Compositions, systems, and methods for increasing nitric oxide in a subject

Abstract

A transdermal / topical emulsion forming composition comprising an organic acid, preferably citric acid; at least one agent, wherein the agent comprises arginine, citrulline, citrulline malate, beetroot, or any combination thereof; water; at least one fatty acid source comprising oleic acid and / or linoleic acid; at least one non-ionic emulsifier comprising a cis unsaturated fatty acid, preferably polysorbate 80; a pH in the range of 2.0 to 5.5; wherein when applied to the skin of the subject the composition is capable of increasing systemic nitric oxide level in the subject.

Description

Attorney Docket No. LAB.003 4.W0.01COMPOSITIONS, SYSTEMS, AND METHODS FOR INCREASING NITRIC OXIDE IN A SUBJECTCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application Serial No. 63 / 719.784, filed on November 13, 2024, U.S. Provisional Application Serial No. 63 / 721,029, filed November 15, 2024, U.S. Provisional Application Serial No. 63 / 858,283 filed August 5, 2025, U.S. Provisional Application Serial No. 63 / 905,201, filed October 24, 2025, and U.S. Provisional Application Serial No. 63 / 905,370, filed October 24, 2025. Each of the aforementioned applications is incorporated herein by reference in its entirety.FIELD OF THE INVENTION

[0002] The present disclosure relates generally to emulsions for topical administration for improving mammalian health, for example by increasing systemic levels of nitric oxide in mammalian subjects, and uses thereof.BACKGROUND

[0003] Nitric oxide acts as an important chemical, affecting many body systems. At levels found in the body, nitric oxide acts as a chemical messenger, impacting the immune, circulatory, nervous, respiratory, digestive, and renal systems, for example. Increasing nitric oxide is reported to provide wide-ranging benefits such as improved heart health, reduced blood pressure, and treating erectile dysfunction, among others.

[0004] The body derives nitric oxide from food sources, such as dark leafy greens, beets, or carrots. Alternatively, supplements such as citrulline and arginine provide precursors for the body to make nitric oxide. Supplements are problematic, as they require the physical ability to swallow sometimes very large pills or capsules. Also, oral supplements provide only a short-lived increase in nitric oxide levels, with levels dropping after 2-6 hours. Oral supplements require repeated dosing to maintain elevated nitric oxide levels in the body over 24 hours. There is a need for a delivery platform for nitric oxide supplements that provides for easier patient compliance and provides for maintained increased levels of nitric oxide in the body.

[0005] Weight loss, for example, from treatment with a weight loss therapeutic, or from a caloric restrictive diet, a nutritional deficient intake protocol diet (fad diet), a medically or medicinally influenced or activated malnutritional condition, or a dietary intake condition often result in muscle mass loss, which can often be disproportionate to overall body weight loss. For example, muscle mass loss is an issue forAttorney Docket No. LAB.0Q3_4.WO.01 GLP-1 agonist therapeutics, which have become exceptionally popular. There is a need for treatments that can aid in reducing muscle mass loss for subjects who are experiencing weight loss.SUMMARY

[0006] Provided herein are transde mial compositions in the form of an emulsion, comprising:at least one weak organic acid comprising citric acid present in total in an amount from 0.2% to 45.0% w / w of the emulsion;at least one agent, wherein the at least one agent in total is present in a weight ratio from 0.1 : 1.0 to 3.0: 1.0 relative to the at least one weak organic acid in total;water, present in a weight ratio from 0.5: 1 to 45: 1 relative to the at least one weak organic acid in total;at least one fatty acid source comprising at least one cis unsaturated fatty acid selected from oleic acid and linoleic acid, wherein the at least one fatty acid source in total is present in a weight ratio from 0.2: 1.0 to 4.0: 1.0 relative to the at least one weak organic acid in total; andat least one non-ionic emulsifier comprising one or more cis unsaturated fatty acids, wherein the at least one non-ionic emulsifier in total is present in a weight ratio from 1.0: 1.0 to 5.0: 1.0 relative to tire at least one weak organic acid in total.wherein the transdermal composition has a pH in the range of 2.0 to 5.5,wherein total fatty acids, and / or CIO or longer non -fatty acid hydrocarbons if present in the emulsion, comprise less than or equal to a total of 15.0% w / w of saturated fatty acids and / or saturated CIO or longer non-fatty acid hydrocarbons,wherein the non-ionic emulsifier comprises polysorbate 80,wherein the agent comprises arginine, citrulline, citrulline malate, beetroot, or any combination thereof, andwherein the transdermal composition is capable of delivering the at least one agent to the blood stream of a subject when applied to the skin of the subject and increasing systemic nitric oxide level in the subject.

