotridecyl alcohol, myristyl alcohol, cetyl alcohol, palmoleyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, elaidyl alcohol, petroselinyl alcohol, linoyl alcohol, linolenyl alcohol, eleostearyl alcohol, arachidyl alcohol, gadoleyl alcohol, behenyl alcohol, erucyl alcohol and brassidyl alcohol (obtained, for example, in the pressure removal of natural fats and oils, in the reduction of aldehydes from Roelen's oxosynthesis or in the dimerization of unsaturated fatty acids), as well as technical grade mixtures thereof (obtained, for example, in the high pressure hydrogenation of fats and oils, or technical grade methyl esters based on aldehydes from Roelen's oxosynthesis, and as monomer fractions in the dimerization of unsaturated fatty alcohols).Additional suitable examples of ester oils include isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl isostearate, isopropyl oleate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, isononyl stearate, isononyl isononanoate, 2-ethylhexyl palmitate, 2-hexyl laurate, 2-hexyldecyl stearate, 2-oleyl palmitate, oleyl oleate, and the like. These include: oleyl erucate, erucyl oleate, erucyl erucate, cetearyl octanoate, cetyl palmitate, cetyl stearate, cetyl oleate, cetyl behenylate, cetyl acetate, myristyl myristate, myristyl behenate, myristyl oleate, myristyl stearate, myristyl palmitate, myristyl lactate, propylene glycol dicaprylate / caprylate, stearyl heptanoate, diisostearyl maleate, and octyl hydroxystearate.

[0111] In certain embodiments, suitable pharma- ceutically acceptable excipients may also include other adjuvants, such as, but not limited to, diethylhexyl 2,6-naphthalate, di-n-butyl adipate, di(2-ethylhexyl)-adipate, di(2-ethylhexyl)-succinate, and diisotridecyl acerate, as well as diol esters, such as ethylene glycol dioleate, ethylene glycol diisotridecanoate, propylene glycol di(2-ethylhexanoate), propylene glycol diisostearate, propylene glycol dipergonate, butanediol diisostearate, and neopentyl glycol dicaprylate. 24 Esters of fatty alcohols and / or Guerbet alcohols with aromatic carboxylic acids (saturated and / or unsaturated), in particular benzoic acid, C2-C 12 Esters of dicarboxylic acids with linear or branched alcohols having 1 to 22 carbon atoms or with polyols having 2 to 10 carbon atoms and 2 to 6 hydroxy groups.

[0112] In certain embodiments, suitable pharma- ceutically acceptable excipients include natural or synthetic triglycerides (including glyceryl esters and derivatives), such as, but not limited to, C6-C triglycerides modified by reaction with other alcohols (e.g., caprylic / capric triglycerides, wheat germ glycerides, etc.). 18 They may include diglycerides or triglycerides based on fatty acids. Polyglycerin fatty acid esters (e.g., polyglyceryl-n, such as polyglyceryl-4 caprate, polyglyceryl-2 isostearate, or castor oil, hydrogenated vegetable oil, sweet almond oil, wheat germ oil, sesame oil, hydrogenated cottonseed oil, coconut oil, avocado oil, corn oil, hydrogenated castor oil, shea butter, cocoa butter, soybean oil, mink oil, sunflower oil, safflower oil, macadamia nut oil, olive oil, hydrogenated beef tallow, apricot kernel oil, hazelnut oil, borage oil, etc.). Additional suitable excipients include waxes containing esters of long chain acids and alcohols, as well as compounds with wax-like properties, such as carnauba wax, beeswax (white or yellow), lanolin wax, candelilla wax, ozokerite, Japanese wax, paraffin wax, microcrystalline wax, ceresin, cetearyl ester wax, synthetic beeswax, etc. Also hydrophilic waxes or partial glycerides such as cetearyl alcohol.

[0113] In certain embodiments, suitable pharma- ceutically acceptable excipients may include pearlescent waxes, such as, but not limited to, alkylene glycol esters, particularly ethylene glycol distearate, fatty acid alkanolamides, particularly coco fatty acid diethanolamide, partial glycerides, particularly stearic acid monoglyceride; esters of polyhydric, unsubstituted, or hydroxy-substituted carboxylic acids with fatty alcohols having 6 to 22 carbon atoms, particularly long chain esters of tartaric acid; fatty substances, such as fatty alcohols, fatty ketones, fatty aldehydes, fatty ethers, and fatty carbonates having a total of at least 24 carbon atoms, particularly lauryl ether and distearyl ether; fatty acids, such as stearic acid, hydroxystearic acid, or behenic acid, ring-opening products of olefin epoxides having 12 to 22 carbon atoms with fatty alcohols having 12 to 22 carbon atoms and / or polyols having 2 to 15 carbon atoms and 2 to 10 hydroxy groups, and mixtures thereof.

[0114] In certain embodiments, suitable pharma- ceutically acceptable excipients may include hydrocarbon oils such as, but not limited to, mineral oil (light or heavy), petrolatum (yellow or white), microcrystalline waxes, paraffin and isoparaffin compounds, hydrogenated isoparaffin molecules such as polydecene and polybutene, hydrogenated polyisobutene, squalane, isohexadecane, isodecane, and others from the plant and animal kingdoms.

[0115] In certain embodiments, suitable pharma- ceutically acceptable excipients may include silicones or siloxanes (organo-substituted polysiloxanes), such as, but not limited to, dimethylpolysiloxane, methylphenylpolysiloxane, cyclic silicones, and amino, fatty acid, alcohol, polyether, epoxy, fluorine, glycoside, and / or alkyl modified silicone compounds, which may be either liquid or resinous at room temperature. Linear polysiloxanes, dimethicone (Dow Corning 200 fluid, Rhodia Mirasil DM), dimethiconol, cyclic silicone fluids, cyclopentasiloxane volatiles (Dow Corning 345 fluid), phenyl trimethicone (Dow Corning 556 fluid). Also suitable is simethicone, a mixture of dimethicone and hydrogenated silicate with an average chain length of 200-300 dimethylsiloxane units. A detailed review of suitable volatile silicones by Todd et al. can additionally be found in Cosm. Toil. 91, 27 (1976).

[0116] In certain embodiments, suitable pharma- ceutically acceptable excipients may include emulsifiers, such as, but not limited to, carboxylic acids and their salts: alkaline soaps of sodium, potassium and ammonium, metal soaps of calcium or magnesium, organic based soaps such as lauric acid, palmitic acid, stearic acid and oleic acid; alkyl phosphates or phosphate esters, acid phosphates, diethanolamine phosphate, potassium cetyl phosphate; ethoxylated carboxylic acids or polyethylene glycol esters, PEG-n acylates; linear fatty alcohols having 8-22 carbon atoms, branched from 2-30 moles of ethylene oxide and / or 0-5 moles of propylene oxide, having fatty acids having 12-22 carbon atoms and alkylphenols having 8-15 carbon atoms in the alkyl group; fatty alcohol polyglycol ethers such as laureth-n, ceteareth-n, steareth-n, oleth-n; fatty acid polyglycole ethers such as PEG-n stearate, PEG-n oleate, PEG-n cocoate; monoglycerides and polyol esters. C12-C22 fatty acid mono- and diesters of addition products of 1-30 moles of ethylene oxide with polyols. Fatty acid and polyglycerol esters such as glycerol monostearate, diisostearoyl polyglyceryl-3-diisostearate, polyglyceryl-3-diisostearate, triglyceryl diisostearate, polyglyceryl-2-sesquiisostearate or polyglyceryl dimerate. Mixtures of compounds from several of these substance classes are also suitable. Fatty acid polyglycol esters such as diethylene glycol monostearate, fatty acid and polyethylene glycol esters, fatty acid and saccharose esters such as sucroesters, glycerol and saccharose esters such as sucroglycerides. Sorbitol and sorbitan, sorbitan mono- and diesters of saturated and unsaturated fatty acids having 6-22 carbon atoms and ethylene oxide adducts. Sorbitan esters such as polysorbate-n series, sesquiisostearate, sorbitan, PEG-(6)-sorbitan isostearate, PEG-(10)-sorbitan laurate, and PEG-17-sorbitan dioleate.Glucose derivatives, C8-C22 alkyl-mono- and oligo-glycosides, as well as ethoxylated analogues with glucose as the preferred sugar component. O / W emulsifiers such as methyl glucose-20 sesquistearate, sorbitan stearate / sucrose cocoate, methyl glucose sesquistearate, cetearyl alcohol / cetearyl glucoside. W / O emulsifiers such as methyl glucose dioleate / methyl glucose isostearate. Sulfates and sulfonated derivatives, dialkyl sulfosuccinates, dioctyl succinate, alkyl lauryl sulfates, linear sulfonated paraffins, sulfonated tetrapropene sulfonates, sodium lauryl sulfate, ammonium and ethanolamine lauryl sulfates, lauryl ether sulfates, sodium laureth sulfate, sulfosuccinates, acetyl isothionates, alkanolamide sulfates, taurine, methyl taurine, imidazole sulfate. Polysiloxane / polyalkyl / polyether copolymers and derivatives, dimethicone, copolyols, silicone polyethylene oxide copolymers, silicone glycol copolymers. Propoxylated or POE-n ethers (Meroxapol), Polaxamer or poly(oxyethylene) m-block-poly(oxypropylene) n-block(oxyethylene). Zwitterionic surfactants carrying at least one quaternary ammonium group and at least one carboxylate and / or sulfonic acid group in the molecule. Particularly suitable zwitterionic surfactants are N-alkyl-N,N-dimethylammonium glycinates, cocoalkyldimethylammonium glycinates, N-acylaminopropyl-N,N-dimethylammonium glycinates, cocoacylaminopropyldimethylammonium glycinates, and 2-alkyl-3-carboxymethyl-3-hydroxyethylimidazolines having 8 to 18 carbon atoms in the alkyl or acyl group, respectively, as well as betaines such as cocoacylaminoethyl hydroxyethylcarboxymethylglycinate, N-alkylbetaines, N-alkylaminobetaines.Alkyl imidazolines, alkyl peptides, lipoamino acids, self-emulsifying bases, and compounds described in KF DePolo, A short textbook of cosmetology, Chapter 8, Table 8-7, p250-251.