[0007] Further provided herein are emulsions for topical administration comprising: an aqueous phase comprising: citric acid, or a salt thereof, in an amount that is about 15% to about 35% w / w of the emulsion; water in an amount that is about 1 % to about 35% w / w of the emulsion; and glacial acetic acid, or a salt or ion thereof, in an amount that is about 0% to about 2% w / w of the emulsion; an agent that is about 15% to about 25% w / w of the emulsion, wherein the agent comprises ascorbic acid or it’s derivative and arginine, citrulline, citrulline malate, beetroot, creatine, glutamine, leucine, norvaline, ornithine, histidine, beta-alanine, phenylalanine, agmatine, betaine, L-theanine, glutathione, or any nitrateAttorney Docket No. LAB.003 4.W0.01 or any nitrite, any nitro, or any nitroso or salt thereof, or any combination thereof; and an oil phase comprising: an oil or one or more oils in a total amount that is about 3% to about 15% w / w of the emulsion, in some embodiments, wherein the oil or one or more oils in total comprises less than 15% saturated fatty acids; an unsaturated fatty acid or one or more unsaturated fatty acids in a total amount that is about 1% to about 20% w / w of the emulsion; glycerin in an amount that is about 0.0% to about 7% w / w of the emulsion; and polysorbate 80 that is about 5% to about 50% w / w of the emulsion, in some embodiments, wherein the emulsion comprises from about 55% to about 75% w / w of the aqueous phase and about 25% to about 45% w / w of the oil phase. In some embodiments, the combination of the oil or one or more oils, and the one or more unsaturated fatty acids in total comprise less than 15%, 12%, or 10% saturated fatty acids with respect to the combined weight of the combination. In some embodiments, the topical administration of the composition to the skin of a subject provides for a relative increase in a systemic nitric oxide level in the subject as compared to a systemic nitric oxide level measured prior to administration of the composition, and wherein the nitric oxide level is imputed from a measure of salivary’ nitrite.

[0008] Further provided herein are emulsions, wherein the oil comprises one or more fish oil, safflower oil, high-oleic oil, grapeseed oil, rapeseed oil, flaxseed oil, hemp oil, walnut oil. poppyseed oil, com oil, soybean oil, cottonseed oil, peanut oil, hemp oil, wheatgerm oil, rice bran oil, pistachio oil, canola oil, egg yolk, linseed oil, sunflower oil, avocado oil, sesame oil, olive oil, canola oil, or any combination thereof. Further provided herein are emulsions, wherein the oil comprises safflower oil. Further provided herein are emulsions, wherein the combination of the weight of one or more oils and one or more unsaturated fatty acids in total comprises less than 15%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, or 2% saturated fatty acid. Further provided herein are emulsions, wherein the unsaturated fatty acid comprises palmitoleic acid, oleic acid, myristoleic acid, linoleic acid, arachidonic acid, or any combination thereof. Further provided herein are emulsions, wherein the unsaturated fatty acid comprises oleic acid. Further provided herein are emulsions, wherein the agent comprises ascorbic acid and citrulline in about a 1 : 1 ratio. Further provided herein are emulsions, wherein the agent comprises ascorbic acid, citrulline, and arginine in about a 1 : 1 : 1-0.25 ratio.

[0009] Provided herein are emulsions comprising: an aqueous phase wherein each 100 g emulsion comprises: 23-27 g citric acid; 23-27 g water; 0.2-0.3 g glacial acetic acid: 6-7 g citrulline; and 6- 7 g ascorbic acid; and an oil phase, wherein each 100 g emulsion comprises: 6-7 g safflower oil; 2.5-3.5 g oleic acid; 0.5-1.5 g glycerin; and 23-27 g polysorbate 80, wherein the emulsion comprises about 60-70% of tire aqueous phase and about 30-40% of the oil phase, wherein topical administration of the composition to the skin of a subject provides for a relative increase in a systemic nitric oxide level in the subject as compared to a systemic nitric oxide level measured prior to administration of the composition.Attorney Docket No. LAB.003 4.W0.01 and wherein tire nitric oxide level is imputed from a measure of salivary nitric oxide.

[0010] Provided herein are emulsions for topical administration comprising: an aqueous phase, wherein each 100 g emulsion comprises: 23-27 g citric acid: 23-27 g water; 0.2-0.3 g glacial acetic acid: 3.5-4.5 g citrulline; 3. -4. g arginine: and 3.5-4.5 g ascorbic acid; and an oil phase, wherein each 100 g emulsion comprises: 6-7 g safflower oil; 2.5-3.5 g oleic acid; 0.5-1.5 g glycerin; and 23-27 g polysorbate 80, wherein the emulsion comprises about 60-70% of the aqueous phase and about 30-40% of the oil phase, wherein topical administration of the composition to the skin of a subject provides for a relative increase in a systemic nitric oxide level in the subject as compared to a systemic nitric oxide level measured prior to administration of the composition, and wherein the nitric oxide level is imputed from a measure of salivary nitrite.

[0011] Provided herein are methods of generating an emulsion for topical administration, comprising: generating an aqueous composition, wherein the aqueous composition comprises: about 30% to about 60% w / w citric acid; about 30% to about 60% w / w water; and about 0% to about 2% w / w glacial acetic acid; stirring the aqueous composition at from about 500 to about 2500 RPM for about 2 to about 15 minutes at 30 to 45 degrees C; further adding to the aqueous composition: about 5% to about 40% w / w of an agent comprising arginine, citrulline, citrulline malate, beetroot, creatine, glutamine, leucine, norvaline, ornithine, histidine, beta-alanine, phenylalanine, agmatine, betaine, L-theanine, glutathione, or any nitrate or any nitrite, any nitro, or any nitroso or salt thereof, or any combination thereof; and about 5% to about 15% w / w ascorbic acid; stirring the aqueous composition at from about 500 to about 2500 RPM for about 2 to about 15 minutes at 30 to 45 degrees C; generating an oil -based composition comprising: about 0% to about 50% w / w of a total of one or more oils comprising less than 20%, 17%, 15%, 12%, 10%, or 5% saturated fatty acids; about 10% to about 50% w / w of a total of an unsaturated fatty acid, and / or more than one unsaturated fatty acids; about 0% to about 10% w / w glycerin; and about 30% to about 90% w / w polysorbate 80; stirring the oil-based composition at about 500 RPM for 2 to about 15 minutes at 20 to 30 degrees C; adding the oil-based composition to the aqueous composition over at least 30 seconds and concurrently stirring the aqueous composition at about 500 and rapidly increasing to about 2500 RPM and 30 to 45 degrees C, thereby forming an emulsion, wherein the emulsion comprises from about 40% to about 70% w / w of the aqueous composition and about 30% to about 60% w / w of the oil-based composition: further stirring the emulsion for a combined total of about 2 to about 30 minutes in steps (g) and (h); stirring the emulsion at about 2000 to about 3500 RPM for 2 to about 15 minutes at 30 to 45 degrees C, wherein topical administration of the composition to the skin of a subject provides for a relative increase in a systemic nitric oxide level in the subject as compared to a systemic nitric oxide level measured prior to administration of the composition, and wherein the nitric oxide level is imputed from a measure of salivary nitric oxide. Further provided herein are methods.Attorney Docket No. LAB.0Q3_4.WO.01 wherein the oil comprises fish oil, safflower oil, high-oleic oil, grapeseed oil, rapeseed oil, flaxseed oil, hemp oil, walnut oil, poppyseed oil, com oil, soybean oil, cottonseed oil, peanut oil. hemp oil. wheatgenn oil, rice bran oil, pistachio oil, canola oil, egg yolk, linseed oil, sunflower oil, avocado oil, sesame oil, olive oil, canola oil, or any combination thereof. Further provided herein are methods, wherein the oil comprises safflower oil. Further provided herein are methods, wherein the oil or one or more oils in combination with the unsaturated fatty acid or more than one unsaturated fatty acids in total comprises less than 20%, 15%. 12%. 10%. 8%, 7%, 6%, 5%, or 2% saturated fatty acid. Further provided herein are methods, wherein the unsaturated fatty acid comprises palmitoleic acid, oleic acid, myristoleic acid, linoleic acid, arachidonic acid, or any combination thereof. Further provided herein are methods, wherein the unsaturated fatty acid comprises oleic acid. Further provided herein are methods, wherein the agent comprises citrulline or citrulline maleate, and wherein the citrulline and ascorbic acid are added in a 1: 1 ratio. Further provided herein are methods, wherein the agent comprises citrulline and arginine, and wherein the citrulline, arginine, and ascorbic acid are added in a 1: 1: 1 ratio.

[0012] Provided herein are methods of generating an emulsion for topical administration, comprising: generating an aqueous composition, wherein each 100 g aqueous composition comprises: 45-55 g citric acid; 45-55 g water: and 0.0-1 g glacial acetic acid; stirring the aqueous composition at about 1000 RPM for about 5 minutes at about 38 degrees C: further adding to each 100 g of aqueous composition: 8-12 g citrulline; 8-12 g ascorbic acid stirring the aqueous composition at about 1000 RPM for about 5 minutes at about 38 degrees C; generating an oil -based composition, wherein each 100g oil-based composition comprises: 16-20 g safflower oil; 7-9 g oleic acid; 2-4 g glycerin; and 70-74 g polysorbate 80; stirring the oil-based composition at about 1000 RPM for about 5 minutes at about 25 degrees C; adding the oilbased composition to the aqueous composition over at least 30 seconds, concurrently stirring the aqueous composition at about 1000 RPM, increasing to 2500 RPM and about 38 degrees C, thereby generating an emulsion, wherein the emulsion comprises from about 40% to about 70% w / w of the aqueous composition and about 30% to about 60% w / w of the oil-based composition; further stirring the emulsion for a combined total of about 5 minutes in steps (g) and (h); stirring the emulsion at about 2500 RPM for about 5-30 minutes at about 38 degrees C, wherein topical administration of the composition to the skin of a subject provides for a relative increase in a systemic nitric oxide level in tire subject as compared to a systemic nitric oxide level measured prior to administration of tire composition, and wherein the nitric oxide level is imputed from a measure of salivary nitric oxide. Further provided herein are methods, wherein step (c) comprises adding to each 100 g of the aqueous composition: 5-8 g citrulline; 3-8 g arginine; 5-8 g ascorbic acid.

[0013] Provided herein are methods of treating a condition comprising low nitric oxide in a subject, the method comprising a topical administration of any of the emulsions provided herein, wherein topicalAttorney Docket No. LAB.0Q3_4.WO.01 administration of the composition to the skin of a subject provides for a relative increase in a systemic nitric oxide level in the subject as compared to a systemic nitric oxide level measured prior to administration of the composition. In some embodiments the nitric oxide level is imputed from a measure of salivary nitric oxide. In some embodiments of such methods, the increase in systemic nitric oxide level is maintained for at least 24 hours. Further provided herein are methods, wherein the increase in systemic nitric oxide level is maintained for at least 12 hours. Further provided herein are methods, wherein the increase in systemic nitric oxide level is maintained for at least 6 hours. Further provided herein are methods, wherein the topical administration comprises application of about 0.5 g to about 10 g of the emulsion to a skin of the subject. Further provided herein are methods, wherein the topical administration comprises application of about 2 g of the emulsion to a skin of the subject.