[0117] Suitable non-ionic bases include, but are not limited to, PEG-6 beeswax (and) PEG-6 stearate (and) polyglyceryl-2-isostearate, glyceryl stearate (and) PEG-100 stearate, PEG-5 glyceryl stearate, sorbitan oleate (and) polyglyceryl-3 ricinoleate, sorbitan stearate and sucrose cocoate, glyceryl stearate and laureth-23, cetearyl alcohol and ceteth-20, cetearyl alcohol and polysorbate 60 and PEG-150 and stearate-20, cetearyl alcohol and cetearyl polyglucoside, cetearyl alcohol and ceteareth-20, cetearyl alcohol and PEG-40 castor oil, cetearyl alcohol and cetearyl glyceryl stearate ... Allyl alcohol and PEG-40 castor oil and sodium cetearyl sulfate, stearyl alcohol and steareth-7 and steareth-10, cetearyl alcohol and steareth-7 and steareth-10, glyceryl stearate and PEG-75 stearate, propylene glycol ceteth-3 acetate, propylene glycol isoceth-3 acetate, cetearyl alcohol and ceteth-12 and oleth-12, PEG-6 stearate and PEG-32 stearate, PEG-6 stearate and ceteth-20 and steareth-20, PEG-6 stearate and ceteth-20, and glyceryl stearate and steareth-20, glyceryl stearate and ceteareth-20.

[0118] Suitable anionic alkali bases include, but are not limited to, PEG-2 stearate SE, glyceryl sulfate SE, propylene glycol stearate. Anionic acid bases such as cetearyl alcohol and sodium cetearyl sulfate, cetearyl alcohol and sodium lauryl sulfate, trilaneth-4 phosphate and glycol stearate and PEG-2 stearate, glyceryl stearate and sodium lauryl sulfate. Cationic acid bases such as cetearyl alcohol and cetrimonium bromide.

[0119] In certain embodiments, suitable pharma- ceutically acceptable excipients may include adjuvants and additives, such as, but not limited to, surfactants, superfatting agents, consistency control agents, thickeners, polymers, stabilizers, bioactive ingredients, swelling agents, additional UV protection factors, antioxidants, hydrotropic agents, preservatives, self-tanning agents, solubilizers, balms, colorants, bacterial inhibitors, and the like.

[0120] In certain embodiments, suitable pharma- ceutically acceptable excipients may include superfatty agents, such as, but not limited to, lanolin and lecithin, and polyethoxylated or acetylated lanolin and lecithin derivatives, polyol fatty acid esters, monoglycerides, and fatty acid alkanolamides, the latter of which simultaneously act as foam stabilizers.

[0121] In certain embodiments, suitable pharma- ceutically acceptable excipients may include surfactants, such as, but not limited to, fatty alcohol polyglycol ether sulfates, sulfate monoglycerides, monoalkyl and / or dialkyl sulfosuccinates, fatty acid isethionates, fatty acid sarcosinates, fatty acid taurides, fatty acid glutamates, alpha-olefin sulfonates, ether carboxylic acids, alkyl oligoglucosides, fatty acid glucamides, alkylamidobetaines, and / or protein fatty acid condensation products, the latter preferably based on wheat protein.

[0122] In certain embodiments, suitable pharma- ceutically acceptable excipients may include consistency regulators / thickeners and rheology modifiers, such as, but not limited to, silicon dioxide, magnesium silicate, aluminum silicate, polysaccharides or derivatives thereof, such as hyaluronic acid, xanthan gum, guar guar, agar, alginates, carrageenan, gellan, pectin, or modified celluloses, such as hydroxycellulose, hydroxypropylmethylcellulose. Furthermore, polyacrylates or homopolymers of reticulated acrylic acid and polyacrylamide, Carbomers (CARBOPOL types 980, 981, 1382, ETD2001, ETD2020, ULTREZ10) or the SALCARE range, such as, for example, SALCARE SC80 (steareth-10 allyl ether / acrylates copolymer), Salcare SC81 (acrylates copolymer), Salcare SC91 and Salcare AST (sodium acrylates copolymer / PPG-1 trideceth-6), SEPIGEL 305 (polyacrylamide / laureth-7), SIMULGEL NS and SIMULGEL EG (hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer), STABILEN 30 (acrylates / vinyl isodecanote crosspolymer), PEMULEN TR-1 (acrylates / C10-30 alkyl acrylate crosspolymer), LUVIGEL EM (Sodium Acrylates Copolymer), ACULYN 28 (Acrylates / Beheneth-25 Methacrylate Copolymer), etc.

[0123] In certain embodiments, suitable pharma- ceutically acceptable excipients may include polymers, such as, but not limited to, anionic, zwitterionic, amphoteric and nonionic polymers contemplated therein, such as vinyl acetate / crotonic acid copolymers, vinylpyrrolidone / vinyl acrylate copolymers, vinyl acetate / butyl maleate / isobornyl acrylate copolymers, methyl vinyl ether / maleic anhydride copolymers and esters thereof, non-crosslinked polyacrylic acid and polyacrylic acid crosslinked with polyols, acrylamidopropyl-trimethylammonium chloride / acrylate copolymers, octylacrylamide / methyl methacrylate-tert-butylaminoethyl methacrylate / 2-hydroxypropyl methacrylate copolymers, polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymers, vinylpyrrolidone / dimethylaminoethyl methacrylate / vinyl caprolactam terpolymers, and optionally derivatized cellulose ethers and silicones.Furthermore, the polymers described in EP1093796 (pages 3-8, paragraphs 17-68) may be used.

[0124] In certain embodiments, suitable pharma- ceutically acceptable excipients include antioxidants, such as, but not limited to, amino acids (e.g., glycine, histidine, tyrosine, tryptophan) and their derivatives, imidazoles (e.g., urocanic acid) and their derivatives, peptides (e.g., D,L-carnosine, D-carnosine, L-carnosine and their derivatives (e.g., anserine), carotenoids, carotene, lycopene and their derivatives, chlorogenic acid and its derivatives, lipoic acid and its derivatives (e.g., dihydrolipoic acid), aurothioglycol, propylthiolacil, and other thiols (e.g., thioredoxin, glutathione, cysteine, cystine, cystamine, and glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl, lauryl, palmitoyl, oleyl, linoleyl, cholesteryl and their glyceryl esters) and their salts, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and its derivatives (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts), as well as sulfoximine compounds (e.g. buthionine sulfoximine, homocysteine ​​sulfoximine, buthionine sulfone, penta-, hexa-, hepta-thionine sulfoximine), and also (metal) chelating agents (e.g. hydrochloride, glyceryl esters ... fatty acids, palmitic acid, phytic acid, lactoferrin), hydroxy acids (e.g., citric acid, lactic acid, malic acid), humic acid, bile acids, bile extracts, bilirubin, biliverdin, EDTA, EDDS, EGTA and their derivatives, unsaturated fatty acids and their derivatives (e.g., linoleic acid, linoleic acid, oleic acid), folic acid and its derivatives, ubiquinone and ubiquinol and their derivatives, vitamin C and derivatives (e.g., ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbyl acetate, ), tocopherol and derivatives (e.g., vitamin E acetate), vitamin A and derivatives (e.g., vitamin A palmitate), and coniferyl benzoate of benzoin resin, rutinic acid and its derivatives, glycosyl rutin, ferulic acid, furfurylidene glucitol, carnosine, butylated hydroxytoluene, butylated hydroxyanisole, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and its derivatives, mannose and its derivatives, superoxide dismutase, N-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionyl]sulfanilic acid (and its salts, e.g., the disodium salt), selenium and its derivatives (e.g., selenium methionine), stilbene and its derivatives (e.g., stilbene oxide, trans-stilbene oxide), as well as suitable derivatives according to the invention of the mentioned active ingredients (salts, esters, ethers, sugars, nucleotides, nucleosides, peptides, and lipids). HALS (= "hindered amine light stabilizer") compounds may also be mentioned.