[0014] Provided herein are methods of preventing or reducing muscle mass loss that is correlated to treatment with a GLP-1 agonist comprising topical administration of a composition comprising: an aqueous phase comprising: citric acid, or a salt thereof, in an amount that is about 15% to about 35% w / w of tire emulsion; water in an amount that is about 15% to about 35% w / w of the emulsion; and glacial acetic acid, or a salt or ion thereof, in an amount that is about 0% to about 2% w / w of the emulsion; an agent that is about 15% to about 25% w / w of the emulsion, wherein the agent comprises ascorbic acid or it’s derivative and arginine, citrulline, citrulline malate, beetroot, creatine, glutamine, leucine, norvaline, ornithine, histidine, beta-alanine, phenylalanine, agmatine, betaine, L-theanine, glutathione, or any nitrate or any nitrite, any nitro, or any nitroso or salt thereof, or any combination thereof; and an oil phase comprising: an oil in amount that is about 3% to about 15% w / w of the emulsion, wherein the oil comprises less than 15% saturated fatty acids; an unsaturated fatty acid in an amount that is about 1% to about 20% w / w of tire emulsion; glycerin in an amount that is about 0.0% to about 7% w / w of the emulsion; and polysorbate 80 that is about 5% to about 50% w / w of tire emulsion, wherein aqueous phase and the oil phase are combined in an emulsion comprising from about 55% to about 75% w / w of the aqueous phase and about 25% to about 45% w / w of the oil phase, wherein topical administration of the composition to the skin of a subject provides for a relative increase in a systemic nitric oxide level in the subject as compared to a systemic nitric oxide level measured prior to administration of the composition, and wherein tire nitric oxide level is imputed from a measure of salivary nitric oxide. Further provided herein are methods, wherein the oil comprises fish oil, safflower oil, high-oleic oil, grapeseed oil, rapeseed oil, flaxseed oil, hemp oil, walnut oil, poppyseed oil, com oil, soybean oil, cottonseed oil, peanut oil, hemp oil, wheatgerm oil, rice bran oil, pistachio oil, canola oil, egg yolk, linseed oil, sunflower oil, avocado oil, sesame oil, olive oil, canola oil, or any combination thereof. Further provided herein are methods, wherein the oil comprises safflower oil. Further provided herein are methods, wherein the oil comprises less than 2% saturated fatty acid. Further provided herein are methods, wherein the unsaturatedAttorney Docket No. LAB.003 4.W0.01 fatty acid comprises palmitoleic acid, oleic acid, myristoleic acid, linoleic acid, arachidonic acid, or any combination thereof. Further provided herein are methods, wherein the unsaturated fatty’ acid comprises oleic acid. Further provided herein are methods, wherein the agent comprises ascorbic acid and citrulline in about a 1 : 1 ratio. Further provided herein are methods, wherein the agent comprises ascorbic acid, citrulline, and arginine in about a 1 : 1 : 1-0.25 ratio. Further provided herein are methods, wherein the emulsion further comprises an additional compound Further provided herein are methods, wherein tire additional compound comprises a nutritional supplement, a systemic medication, a targeted therapy, or any combination thereof. Further provided herein are methods, wherein the condition comprises muscle mass loss, muscle fatigue, nausea, high blood pressure, reduced blood flow, reduced blood oxygen, or any combination thereof. Further provided herein are methods, wherein the condition is a side effect of a treatment with a GLP-1 agonist. Further provided herein are methods, wherein the GLP-1 agonist comprises dulaglutide, exenatide, semaglutide, liraglutide, lixisenatide, or any combination thereof.

[0015] Further details regarding aspects and embodiments of the present disclosure are provided throughout this patent application. Sections and section headers are for ease of reading and are not intended to limit combinations of disclosure, such as methods, compositions, and formulations or functional elements therein across sections. Further details regarding aspects and embodiments of the present disclosure are provided throughout this patent application. Sections and section headers are for ease of reading and are not intended to limit combinations of disclosure, such as methods, compositions, or other functional elements therein across sections.BRIEF DESCRIPTION OF THE DRAWING

[0016] A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which tire principles of the invention are utilized, and the accompanying drawings of which:

[0017] FIGS. 1A-1F provides bar graphs depicting various data. FIG. 1A is a bar chart showing subject scores at baseline and after tests 1, 2, and 3 in the Trails A test for Attention. FIG. IB is a bar chart showing subject scores at baseline and after tests 1, 2, and 3 in the Trails B test for Mental Flexibility. FIG. 1C is a bar chart showing subject scores at baseline and after tests 1, 2, and 3 in the Digital Symbol Substitution test for Executive Function. FIG. ID is a bar chart showing subject scores at baseline and after tests 1, 2, and 3 in the Stroop test for Executive Function. FIG. IE is a bar chart showing subject scores at baseline and after tests 1, 2, and 3 in the Immediate Recognition test for Memory'. FIG. IF is a bar chart showing subject scores at baseline and after tests 1, 2, and 3 in tire Delayed Recognition test for Memory.

[0018] FIGS 2A-2N illustrate relative amounts of sub-2 micron diameter particles in emulsionAttorney Docket No. LAB.0Q3_4.WO.01 formulations as measured by percent intensity: FIG. 2A and FIG. 2B show size distribution of Batch 1, sample A, diluted to 1:200 and 1:400, respectively. FIG. 2C and FIG. 2D show size distribution of Batch 1, sample B, diluted to 1:200 and 1:400, respectively. FIG. 2E and FIG. 2F show size distribution of Batch 2, sample A, diluted to 1 :200 and 1 :400, respectively. FIG. 2G and FIG. 2H show size distribution of Batch 2, sample B, diluted to 1:200 and 1:400, respectively. FIG. 21 and FIG. 2J show size distribution of Batch 3, sample A, diluted to 1:200 and 1:400, respectively . FIG. 2K and FIG. 2L show size distribution of Batch 3, sample B. diluted to 1:200 and 1:400. respectively. FIG. 2M and FIG. 2N show size distribution ofBatch 1, sample A, diluted in tap orHPLC water to 1:200 and 1:400, respectively.

[0019] FIG. 3 is a line graph showing blood pressure, heart rate, blood oxygen, and nitric oxide levels measured at time points to 360 minutes after topical application of an emulsion comprising nitric oxide precursors and caffeine.

[0020] FIG. 4 is a table showing nitric oxide test strips used at timepoints after application of an emulsion as described herein, indicating increased nitric oxide levels 12-14 hours after topical application of an emulsion comprising nitric oxide precursors.Definitions

[0021] The terminology used herein is for the purpose of describing particular cases only and is not intended to be limiting. As used herein, the singular forms “a”, “an” and “the” can include the plural forms as well, unless the context clearly indicates otherwise. Furthermore, to the extent that the terms “contains,” “containing,” “including”, “includes,” “having,” “has”, “with”, or variants thereof are used in either the detailed description and / or the claims, such terms are intended to be inclusive in a manner similar to the term “comprising.”

[0022] The term “about” or “approximately” can mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. Where particular values are described in the application and claims, unless otherwise stated the tenn “about”should be assumed to mean an acceptable error range for the particular value, such as ±10% of the value modified by the term “about”.

[0023] The term “systemic delivery,” as used herein, refers to delivery of a substance into the circulatory system.

[0024] As used herein, the terms “transdermal delivery” and “transdermal administration” refer to delivery of an agent through the skin so it enters the bloodstream and acts systemically.

[0025] As used herein, the terms “lipophilic” and “hydrophobic” are used interchangeably to refer to agents that preferentially partition into nonpolar or lipid phases.Attorney Docket No. LAB.003 4.W0.01

[0026] As used herein, the term “unsaturated fatty acid” refers to a fatty acid comprising one or more C=C double bonds. C=C double bonds can adopt either a “cis” or a “trans” configuration and thereby yield either a “cis unsaturated fatty acid” or a “trans unsaturated fatty acid.”

[0027] As used herein, the term “cis unsaturated fatty acid” refers to a fatty acid comprising one or more C C double bonds in a “cis” configuration, wherein two hydrogen atoms adjacent to the double bond stick out on the same side of the C=C chain. Hie rigidity of a double bond freezes its conformation and. in the case of the cis isomer, causes the chain to bend and restricts the confonnational freedom of the fatty acid. The more double bonds the chain has in the cis configuration, the less flexibility it has. When a chain has many cis bonds, it becomes quite curved in its most accessible conformations.

[0028] As used herein, the term “trans unsaturated fatty acid” refers to a fatty acid comprising one or more C=C double bonds in a “trans” configuration, wherein two hydrogen atoms adjacent to the double bond lie on opposite sides of the chain. As a result, they do not cause the chain to bend much, and their shape is similar to straight saturated fatty acids. In most naturally occurring unsaturated fatty acids, each double bond has three (n-3), six (n-6), or nine (n-9) carbon atoms after it, and all double bonds have a cis configuration.

[0029] As used herein, “room temperature” is understood to be about 25 degrees C.

[0030] As used herein, “nitric oxide” encompasses the compound scientifically represented by NO, as well as any nitrate, nitrite, nitro, nitroso from which NO can be derived, or any salt thereof. It will be further understood that where features or aspects of the disclosure are described in temis of Markush groups, the disclosure is also intended to be described in terms of any individual member or subgroup of members of the Markush group. Similarly, all ranges disclosed herein also encompass all possible sub-ranges and combinations of sub-ranges and that language such as “between,” “up to,” “at least,” “greater than,” “less than,” and tire like include the number recited in the range and includes each individual member. “As used herein, the terms “lipophilic” and “hydrophobic” are used interchangeably to refer to agents that preferentially partition into nonpolar or lipid phases.

[0031] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The singular temis “a,” “an,” and “the” include plural referents unless the context clearly indicates otherwise.“Comprising A or B” means including A, or B, or A and B. It is further to be understood that all base sizes or amino acid sizes, and all molecular weight or molecular mass values, given for nucleic acids or polypeptides are approximate, and are provided for description. As used herein, “about” or “consisting essentially of’ mean ± 10% of the indicated range, value, or structure, unless otherwise indicated.

[0032] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. AllAttorney Docket No. LAB.003 4.W0.01publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entireties. In case of conflict, the present specification, including explanations of terms, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. It will be understood that if an amino acid is recited without a D or L chirality indicated, it is L chirality.DETAILED DESCRIPTION

[0033] Nitric oxide (NO) affects blood vessel dilation, stimulation of hormone release, and signaling and regulation of neurotransmission. Nitric oxide supplementation improves cardiac health, improves physical performance and exercise recovery, reduces blood pressure, and improves healing. NO is synthesized from dietary sources, such as dark leafy greens, beets, and carrots. NO is also synthesized directly from amino acids such as arginine and citrulline, as an arginine precursor. Provided herein are compositions, methods of use thereof, and methods of manufacture thereof, that provide for delivery7of supplements to produce a sustained increase in systemic nitric oxide level.Increasing Systemic Nitric Oxide

[0034] Compositions and emulsions provided herein provide for topical application of compounds to increase nitric oxide production systemically. Compositions comprise supplements, typically referred to as agents, that, applied topically, provide delivery of the supplements (agents), for example arginine or citrulline, to the circulatory system where they are processed to nitric oxide. It is further noted that ascorbic acid, delivered in combination with amino acids, accelerates nitric oxide production in the body.