[0125] In certain embodiments, suitable pharma- ceutically acceptable excipients may include hydrotropic agents, such as, but not limited to, ethoxylated or non-ethoxylated monoalcohols, diols or polyols having a low number of carbon atoms, or their ethers (e.g., ethanol, isopropanol, 1,2-dipropanediol, propylene glycol, glycerin, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol monobutyl ether, diethylene glycol monomethyl ether; diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, and similar products). Polyols considered for that purpose preferably have 2 to 15 carbon atoms and at least two hydroxyl groups. Polyols may also contain further functional groups, in particular amino groups, and / or may be modified with nitrogen. Typical examples are: glycerol, alkylene glycols, such as ethylene glycol, diethylene glycol, propylene glycol, butylene glycol, hexylene glycol, and also polyethylene glycols with an average molecular weight of 100 to 1000 Daltons; technical oligoglycerol mixtures with an inherent degree of condensation of 1.5 to 10, for example technical diglycerol mixtures with a diglycerol content of 40 to 50% by weight; methylol compounds, such as, in particular, trimethylolethane, trimethylolpropane, trimethylolbutane, pentaerythritol and dipentaerythritol; lower alkyl glucosides, in particular those with 1 to 8 carbon atoms in the alkyl radical, such as methyl and butyl glucoside; sugar alcohols with 5 to 12 carbon atoms, such as, for example, sorbitol or mannitol; sugars with 5 to 12 carbon atoms, such as, for example, glucose or sugar; amino sugars, such as, for example, glucamine; dialcoholamines, such as diethanolamine or 2-1,3-propanediol.

[0126] In certain embodiments, suitable pharma- ceutically acceptable excipients may include preservatives, such as, but not limited to, methyl, ethyl, propyl, butyl-paraben, benzalkonium chloride, 2-bromo-2-nitro-propane-1,3-diol, dehydroacetic acid, diazolidinyl urea, 2-dichloro-benzyl alcohol, DMDM ​​hydantoin, formaldehyde solution, methyldibromoglutanitrile, phenoxyethanol, sodium hydroxymethylglycinate, imidazolidinyl urea, triclosan, and further classes of substances listed in the following references: KFDePolo-A short textbook of cosmetology, Chapter 7, Tables 7-2, 7-3, 7-4 and 7-5, p210-219.

[0127] In certain embodiments, suitable pharma- ceutically acceptable excipients may include bacterial inhibitors, such as, but not limited to, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, chlorhexidine (1,6-di(4-chlorophenyl-biguanide)hexane) or TCC (3,4,4'-trichlorocarbanilide). Many aromatic substances and ethereal oils also have antibacterial properties. Typical examples are eugenol, menthol, and thymol, which are active ingredients in clove oil, mint oil, and thyme oil. A natural deodorant of interest is the terpene alcohol farnesol (3,7,11-trimethyl-2,6,10-dodecatrien-1-ol), which is present in lime blossom oil. Glycerol monolaurate has also been shown to be a bacteriostatic agent.

[0128] Other pharma- ceutically acceptable excipients may also be utilized, as will be recognized by those skilled in the art.

[0129] In certain embodiments, the pharma- ceutically acceptable excipients may be included (individually or cumulatively) in the pharmaceutical, cosmetic, cosmetic, nutraceutical, or nutritional compositions described herein in a concentration ranging from about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% to about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% by weight, or any subrange or single value therein, based on the total weight of the composition.

[0130] In certain embodiments, the liposomal composition reduces the cellular senescence of human endothelial cells. The reduction can be in vivo or in vitro. In certain embodiments, for example, compared to a control, the reduction of senescent cells is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%. In certain embodiments, the liposomal composition reduces senescent cells by at least 5%, at least 10%, at least 15%, at least 20%, or at least 25% compared to a NAD+ non-liposomal composition. In certain embodiments, the endothelial cells are human aortic endothelial cells.

[0131] In certain embodiments, the liposomal composition reduces the cellular senescence of human epidermal cells. The reduction can be in vivo or in vitro. In certain embodiments, for example, the reduction of senescent cells is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35% compared to a control. In certain embodiments, the liposomal composition reduces senescent cells by at least 5%, at least 10%, or at least 15% compared to a NAD+ non-liposomal composition. In certain embodiments, the epidermal cells are human epidermal keratinocytes.

[0132] In certain embodiments, the liposomal composition results in an increase in cell survival of human endothelial cells. The increase can be in vivo or in vitro. In certain embodiments, the increase is, for example, at least 5%, at least 10%, at least 15%, or at least 20% compared to a control. In certain embodiments, the liposomal composition results in an increase in cell survival of at least 25% or at least 5% compared to a NAD+ non-liposomal composition. In certain embodiments, the endothelial cells are human aortic endothelial cells.

[0133] In certain embodiments, the liposome composition results in an increase in cell survival of human epidermal cells. The reduction can be in vivo or in vitro. In certain embodiments, the epidermal cells are human epidermal keratinocytes.

[0134] In certain embodiments, the liposomal formulation of the present invention has increased permeability through human skin. The permeability can be in vivo or can be an external model, such as a perfex vivo model. In certain embodiments, the increase is at least about 135%, at least about 150%, at least about 160%, at least about 175%, or at least about 190%, for example, as measured by NCLS score relative to a control. In certain embodiments, the increase is at least about 10%, at least about 15%, at least about 25%, at least about 35%, or at least about 50%, for example, as measured by NCLS score relative to a non-liposomal formulation.

[0135] In certain embodiments, compositions of the invention are stored at a temperature of about 2°C to about 30°C, about 2°C to about 20°C, or about 2°C to about 10°C.

[0136] In certain embodiments, the compositions of the present invention have a temperature of about 2°C to about 30°C, about 2°C to about 20°C, or about 2°C to about 10°C.

[0137] In certain embodiments, the present invention is directed to methods of dispensing the formulations described herein by transporting the product under refrigeration, for example, by electrical (e.g., a freezer), chemical (e.g., ice packs such as dry ice), mechanical means (e.g., a cooler), or a combination thereof.

[0138] stability In certain embodiments, any of the compositions described herein exhibits long-term storage stability. The term "storage stability" as used herein refers to one or more of chemical stability, physical stability, and / or microbial stability.

[0139] The term "chemical stability" refers to an assessment of the change, e.g., decrease or increase, in the amount (or content) of an active agent in a composition after a storage period (e.g., after 1 month storage (t=1), after 3 months storage (t=3), after 6 months storage (t=6), or after 12 months storage (t=12)) compared to the amount (or content) of the active agent before storage began. A smaller change (or no change) in the amount (content) of the active agent in the composition after a given storage period indicates chemical stability of the active agent in a given composition. The chemical stability of the active agent may be analyzed by a suitable HPLC method.

[0140] In certain embodiments, any of the compositions described herein maintains greater than about 90% by weight, greater than about 92% by weight, greater than about 94% by weight, greater than about 96% by weight, greater than about 98% by weight, greater than about 99% by weight, or about 100% by weight of the active agent after storage for about 1 month, about 3 months, about 6 months, or about 12 months at a temperature of about 2° C. to about 8° C., compared to the weight of the active agent in the composition before storage (t=0).

[0141] In certain embodiments, any of the compositions described herein maintains greater than about 90% by weight, greater than about 92% by weight, greater than about 94% by weight, greater than about 96% by weight, greater than about 98% by weight, greater than about 99% by weight, or about 100% by weight of the active agent after storage for about 1 month, about 3 months, about 6 months, or about 12 months at a temperature of about 20° C. to about 30° C., compared to the weight of the active agent in the composition before storage (t=0).