[0035] Accordingly, compositions and emulsions provided herein typically include one or more NO- increasing agents, as shown in non-limiting examples in Table 1 below.

[0036] TABLE 1: Exemplary NO-increasing agents also referred to herein as NO -accelerating agentsAttorney Docket No. LAB.003 4.W0.01

[0037] Illustrative systems, compositions, formulations, and / or emulsions herein, or methods that include such systems, compositions, formulations and / or emulsions, typically include 1, 2, 3 or more direct NO precursors and / or plant-based nitrate sources. In illustrative embodiments, they include 1, 2, 3 or more direct NO precursors. In illustrative embodiments, they include arginine and / or citrulline, which can be in the form of citrulline malate.

[0038] Where a plant-based nitrate source is included in a system, composition, formulation, and / orAttorney Docket No. LAB.0Q3_4.WO.01 emulsion herein, or method that includes such system, composition, formulation and / or emulsion in some embodiments, the plant-based nitrate source can be beet or beetroot or a plant having at least 500, 750, or 1,000 mg / kg dry weight of nitrates. In some embodiments, the plant-based nitrate source in a dose of an emulsion herein provides at least 100, 200, 250, 300, 400, or 500 mg of nitrates.

[0039] In some embodiments of any system, composition, formulation, and / or emulsion herein, or method that includes such system, composition, formulation and / or emulsion, the agent can include, and in illustrative embodiments further includes in addition to one or more direct NO precursors; 1, 2. 3 or more other nitric oxide pathway nitrogenous agents, 1, 2, 3 or more nitric oxide supporting agents, 1, 2, 3 or more nitric oxide adjuncts, or a combination thereof. Exemplary other nitric oxide pathway nitrogenous agents, nitric oxide supporting agents, and nitric oxide adjunct are provided in Table 1. In one embodiment, in addition to one or more direct NO precursors, the agents further include creatine, glutamine, norvaline, ornithine, histidine, beta-alanine, agmatine, betaine, L-theanine, glutathione, or any nitrate, or any combination thereof

[0040] Methods are known fortesting nitric oxide levels. Such methods can be used to confirm systemic nitric oxide production. Such testing is a step in some non-limiting embodiments provided herein.

[0041] Nitric oxide (NO) levels can be tested using a blood, saliva, or breath test. Due to the instability of NO, blood or plasma testing is not a reliable measurement. A breath test measures NO in exhaled breath. Elevated levels indicate possible airway inflammation or lung swelling. Saliva test strips quantify the amount of NO present in saliva, which corresponds to overall bioavailable nitric oxide in the body. In some embodiments of methods described herein, a nitric oxide level is measured using a blood or plasma test, a breath test, or a saliva test. Typically, a fasting baseline would return a saliva test of about 0 pmol / 1. Consumption of arginine or a spinach salad produces NO elevation to about 400 to 800 pmol / l for about 2 hours. Consumption of a beet salad produces NO elevation to about 400 to 800 pmol / l for about 2 hours.

[0042] In some embodiments described herein, topical application of an emulsion described herein produces elevated NO levels for 6 to 36, or in illustrative embodiments from about 6 or 6. to about 24 or 24 hours. In some embodiments described herein, topical application of an emulsion described herein produces elevated NO levels for at least 2, at least 4, at least 6, at least 8, at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, at least 22, at least 24 hours. In some embodiments described herein, topical application of an emulsion described herein produces elevated NO levels for more than 4, more than 6, more than 8, more than 10, more than 12, more than 14, more than 16, more than 18, more than 20, more than 22, more than 24 hours.Topical Formulations

[0043] Provided herein are compositions, formulations, emulsions and multi-component systems for topical application that provide for systemic delivery of one or more agents and / or additional compounds.Attorney Docket No. LAB.003 4.W0.01Such compositions, formulations, emulsions, and multi-component systems in some aspects and embodiments can be referred to herein as transdennal compositions, fonnulations, emulsions and multicomponent systems, molecular administration compositions, formulations, emulsions and multicomponent systems, skin-penetrating compositions, formulations, emulsions and multi-component systems, skin absorptive compositions, formulations, emulsions and multi-component systems, skin permeable compositions, formulations, emulsions and multi-component systems, dermal transport compositions, formulations, emulsions and multi-component systems, bioavailable topical compositions, formulations, emulsions and multi-component systems, skin administration compositions, formulations, emulsions and multi-component systems, molecular administration biomaterial compositions, formulations, emulsions and multi-component systems, appendageal molecular transport medium and systems, topical and topical delivery compositions, formulations, emulsions and multi-component systems, and appendageal molecular transport pathway compositions, formulations, emulsions, emulsions and multi-component systems. In some embodiments, a formulation described herein comprises an aqueous phase and an oil phase. In some embodiments, the aqueous phase and the oil phase are combined with sufficient energy to fonn a stable emulsion. In some embodiments, the emulsion comprises an oil-in-water emulsion. In some embodiments, the emulsion comprises a water-in-oil emulsion. In some embodiments, an emulsion described herein comprises from about 40% w / w to about 90% w / w aqueous phase. In some embodiments, an emulsion described herein comprises from about 50% w / w to about 80% w / w aqueous phase. In some embodiments, an emulsion described herein comprises from about 60% w / w to about 70% w / w aqueous phase. In some embodiments, an emulsion described herein comprises about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w, about 60% w / w, about 65% w / w, about 70% w / w, about 75% w / w, about 80% w / w, about 85% w / w, about 90% w / w, about 95% w / w aqueous phase. Components of, and additional percentages for aqueous phases are provided herein for various aspects and embodiments.