[0142] In certain embodiments, any of the compositions described herein maintains greater than about 90% by weight, greater than about 92% by weight, greater than about 94% by weight, greater than about 96% by weight, greater than about 98% by weight, greater than about 99% by weight, or about 100% by weight of the active agent after storage for about 1 month, about 3 months, about 6 months, or about 12 months at a temperature of about 35° C. to about 45° C., compared to the weight of the active agent in the composition before storage (t=0).

[0143] In certain embodiments, any of the compositions described herein may exhibit any of the above chemical stabilities upon storage at temperatures ranging from about -80°C to about 100°C, about -50°C to about 80°C, about -20°C to about 60°C, about -5°C to about 50°C, 0°C to about 45°C, about 2°C to about 8°C, about 20°C to about 30°C, about 35°C to about 45°C, or any subrange or single value therein, at a relative humidity ranging from about 30% to about 50%, for an extended period of time (e.g., 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, or 24 months, or any subrange or single value therein).

[0144] The term "physical stability" refers to an assessment of the change in a physical property (e.g., but not limited to, color, pH, viscosity, homogeneity, phase separation, etc.) of a composition after a storage period (e.g., after 1 month storage (t=1), after 3 months storage (t=3), after 6 months storage (t=6), or after 12 months storage (t=12)) compared to the same physical property of the composition before storage begins (t=0). A smaller change (or no change) in the physical property of the composition after a given storage period indicates physical stability of the given composition. Depending on the property being tested, various methods can be used to analyze the physical stability of a composition. For example, a pH probe can be utilized to assess the pH of the composition at various time points. In another example, a viscometer can be used to assess the viscosity of the composition at various times.

[0145] In certain embodiments, any of the compositions described herein maintains a pH in the range of about 4 to about 9, about 5.5 to about 8.5, or about 6 to about 7 after storage for about 1 month, about 3 months, about 6 months, or about 12 months at a temperature of about 2° C. to about 8° C.

[0146] In certain embodiments, any of the compositions described herein maintains a pH in the range of about 4 to about 9, about 5.5 to about 8.5, or about 6 to about 7 after storage for about 1 month, about 3 months, about 6 months, or about 12 months at a temperature of about 20° C. to about 30° C.

[0147] In certain embodiments, any of the compositions described herein maintains a pH in the range of about 4 to about 9, about 5.5 to about 8.5, or about 6 to about 7 after storage for about 1 month, about 3 months, about 6 months, or about 12 months at a temperature of about 35° C. to about 45° C.

[0148] In certain embodiments, any of the compositions described herein may exhibit physical stability upon storage at temperatures ranging from about -80°C to about 100°C, about -50°C to about 80°C, about -20°C to about 60°C, about -5°C to about 50°C, 0°C to about 45°C, about 2°C to about 8°C, about 20°C to about 30°C, about 35°C to about 45°C, or any subrange or single value therein, at a relative humidity ranging from about 30% to about 50%, for an extended period of time (e.g., 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, or 24 months, or any subrange or single value therein).

[0149] The term "microbial stability" refers to a change, e.g., an increase or decrease, in the microbial content of a composition after a storage period (e.g., after 1 month storage (t=1), after 3 months storage (t=3), after 6 months storage (t=6), or after 12 months storage (t=12)) compared to the microbial content in the composition before storage begins (t=0). The microbial content of a composition after a given storage period is indicative of the microbial stability of a given composition.

[0150] In certain embodiments, any of the compositions described herein may exhibit microbial stability upon storage at temperatures ranging from about -80°C to about 100°C, about -50°C to about 80°C, about -20°C to about 60°C, about -5°C to about 50°C, 0°C to about 45°C, about 2°C to about 8°C, about 20°C to about 30°C, about 35°C to about 45°C, or any subrange or single value therein, at a relative humidity ranging from about 30% to about 50%, for an extended period of time (e.g., 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, or 24 months, or any subrange or single value therein).

[0151] In certain embodiments, the present disclosure is directed to a method for stabilizing an active agent selected from nicotinic acid (NA), nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), nicotinamide adenine dinucleotide + hydrogen (NADH), nicotinamide adenine dinucleotide phosphate (NADP), nicotinic acid adenine dinucleotide phosphate (NAADP), nicotinamide adenine dinucleotide phosphate (NADPH), nicotinamide adenine dinucleotide (NAD+), or mixtures thereof.In one embodiment, the present disclosure is directed to a method for stabilizing NAD+.

[0152] In certain embodiments, the method includes encapsulating any of the active agents described herein above (such as, but not limited to, NAD+) into liposomes. In certain embodiments, encapsulating any of the active agents described herein above (such as, but not limited to, NAD+) into liposomes provides a liposome composition that exhibits long-term storage stability at various temperatures. In certain embodiments, long-term refers to a period ranging from about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months to about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 15 months, about 18 months, about 21 months, or about 24 months, or any subrange or single value therein. In certain embodiments, storage stability refers to one or more of chemical stability, physical stability, and / or microbial stability. In certain embodiments, the various temperatures refer to temperatures in the ranges of about -80°C to about 100°C, about -50°C to about 80°C, about -20°C to about 60°C, about -5°C to about 50°C, 0°C to about 45°C, about 2°C to about 8°C, about 20°C to about 30°C, about 35°C to about 45°C, or any subrange or single value therein.

[0153] Preparation method In certain embodiments, the present disclosure relates to a method of preparing any of the compositions described herein, hi certain embodiments, the method includes forming a solution including an active agent and a solvent.

[0154] In certain embodiments, the active agent is selected from nicotinic acid (NA), nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), nicotinamide adenine dinucleotide + hydrogen (NADH), nicotinamide adenine dinucleotide phosphate (NADP), nicotinic acid adenine dinucleotide phosphate (NAADP), nicotinamide adenine dinucleotide phosphate (NADPH), nicotinamide adenine dinucleotide (NAD+), or mixtures thereof.In one embodiment, the active agent can be NAD+.

[0155] In certain embodiments, the solvent may include, but is not limited to, an alcohol, water, or a mixture thereof. In certain embodiments, the solvent includes an alcohol selected from ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl, monobutyl ether, propylene glycol monomethyl, propylene glycol monoethyl ether, propylene glycol monobutyl ether, diethylene glycol monomethyl, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, butylene glycol, pentylene glycol, sorbitol, or a mixture thereof. In certain embodiments, the solvent includes water, glycerol, and pentylene glycol.

[0156] In certain embodiments, forming a solution comprising an active agent and a solvent comprises mixing the active agent with a first solvent, optionally adding a pH adjuster, followed by adding a second solvent. In an exemplary embodiment, the active agent is mixed with a solution of glycerin in water, followed by adding a pH adjuster (e.g., sodium hydroxide), followed by adding pentylene glycol.

[0157] In certain embodiments, the method may further include combining (e.g., adding and mixing) the liposome matrix with the active agent solution to encapsulate the active agent in the liposome. In certain embodiments, the liposome matrix may include any of the above-mentioned vesicle-forming lipids (e.g., but not limited to, lecithin), one or more of the above-mentioned solvents (e.g., but not limited to, glycerin, water, pentylene glycol, or mixtures thereof), optionally a pH adjuster (e.g., but not limited to, sodium hydroxide), and optionally an antioxidant (e.g., but not limited to, tocopherol).

[0158] In certain embodiments, the method further comprises adjusting the pH of the composition by adding a pH adjuster, such as sodium hydroxide.

[0159] In certain embodiments, the disclosure may be directed to methods of preparing pharmaceutical, cosmetic, beauty, nutraceutical, or nutritional compositions. The term "pharmaceutical composition" refers to a composition manufactured for use for medicinal purposes. The term "cosmetic composition" refers to a cosmetic composition scientifically proven to have medical properties. The term "cosmetic composition" refers to a composition that can maintain, protect, cleanse, add fragrance, change the appearance, etc., without penetrating the skin or altering its function. The term "nutraceutical composition" refers to a composition that can be used for medicinal purposes other than nutrition. The term "nutraceutical composition" refers to a supplement intended to complement a subject's diet by providing additional nutrients.

[0160] In certain embodiments, any of these compositions may be prepared by combining the liposomally encapsulated active agent with one or more additional pharma- ceutically acceptable excipients (such as those detailed above or understood by one of skill in the art) suitable to form a particular composition (e.g., a pharmaceutical, cosmetic, beauty, nutraceutical, or nutritional composition).

[0161] In certain embodiments, the present disclosure may be directed to a method of preparing a topical composition by combining a liposomally encapsulated active agent with one or more additional pharma- ceutically acceptable excipients, wherein the active agent is selected from nicotinic acid (NA), nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), nicotinamide adenine dinucleotide + hydrogen (NADH), nicotine adenine dinucleotide phosphate (NADP), nicotinic acid adenine dinucleotide phosphate (NAADP), nicotinamide adenine dinucleotide phosphate (NADPH), nicotinamide adenine dinucleotide (NAD+), or a mixture thereof, preferably, the active agent is NAD+.

[0162] Exemplary topical compositions may be in the form of serums, emulsions, creams, foams, sprays, ointments, gels, lotions, or may be pad or roll-on application formulations. As will be appreciated by those skilled in the art, other suitable forms of topical compositions are also contemplated herein.

[0163] In certain embodiments, the present disclosure may be directed to a method of preparing an oral composition by combining a liposomally encapsulated active agent with one or more additional pharma- ceutically acceptable excipients, wherein the active agent is selected from nicotinic acid (NA), nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), nicotinamide adenine dinucleotide + hydrogen (NADH), nicotine adenine dinucleotide phosphate (NADP), nicotinic acid adenine dinucleotide phosphate (NAADP), nicotinamide adenine dinucleotide phosphate (NADPH), nicotinamide adenine dinucleotide (NAD+), or a mixture thereof, preferably, the active agent is NAD+.

[0164] Exemplary oral compositions may be in the form of a tablet, capsule, caplet, lozenge, troche, chewable tablet, gum, gummy, syrup, liquid solution, suspension, emulsion, buccal film, sublingual film, oral adhesive film, powder, solid crystal, orally disintegrating tablet, paste, oral cream, oral gel, or oral ointment. As will be appreciated by those skilled in the art, other suitable forms of oral compositions are also contemplated herein.

[0165] In certain embodiments, the present disclosure may be directed to a method of preparing a parenteral composition by combining a liposomally encapsulated active agent with one or more additional pharma- ceutically acceptable excipients, wherein the active agent is selected from nicotinic acid (NA), nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), nicotinamide adenine dinucleotide + hydrogen (NADH), nicotine adenine dinucleotide phosphate (NADP), nicotinic acid adenine dinucleotide phosphate (NAADP), nicotinamide adenine dinucleotide phosphate (NADPH), nicotinamide adenine dinucleotide (NAD+), or a mixture thereof, preferably, the active agent is NAD+.

[0166] Various compositions described herein can be formulated to have a customized release profile for an active agent, including, but not limited to, an immediate release profile, a controlled release profile, a delayed release profile, an enteric release profile, a zero order release profile, a first order release profile, a pulsatile release profile, a targeted release at a particular location within the body, such as a targeted location within the gastrointestinal tract.

[0167] Treatment method In certain embodiments, the present disclosure is directed to a method of treating a condition in a subject by administering any of the compositions described herein (including liposome-encapsulated NAD, its precursors, its derivatives, or mixtures thereof, preferably NAD+) to a subject in need thereof. Administration can be oral administration of an oral composition, topical administration of a topical composition, or parenteral administration of an injectable composition.

[0168] In certain embodiments, subjects may be treated for one or more of the following skin conditions: loss of skin firmness, decreased skin thickness, fine lines, wrinkles, loss of elasticity, sagging, dryness, age spots, decreased turnover rate, abnormal desquamation, decreased density and disorganization of the extracellular matrix in the dermis and other histological changes, roughness of the skin, skin smoothness, brightness, radiance, UV damage, free radical damage, radiation damage, pollution damage, damage from environmental toxins or irritants or allergens, skin tone, sunburned appearance, yellowing, reduced visibility of skin pores, pigmentation, scarring, irregularities in the skin surface, rosacea, extrinsic eczema, acne, psoriasis, skin renewal and regeneration process, redness, ichthyosis, lack of tactile smoothness, lack of visual smoothness, lack of softness, lack of brightness, lack of radiance, skin texture, crow's feet wrinkles, nasolabial folds, pigmentation disorders, crepe paper-like skin texture, decreased skin elasticity, and other damaging skin conditions.

[0169] In certain embodiments, a subject may be treated for one or more of fatigue (e.g., chronic fatigue syndrome), neurocognitive disorders, sleep disorders, post-exercise fatigue, headaches, muscle weakness, joint pain, muscle pain, allergies, swollen and tender lymph nodes, depression, and other stress-related conditions or conditions that may benefit from modulation of cellular energy metabolism.

[0170] In certain embodiments, the method may include administering any of the compositions described herein periodically for a period ranging from about 1 week to about 52 weeks, about 2 weeks to about 40 weeks, about 4 weeks to about 20 weeks, about 8 weeks to about 16 weeks, or any single value or subrange therein. In certain embodiments, the method may include administering any of the compositions described herein periodically for a period of at least 1 week, at least 2 weeks, at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks. In certain embodiments, the method may include administering any of the compositions described herein periodically for a period of up to 10 years, up to 8 years, up to 5 years, up to 3 years, up to 2 years, up to 1 year, up to 9 months, up to 6 months, or up to 3 months.

[0171] In certain embodiments, administration may range from once a month to four times a day, once every two weeks to twice a day, or once a week to once a day, or any single value or subrange therein (such as, but not limited to, twice a day, three times a day, once every two days, once every three days, etc.).

[0172] In certain embodiments, regular administration of the compositions described herein may improve the appearance of skin tone, skin elasticity, skin tone ... In one embodiment, the subject exhibits actual or perceived improvement in one or more of the following: tanned appearance, yellowing, reduced appearance of skin pores, pigmentation, scarring, skin surface irregularities, rosacea, extrinsic eczema, acne, psoriasis, skin renewal and regeneration processes, redness, ichthyosis, lack of tactile smoothness, lack of visual smoothness, lack of softness, lack of brightness, lack of radiance, skin texture, crow's feet wrinkles, nasolabial folds, pigmentation abnormalities, crepe paper-like skin texture, reduced skin elasticity, and other damaging skin conditions.

[0173] In certain embodiments, regular administration of the compositions described herein shows actual or perceived improvement in one or more of fatigue (e.g., chronic fatigue syndrome), neurocognitive disorders, sleep disorders, post-exercise fatigue, headaches, muscle weakness, joint pain, muscle pain, allergies, swollen and tender lymph nodes, depression, and other stress-related conditions or conditions that may benefit from modulation of cellular energy metabolism.

[0174] In certain embodiments, administering the topical composition includes applying the topical composition to a patient's skin surface. The terms "application", "applying" and "applying" with respect to the disclosed topical compositions or methods of using the disclosed topical compositions refer to any method of administering the topical composition to a patient's skin in medical or cosmetic practice that delivers the composition to a patient's skin surface. As used herein, smearing, rubbing, spreading, spraying the disclosed topical composition on a patient's skin, with or without the aid of a suitable device, are all included within the scope of the term "application". The terms "topical" or "topically" with respect to administration or application of the disclosed formulations refer to epidermal administration or application, or administration to the skin.

[0175] In certain embodiments, administering the oral composition comprises ingesting the oral composition, inhaling the oral composition, applying the oral composition to the patient's oral cavity, or placing the oral composition in the patient's oral cavity.

[0176] In certain embodiments, administering a parenteral composition to a patient comprises injecting the composition into the patient's muscle (intramuscular administration), into the patient's vein (intravenous administration), or under the patient's skin (subcutaneous administration). EXAMPLES

[0177] The following examples are provided to aid in the understanding of the present invention and, of course, should not be construed as specifically limiting the invention described and claimed herein. Such variations of the present invention, including the substitution of all equivalents now known or later developed that would be within the skill of a person skilled in the art, and changes in formulations or minor changes in experimental design, are to be construed as being included within the scope of the invention incorporated herein.

[0178] Example 1 - Preservative-free, self-preserved liposomal concentrate of NAD+ in glycerin / water A liposomal concentrate of NAD+ in glycerin / water according to an embodiment of the present disclosure was prepared in Batch Preparation 1. Batch Preparation 1 had the concentrations shown in the table below. [Table 1]

[0179] Batch preparation 1 had a fluid appearance and a beige cloudy color. The pH value of Batch Preparation 1 at 25° C. was in the range of 5.5-7 (per SOP method 0009) and the density at 20° C. (per SOP method 0007) was 1.175-1.195 g / cm 3 The refractive index at 20°C (per SOP method 0008) was 1.435-1.455 and the water content (per SOP method 0025) ranged from 21.0-25.0 wt%. When the solubility of the sample from batch preparation 1 was evaluated in 10% water, the solution was cloudy. When the solubility of the sample from batch preparation 1 was evaluated in IPA, it precipitated. The mesophilic aerobic bacteria (per SOP method 0216) of batch preparation 1 was up to 100 cfu / g. The yeast and mold (per SOP method 0217) of batch preparation 1 was up to 50 cfu / g. The e. coli (per SOP method 0254) of batch preparation 1 was negative.