[0044] An aqueous phase of an emulsion described herein comprises, in some embodiments, water, an acid, and an agent that provides for increasing nitric oxide in a subject. In some embodiments, the water is deionized, distilled, alkaline, reverse osmosis-treated, tap water, ultra-filtered, purified, boiled, UV-light treated, chlorinated or any combination thereof. In some embodiments, the aqueous phase of an emulsion described herein comprises from about 30% w / w to about 60% w / w of water. In some embodiments, the aqueous phase of an emulsion described herein comprises from about 35% w / w to about 50% w / w of water. In some embodiments, the aqueous phase of an emulsion described herein comprises from about 35% w / w to about 40% w / w of water. In some embodiments, the aqueous phase of an emulsion described herein comprises from about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w, about 60% w / w of water. In some embodiments, anAttorney Docket No. LAB.003 4.W0.01 emulsion described herein comprises from about 15% w / w to about 35% w / w of water. In some embodiments, an emulsion described herein comprises from about 20% to about 30% w / w of water. In some embodiments, an emulsion described herein comprises about 15% w / w, about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w of water. Additional percentages for water and ratios with other components, for example the weak organic acid (e.g., citric acid) are provided herein for various aspects and embodiments.

[0045] Emulsions described herein comprise an acidic pH. An acidic composition provides for improved transport across the dermal barrier, or stratum comeum. In some embodiments, the emulsion comprises a weak organic acid. It is observed that weak organic acids, particularly, those having a pKa at or below the pH of the skin, i.e. below about 4.2, greatly enhance skin permeability and delivery of drugs, nutrients, and other compounds through the skin and into the bloodstream. As used herein, the tenn ‘weak organic acid7’ refers to a compound that partially dissociates when dissolved in a solvent. Exemplary weak organic acids with a pKa less than or equal to 4.2 are provided in Table 2.Table 2: Median Acidic Dissociation Constants (pKa) of Weak Organic Acids"Atorney Docket No. LAB.003 4.W0.01"><Attorney Docket No. LAB.0Q3_4.WO.01

[0046] In some embodiments, an emulsion described herein comprises one or more weak organic acids. In some embodiments, the one or more weak organic acids comprise lactic acid, acetic acid, formic acid, citric acid, oxalic acid, gallic acid, malic acid, maleic acid, malonic acid, succinic acid, tartaric acid, fumaric acid, or any combination thereof. In some embodiments, an emulsion described herein comprises citric acid. In some embodiments, an emulsion described herein comprises citric acid and acetic acid. In some embodiments, the aqueous phase of an emulsion described herein comprises from about 20% w / w to about 60% w / w of one or more weak organic acids. In some embodiments, the aqueous phase of an emulsion described herein comprises from about 30% w / w to about 50% w / w of one or more weak organic acids. In some embodiments, the aqueous phase of an emulsion described herein comprises from about 40% w / w to about 45% w / w of one or more weak organic acids. In some embodiments, the aqueous phase of an emulsion described herein comprises about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w, or about 60% w / w of one or more weak organic acids. In some embodiments, an emulsion described herein comprises from about 10% w / w to about 40% w / w of one or more weak organic acids. In some embodiments, an emulsion described herein comprises from about 15% w / w to about 35% w / w of one or more weak organic acids. In some embodiments, an emulsion described herein comprises from about 20% w / w to about 30% w / w of one or more weak organic acids. In some embodiments, an emulsion described herein comprises about 10% w / w. about 15% w / w, about 20% w / w. about 25% w / w, about 30% w / w. about 35% w / w, about 40% w / w of one or more weak organic acids. Additional percentages for weak organic acids, and ratios to other components in the aqueous phase or in a formulation, composition, or emulsion, and ratios with other components, are provided herein for various aspects and embodiments.