[0180] A 100 kg batch designated "Batch Preparation 1" (containing the composition outlined in the table above as Preparation 2) was prepared according to the process detailed below.

[0181] All ingredients / components were pre-chilled. Then 68.8 kg of 85% glycerin solution was charged to a stirred tank followed by the addition of 5.0 kg of NAD+ followed by mixing for 15 minutes, followed by the addition of 3.0 kg of 10% NaOH solution followed by short mixing, followed by the addition of 3.0 kg of pentylene glycol followed by short mixing, followed by the addition of 20.0 kg of Natipide™ Eco followed by mixing for 15 minutes, followed by the pH adjustment to pH 6.5 with NaOH. Batch preparation 1 was stored at 2-8° C. until the start of the stability study.

[0182] Example 2 - Stability Studies Three batch preparations are prepared as follows. Batch preparation 1 - Liposomes prepared according to Example 1 (glycerin + 5% NAD+ in water) Batch preparation 2 - Mixture of 5% NAD+ in glycerin + water without liposome formation Batch Preparation 3 - 5% NAD+ in water with preservatives (0.15% potassium sorbate and 0.3% sodium benzoate) with pH adjusted to 4.2 with NaOH and without any additional ingredients.

[0183] Samples from each batch preparation are stored at the following temperatures: ○ Refrigerate at 4℃~8℃ ○ Room temperature (RT) of approximately 21°C to 25°C ○Oven temperature: approx. 40℃

[0184] Samples from each batch preparation at each temperature are analyzed after the following storage time points: ○T=0 (before storage begins) T=1 (after 1 month of storage) T=3 (after 3 months of storage) T=6 (after 6 months of storage) ○T=12 (after 12 months of storage)

[0185] The stability studies were conducted without humidity control, and the humidity at various storage conditions ranged from about 30% to about 50%.

[0186] At each time point, samples are analyzed to assess their chemical stability by measuring the NAD+ assay (content) against baseline specifications. Measurement of NAD+ content was performed with a customized HPLC method. At each time point, samples are analyzed to assess their physical stability by evaluating characteristics such as one or more of appearance, color, odor, and pH. [Table 2] [Table 3] [Table 4]

[0187] The physical properties of Batch Preparation 1 at 6° C., RT, and 40° C. were also analyzed at T=0, T=1, T=3, T=6, and T=12. The results are summarized in the table below. [Table 5] [Table 6] [Table 7]

[0188] It was found that Batch 1 had similar data to Batch 2, even though the active had been exposed to additional excipients and possible degradation from the liposomal preparation. Additionally, it was found that for optimal stability, NAD+ should be stored cold, for example, at about 6°C. This is noteworthy because commercially available cosmetic products containing NAD+ are not handled or stored in the cold. Rather, these cosmetic products are stored at room temperature.

[0189] Additional tests were performed to validate the formulation of different concentrations and NAD+ liposome content at various temperatures, which ensured that the final cosmetic product could be stored for longer periods.

[0190] Formulation 1 was prepared with a NAD+ liposome content of 1%. Formulation 2 was prepared with a NAD+ liposome content of 5%. The amount of NAD+ liposome was measured at different time points. The results are presented in the table below. [Table 8]

[0191] From this study it was found that formulations with 1% and 5% had similar results with respect to stability at 6°C and room temperature, both being stable for a minimum of 3 months at 20°C and 6 months at 6°C.

[0192] permeability research A permeability study was conducted to evaluate the permeability of two formulations through human skin by infrared spectroscopy using frozen human skin explants Perfex vivo. Formulation A was prepared using 5% NAD+ in glycerin and water without liposomes, and formulation B was prepared using 5% NAD+ liposome concentrate.

[0193] The study was designed to be carried out in three consecutive stages. In stage 1, a feasibility study was performed. During the feasibility study, the spectral signatures of formulations A and B were determined to ensure that it was possible to detect peaks specific to the molecules analyzed by infrared assay. If the results were negative, the study was terminated. In stage 2, a preliminary test was performed to test the penetration of the formulations through human skin Perfex vivo after 24 hours. If the formulations could not be detected in the skin, the study was terminated. In stage 3, a full penetration test was performed.

[0194] The two formulations tested are presented below. In formulation A, NAD+ is at a 5% concentration. Formulations were stored at 4° C. before, during, and after the study period. [Table 9]

[0195] To prepare Formulation A for testing, it was dissolved at 5% in sterile distilled water. Formulation B was tested in its pure form.

[0196] To prepare Perfex vivo explants, 13 circular skin explants (with type II phenotype, without stretch marks, without hair) with a diameter of 38 mm from a 29-year-old Caucasian female (reference: P2389-AB29) were prepared from an abdominal cavity plasty. The explants were held on a specially designed support composed of a reservoir of culture medium surmounted by a grid on which the skin was stretched. The skin support was connected by a fluidic circuit to a second reservoir of culture medium, which was stored in an incubator at 37 °C (high RH% + 5% CO2). Circulation of the culture medium was ensured by a peristaltic pump.

[0197] Perfex vivo explants were divided into three batches as follows. [Table 10]

[0198] On day 0 (D0), test products P1 and P2 were administered at 9 μL per explant (2 μL / cm 2 ) and spread using a small spatula. Control T did not receive any treatment.

[0199] On D1, three explants forming batch T0 were collected and cut into three parts. One quarter was fixed in a buffered formalin solution, one quarter was frozen at -80°C for histological analysis, and one half was kept at -80°C and sent for Raman spectroscopy analysis. On D1, three explants from the relevant batch were collected and processed in the same way as on D0. On D1, explants from each batch are sampled. Each Perfex vivo explant is frozen at -80°C. Each explant was serially sectioned into six parts. Three parts were stored at -80°C and three parts were frozen at -80°C and cryosectioned, as shown in Figure 1.

[0200] Sections of the explants were prepared for histological processing by making 10 μm thick sections using a Leica RM 2125 Minot type microtome and mounting the sections on CaF2 specific supports for infrared spectroscopy imaging analysis.

[0201] The acquisition parameters were also infrared. To optimize the acquisition parameters, data collection was performed using a Spotlight 400 (Perkin Elmer). Different acquisition parameters were tested and adapted to the studied skin sections. -Spectral range: 750-4000cm -1 -Spectral resolution: 4cm -1 Spectral resolution -Pixel size (spatial resolution): 6.25*6.25μm 2 - Average number of spectra in a hyperspectral image: 15,000 spectra - Average surface of hyperspectral image: 500000μm 2 (0.5mm 2 ) -Average acquisition time per hyperspectral FTIR image: 12 hours

[0202] Six reference spectra were collected for formulations P1 and P2. FTIR signal pretreatment and processing was also performed. Classical data pretreatment (atmospheric correction, signal-to-noise evaluation, smoothing, baseline correction and normalization) was performed. - Atmospheric correction allows the elimination of the contributions of atmospheric H2O and CO2 from each spectrum of the spectral image. -Signal-to-noise evaluation allowed the elimination of collected spectra from outside the skin section -Smoothing was performed using a fourth-order polynomial Savitzky-Golay algorithm with a 12-point window. -Baseline removal: Baseline correction was performed using a polynomial function. -Normalization: All spectra are normalized to 2800-3000 cm -1The normalization was based on the integral AUC of the CH stretch band.

[0203] An in-house data processing procedure was developed for this study using Matlab (Matworks). Both univariate and multivariate data analysis were applied to detect and track "P1" and "P2" in the epidermis. For semi-quantitative evaluation, all data were extracted for the hyperspectral images, values ​​from the regions of interest were averaged, and standard deviations were calculated. In this study, "SD" refers to standard deviation, and "D" and "J" refer to days. Note that "J" stands for "Jours", the French word for days used in the figures.

[0204] Stage 1: Formulations P1 and P2 were analyzed by infrared spectroscopy to determine their molecular signatures and to determine the chemical tracer (peak) used to track penetration across the skin. Figure 2 shows the FTIR spectrum of formulations P1 and P2. In Figure 2, the peak at approximately 1030 cm -1 The band at 2930 cm showed the highest intensity in the active ingredient spectrum and was selected to track the penetration of the product into the skin. Observation of the spectrum in Figure 2 shows that both the active ingredient and the liposomes contribute to the high wavenumber region. Product "P2" has a band at 2930 cm -1 The peak exhibits a spectral band of 100 nm and is therefore potentially associated with liposomes. This peak was also used to follow the penetration of the product into the skin.

[0205] Stages 2 and 3: 1030cm -1 The band analysis was performed. For batches TJ1, P1J1 and P2J1, -1 The FTIR chemical images showing the variation of the AUC of the band at 1030 cm are presented in Figure 3. On day 1, in the control batch, -1 Very little signal was detected in both the stratum corneum and epidermis for the band at approximately 1030 cm. -1 A slight signal of the band of about cm was observed in the stratum corneum and very little in the epidermis. -1A fairly clear signal of the band was observed in the stratum corneum, and a moderate signal was observed in the epidermis.

[0206] 2930cm -1 The bands were also analyzed. The CH2 stretching band (2930 cm -1 ) is regularly used as a lipid descriptor, and the CH3 stretching band (2960 cm -1 ) is used as the protein descriptor. Formulation P2 has a peak at 2930 cm -1 The ratio 2930 / 2960 cm is commonly used to track lipid to protein ratios to indicate the spectral bands at -1 was used in the study to detect the contribution of active ingredients and liposomes in each pixel of the hyperspectral image. -1 Chemical images showing the variation of the ratio of 2930 / 2960 cm are shown in Figure 4. Due to the high lipid content in the stratum corneum, -1 The analysis of the ratio of 2930 / 2960 cm is realized only in the viable epidermis and papillary dermis. -1 The ratio of 2930 / 2960cm was weak in the epidermis and very weak in the papillary dermis. -1 The ratio was weak in the epidermis and very weak in the papillary dermis. On day 1 of batch P2J2, the ratio was 2930 / 2960cm -1 The ratio was moderate in the epidermis and weak in the papillary dermis.

[0207] Classical least squares (CLS) fitting with non-negativity constraints: For the spectral fitting in the third analysis, a classical least squares (NCLS) analysis with non-negativity constraints was realized. It was a spectral unmixing method that aimed to estimate the concentration (or fraction of abundance) of known spectral signatures in terms of the measured linear mixture of these signatures. The originality of this method is to add a positive constraint of concentration to the classical least squares procedure. The details of the calculation are reported in the literature (Tfayli et al., 2009). The NCLS fitting estimates the contribution percentage of the reference spectrum in each spectrum in the hyperspectral image. Given that some spectral features overlap between the skin and the main active ingredients, it is typical to have some pixels with a small percentage contribution in the control sample. For each pixel of the image, the positive fraction of abundance of the reference spectrum was estimated individually using the CLS algorithm. The scores of the contribution of the active ingredient signatures in each batch are shown in Figure 5.

[0208] On day 1, in blank batch TJ1, a very slight contribution of the active ingredient on the blank batch spectrum was observed. In batch P1J1, the NCLS score was moderate. In batch P2J1, the NCLS score was quite clear.

[0209] Analysis of the NCLS score: The analysis of the NCLS score makes it possible to semi-quantify the penetration of the active agent into the skin. It is then possible to determine the percentage of variation in the penetration of the active ingredient between batches P1 and P2.

[0210] The NCLS scores of different batches are shown below. [Table 11]

[0211] The NCLS scores of the different batches are also presented in FIG. 6. For blank batch TJ1, the NCLS score was equal to 0.050607. The effect of product application on the NCLS score was compared with blank batch TJ1. Formulation P1 induced a significant increase of 123%. Formulation P2 induced a significant increase of 191%. When compared with batch P1J1, formulation P2 induced a significant increase of 30%. Thus, formulation P2 induced a significant increase in active ingredient penetration of 30% when compared with formulation P1.

[0212] According to the experimental conditions described above, the penetration of formulation A: NAD+ (reference 740103.00.0) at 5% in sterile distilled water (P1) and NAD+-liposome customized development (P2) was performed at approximately 1030 cm -1 Band, 2930cm -1 The hyperspectral images were analyzed according to the bands of the skin and the NCLS score was evaluated by infrared spectroscopy. -1 The active ingredient could be detected thanks to the band of . Its presence was more pronounced on the skin sections treated with "P2", revealing a better penetration of the product NAD+-Liposome Customized Development (P2) compared to formulation A: NAD+ (reference 740103.00.0) at 5% (P1). By analysis of the NCLS score (percentage contribution of the active ingredient spectrum in each spectrum in the hyperspectral image), it was determined that the product NAD+-Liposome Customized Development (P2) induced a significant increase of 30%** of the active ingredient A: NAD+ (reference 740103.00). These results showed that the liposomes present in product P2 favor the penetration of NAD+ into the skin. It is noted that ** is understood as p<0.01 (99%).

[0213] Cell survival and aging research Studies were conducted to test the efficacy of a liposomal formulation of NAD+ on cell survival, NAD+ intracellular delivery, and cellular senescence in primary human keratinocytes and endothelial cells.

[0214] Materials and Methods: cell culture Primary human aortic endothelial cells (HAEC) and human epidermal keratinocytes (HEKa) were purchased from Lonza (Basel, Switzerland). Adherent cells were grown on fibronectin-coated 75 cm plates in endothelial growth medium (EGM-2, Lonza) or dermal basal cell medium (DCBM, Lonza) for HAEC and HEKa, respectively. 2 Cells were grown to confluence in flasks and the medium was supplemented with 10% fetal bovine serum (FBS).

[0215] Western blot and cell viability assays Cells were detached by using trypsin / EDTA and reseeded in 6-well plates (180,000 / well). Cells were grown to 80% confluence and rested for 24 h in medium containing 0.5% FBS. Cells were then treated with NAD+ 200 μM or NAD+ in liposomal matrix (LIPONAD) at different concentrations (1:1, 1:2, or 1:3) for 24 h. The supernatant was then collected and cells were treated with lysis buffer containing Tris 50 mM, NaCl 150 mM, EDTA 1 mM, NaF 1 mM, DTT 1 mM, aprotinin 10 mg / mL, leupeptin 10 mg / mL, Na3VO4 0.1 mM, phenylmethylsulfonyl fluoride (PMSF) 1 mM, and NP-40 0.5%. Protein concentrations were determined according to the manufacturer's recommendations (Bio-Rad Laboratories AG, Fribourg, Switzerland). Approximately 20–30 μg of total protein lysates were separated on a 10% SDS-PAGE and then transferred to a polyvinylidene difluoride membrane using the wet transfer method (Bio-Rad). Membranes were incubated overnight at 4 °C on a shaker with a primary antibody against SIRT1 (1:1000, Abcam, Cambridge, UK). The following incubation with secondary antibody (anti-mouse 1:2000, Southern Biotechnology, Birmingham, AL, USA) was performed for 1 h at room temperature. Densitometric analysis (Amersham Imager 600, GE Healthcare Europe GmbH, Glattbrugg, Switzerland) was performed and protein expression was normalized to GAPDH. Lactate dehydrogenase (LDH) release was measured by a colorimetric assay (Roce Diagnostics GmBH, Mannheim, Germany). Absorbance was measured using a wavelength of 490 nm (reference >600 nm) in a microplate reader (Tecan, Mannendorf, Switzerland). Absorbance values ​​were normalized to the maximum release obtained by treatment with 1% TritonX-100. Cell survival was defined as (100-% cell death) and normalized to the control.

[0216] Cellular senescence assay Cells were detached by using trypsin / EDTA and reseeded in 2-well slides (100,000 / well). Cells were then treated with NAD+200 μM or NAD+200 μM+LIPONAD 1:3 for 48 h. Senescent cells were revealed by staining for senescence-associated β-galactosidase (SABG) (Merck KGaA, Darmstadt, Germany). The percentage of positively stained cells was counted in four fields of each slide using a microscope and normalized to the control.

[0217] statistical analysis Values ​​are expressed as mean ± SEM. The significance threshold for the type I error probability was set at <0.05. Comparisons between two groups were performed using unpaired t-tests. Comparisons between multiple groups were performed using ANOVA tests with Tukey post-hoc analysis.

[0218] Results: A significant increase in cell survival was observed in HAECs treated with LIPONAD 1:3 compared to control (+19.5%, 95% CI 6.8-32.3%) and NAD+ alone (+4.3%, 95% CI 1.2-7.4%), as shown in Figure 7. Instead, a non-significant increase was observed in HEKa.

[0219] NAD+ intracellular delivery Intracellular delivery of NAD+ was measured by induction of SIRT1 expression. No significant increase in SIRT1 expression was observed between treated and untreated cells in either HAEC or HEKA. Additional studies are underway whereby SIRT1 expression will be assayed by ELISA as opposed to Western blot.

[0220] cellular aging A significant reduction in the number of senescent cells was observed in both HAEC and HEKa treated with LIPONAD 1:3. Notably, compared to controls, the mean reduction in senescent cell numbers was 51.3% (95% CI 3.9-63.9%) for HAEC and 36.6% (95% CI 1.6-66.3%) for HEKA (Figures 2a and 3a). Compared to NAD+ alone, the mean reduction was 28.7% (95% CI 9.4-33.9%) and 15.4% (95% CI 4.9-24.3%) for HAEC and HEKa, respectively. This can be seen in Figures 8 and 9.

[0221] These results indicate that a liposomal formulation of NAD+ (LIPONAD) is superior to NAD+ alone in reducing cellular senescence in cultured human endothelial and epidermal cells, and is also superior to NAD+ alone in increasing cell survival in cultured human endothelial cells.

[0222] Based on the experimental results and from a translational perspective, treatment with NAD+LIPONAD appears to be superior to NAD+ alone in slowing skin aging. In particular, the results on endothelial cells suggest that NAD+LIPONAD improves the function of the dermal microcirculation, which is an important factor in skin tropism and color.

[0223] For ease of explanation, embodiments of the methods of the present disclosure are depicted and described as a series of operations. However, operations according to the present disclosure may occur in various orders and / or simultaneously, as well as with other operations not shown and described herein. Moreover, not all illustrated operations may be required to implement a methodology in accordance with the disclosed subject matter. In addition, those skilled in the art will understand and appreciate that a methodology may alternatively be represented as a series of interrelated states via a state diagram or events.

[0224] In the above description, many specific details are set forth, such as specific materials, dimensions, process parameters, etc., to provide a thorough understanding of the invention. Particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments. The word "example" or "exemplary" is used herein to mean serving as an example, instance, or illustration. Any aspect or design described herein as "example" or "exemplary" should not necessarily be construed as preferred or advantageous over other aspects or designs. Rather, use of the word "example" or "exemplary" is intended to present concepts in a concrete manner. As used in this application, "or" is intended to mean an inclusive "or" rather than an exclusive "or." That is, unless otherwise specified or clear from the context, "X includes A or B" is intended to mean all natural inclusive permutations. That is, if X includes A, if X includes B, or if X includes both A and B, then "X includes A or B" is satisfied under any of the above illustrative examples. References throughout this specification to "an embodiment," "a particular embodiment," or "one embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment. Thus, the appearances of the phrases "an embodiment," "a particular embodiment," or "one embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment.

[0225] The invention has been described with reference to specific exemplary embodiments thereof. The specification and drawings are accordingly to be regarded in an illustrative rather than a restrictive sense. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

Claims

1. 1. A composition comprising: Liposomes, an active agent encapsulated in said liposome, The composition, wherein the active agent comprises nicotinamide adenine dinucleotide (NAD+), a precursor thereof, a derivative thereof, or a combination thereof.

2. 3. The composition of claim 2, wherein the active agent is selected from nicotinic acid (NA), nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), nicotinamide adenine dinucleotide plus hydrogen (NADH), nicotinamide adenine dinucleotide phosphate (NADP), nicotinic acid adenine dinucleotide phosphate (NAADP), nicotinamide adenine dinucleotide phosphate (NADPH), nicotinamide adenine dinucleotide (NAD+), or a mixture thereof.

3. The composition of claim 3 , wherein the active agent comprises NAD+.

4. 4. The composition of any one of claims 1 to 3, wherein greater than 0% up to about 20%, about 0.5% to about 15%, or about 1% to about 10% by weight of NAD or a derivative thereof is encapsulated in the liposome, based on the total weight of the composition.

5. The composition of any one of claims 1 to 4, wherein the liposome comprises a vesicle-forming lipid.

6. 6. The composition of claim 5, wherein the vesicle-forming lipid is selected from phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidic acid (PA), phosphatidylinositol (PI), sphingomyelin (SM), polyvinylpyrrolidone, polyvinylmethylether, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyloxazoline, polyhydroxypropylmethacrylamide, polymethacrylamide, polydimethylacrylamide, polyhydroxypropylmethacrylate, polyhydroxyethylacrylate, hydroxymethylcellulose, hydroxyethylcellulose, polyethyleneglycol, polyaspartamide, lecithin, dipalmitoyllecithin, distearoylphosphatidylcholine, or mixtures thereof.

7. The composition of claim 6 , wherein the vesicle-forming lipid comprises lecithin.

8. 8. The composition of any one of claims 1 to 7, comprising vesicle-forming lipids in an amount of from greater than 0% up to about 20% by weight, from about 0.5% to about 15% by weight, or from about 1% to about 10% by weight, based on the total weight of the composition.

9. The composition of any one of claims 1 to 8, further comprising a solvent.

10. The composition of claim 9, wherein the solvent is selected from an alcohol, water, or a mixture thereof.

11. 11. The composition of claim 10, wherein the solvent comprises an alcohol selected from ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl, monobutyl ether, propylene glycol monomethyl, propylene glycol monoethyl ether, propylene glycol monobutyl ether, diethylene glycol monomethyl, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, butylene glycol, pentylene glycol, sorbitol, or mixtures thereof.

12. 12. The composition of any one of claims 9 to 11, wherein the solvent is present in an amount ranging from 50 wt% to about 99 wt%, from about 70 wt% to about 97 wt%, or from about 85 wt% to about 95 wt%, based on the total weight of the composition.

13. The composition of claim 11 , wherein the solvent comprises water, glycerol, and pentylene glycol.

14. The composition of claim 1, which results in a reduction of cellular senescence in human endothelial cells.

15. The composition of claim 1 , which results in a reduction of cellular senescence of human epidermal cells.

16. 15. The composition of claim 14, which results in a reduction of senescent cells by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45% or at least 50%.

17. The composition of claim 16 , wherein the cells are human aortic endothelial cells.

18. 16. The composition of claim 15, which results in a reduction of senescent cells by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35%.

19. The composition of claim 17 , wherein the cells are human epidermal keratinocytes.

20. The composition of claim 1 , which increases cell survival of cultured human endothelial cells.

21. 10. The composition of claim 1, wherein about 30% more of the active agent penetrates the skin when compared to NAD+ without the liposome.

22. The composition of claim 1 , wherein the composition increases penetration of the active agent into the skin.

23. 1. A method for formulating nicotinamide adenine dinucleotide (NAD+), its precursors, its derivatives, or mixtures thereof, comprising encapsulating the NAD+, its precursors, its derivatives, or the mixtures thereof in a liposome.

24. 24. The method of claim 23, wherein after storage at a temperature of about 2° C. to about 8° C. for about 1 month, about 3 months, about 6 months, or about 12 months, greater than about 90%, greater than about 92%, greater than about 94%, greater than about 96%, greater than about 98%, greater than about 99%, or about 100% by weight of the NAD+, the precursor thereof, the derivative thereof, or the mixture thereof is maintained compared to the weight of the NAD+, the precursor thereof, the derivative thereof, or the mixture thereof in the composition before storage (t=0).

25. 24. The method of claim 23, wherein after storage at a temperature of about 20° C. to about 30° C. for about 1 month, about 3 months, about 6 months, or about 12 months, greater than about 90%, greater than about 92%, greater than about 94%, greater than about 96%, greater than about 98%, greater than about 99%, or about 100% by weight of the NAD+, the precursor thereof, the derivative thereof, or the mixture thereof is maintained compared to the weight of the NAD+, the precursor thereof, the derivative thereof, or the mixture thereof in the composition before storage (t=0).

26. 24. The method of claim 23, wherein after storage at a temperature of about 35° C. to about 45° C. for about 1 month, about 3 months, about 6 months, or about 12 months, greater than about 90%, greater than about 92%, greater than about 94%, greater than about 96%, greater than about 98%, greater than about 99%, or about 100% by weight of the NAD+, the precursor thereof, the derivative thereof, or the mixture thereof is maintained compared to the weight of the NAD+, the precursor thereof, the derivative thereof, or the mixture thereof in the composition before storage (t=0).

27. A method for preparing a composition according to any one of claims 1 to 22, comprising the steps of: forming a solution comprising an active agent and a solvent; combining the solution with vesicle-forming lipids; The method, wherein the active agent comprises nicotinamide adenine dinucleotide (NAD+), a precursor thereof, a derivative thereof, or a combination thereof.

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