[0047] An emulsion as described herein further comprises an agent that provides for increased nitricAttorney Docket No. LAB.003 4.W0.01oxide in a subject (i.e., an NO-increasing agent). In some embodiments, the agent comprises at least one compound that is processed in the body to generate nitric oxide. In some embodiments, the agent comprises arginine, citrulline, citrulline malate, beetroot, creatine, glutamine, norvaline, ornithine, histidine, beta-alanine, agmatine, betaine, L-theanine, glutathione, or any nitrate or any nitrite, any nitro, or any nitroso or salt thereof, or any combination thereof. In illustrative embodiments, the agent comprises arginine, citrulline, citrulline malate, or a combination thereof. Ascorbic acid accelerates nitric oxide production in the body. In some embodiments, an emulsion described herein further comprises ascorbic acid. In some embodiments, an emulsion described herein comprises citrulline and ascorbic acid. In some embodiments, an emulsion described herein comprises citrulline malate and ascorbic acid. In some embodiments, an emulsion described herein comprises citrulline, arginine, and ascorbic acid. In some embodiments, an emulsion described herein comprises citrulline malate, arginine, and ascorbic acid. In some embodiments, an emulsion described herein comprises citrulline, citrulline malate, arginine, and ascorbic acid. In some embodiments, the ratio of ascorbic acid to the one or more compound(s) (agents) that is processed to generate nitric oxide is about 1:0.2, about 1:0.3. about 1:0.4, about 1:0.5, about 1:0.6, about 1:0.7, about 1:0.8. about 1:0.9, about 1:1, about 1:1.2, about 1:1.3, about 1:1.5, about 1:1.6, about 1:1.7, about 1:1.8. about 1:1.9, about 1:2, about 1:2.2. about 1:2.4, about 1:2.6, about 1:2.8. about 1:3. In some embodiments, the aqueous phase of an emulsion described herein comprises from about 5% w / w to about 30% w / w of the agent. In some embodiments, the aqueous phase of an emulsion described herein comprises from about 10% w / w to about 30% w / w of the agent. In some embodiments, the aqueous phase of an emulsion described herein comprises from about 15% w / w to about 25% w / w of the agent. In some embodiments, the aqueous phase of an emulsion comprises from about 15% w / w to about 20% w / w of the agent. In some embodiments, the aqueous phase of an emulsion described herein comprises, about 5% w / w, about 10% w / w, about 15% w / w, about 20% w / w, about 25% w / w, about 30% w / w of the agent. In some embodiments, an emulsion described herein comprises from about 5% w / w to about 35% w / w of the agent. In some embodiments, an emulsion described herein comprises from about 10% w / w to about 30% w / w of the agent. In some embodiments, an emulsion described herein comprises from about 10% w / w to about 20% w / w of the agent. In some embodiments, an emulsion described herein comprises about 5% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, about 15% w / w, about 20% w / w, about 25% w / w. about 30% w / w of the agent. In some embodiments, the agent is calculated to be from about 1% w / w to about 60% w / w of the water in the emulsion. In some embodiments, the agent is calculated to be from about 10% w / w to about 60% w / w of the water in the emulsion. In some embodiments, the agent is calculated to be from about 20% w / w to about 60% w / w of the water in the emulsion. In some embodiments, the agent is calculated to be from about 30% w / w to about 60% w / w of the water in the emulsion. In some embodiments, the agent is calculated to be fromAttorney Docket No. LAB.003 4.W0.01about 40% w / w to about 60% w / w of the water in the emulsion. In some embodiments, the agent is calculated to be about 40% w / w, about 45% w / w about 50% w / w, about 55% w / w, about 60% w / w of the water in the emulsion. Additional examples and details re: NO-increasing agents, and percentages for NO-increasing agents in various compositions, formulations, and emulsions, and ratio with other components, for example the weak organic acid (e.g., citric acid), are provided herein for various aspects and embodiments.

[0048] An oil phase of an emulsion described herein comprises, in some embodiments, an oil. one or more fatty acids, at least one non-ionic surfactant, and optionally a scaffold compound. In some embodiments, an oil comprises an oil with a greater fraction of unsaturated fatty acids compared to saturated fatty acids. In some embodiments, an oil comprises a plant oil, a fish oil, a nut oil, a seed oil, or any combination thereof. In some embodiments, an oil comprises squalene, squalane, safflower oil, high-oleic oil, grapeseed oil, rapeseed oil, flaxseed oil, hemp oil, walnut oil, poppyseed oil, com oil, soybean oil, cottonseed oil, peanut oil, hemp oil, wheatgerm oil, rice bran oil, pistachio oil, canola oil, egg yolk, linseed oil, sunflower oil, avocado oil, sesame oil, olive oil, canola oil, or any combination thereof. In some embodiments, the oil phase of an emulsion described herein comprises from about 0% w / w to about 50% w / w of the oil. In some embodiments, the oil phase of an emulsion described herein comprises from about 5% w / w to about 40% w / w of the oil. In some embodiments, the oil phase of an emulsion described herein comprises from about 10% w / w to about 30% w / w of the oil. In some embodiments, the oil phase of an emulsion described herein comprises from about 15% w / w to about 20% w / w of the oil. In some embodiments, the oil phase of an emulsion described herein comprises about 3% w / w, about 5% w / w. about 10% w / w, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, about 25% w / w, about 30% w / w of the oil. In some embodiments, an emulsion described herein comprises from about 3% to about 15% of the oil. In some embodiments, an emulsion described herein comprises from about 5% w / w to about 10% w / w of the oil. In some embodiments, an emulsion described herein comprises about 3% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 15% of the oil. Components of, and additional percentages of the oil phase are provided herein for various aspects and embodiments.

[0049] In some embodiments of any of the aspects and embodiments provided herein is a composition (e.g., a formulation) comprising at least one fatty acid source, and methods for making and using the same. The fatty acid source(s) typically comprises at least one unsaturated fatty acid, in illustrative embodiments, at least one cis-unsaturated fatty acid. In some embodiments, the unsaturated fatty acids include one or more oleic acid, linoleic acid, linolenic acid, ricinoleic acid, and erucic acid. In illustrative embodiments, the unsaturated fatty acids include oleic acid, and / or linoleic acid.

[0050] In some embodiments, the fatty acid source(s) can include a naturally occurring source such as oneAttorney Docket No. LAB.0Q3_4.WO.01 or more oils which in illustrative embodiments include at least one cis-unsaturated fatty acid, and typically include at least one cis-unsaturated fatty acid if no other source of cis-unsaturated fatty acids is present in the composition. In some embodiments, the oil(s) include one or more vegetable oils, fish oils, and / or animal oils. In illustrative embodiments, the oil(s) include one or more vegetable oils, in some embodiments, the vegetable oils can include one or more safflower oil, macademia oil, maracuja oil, grapeseed oil, rapeseed oil, flaxseed oil, hemp oil, walnut oil, poppyseed oil, com oil, soybean oil, cottonseed oil, peanut oil, wheatgerm oil, rice bran oil, pistachio oil, canola oil, linseed oil, sunflower oil, avocado oil, sesame oil, olive oil, canola oil, jojoba oil, and tea tree oil. In illustrative embodiments, the vegetable oil include one or more safflower oil, olive oil, jojoba oil, and tree tea oil.

[0051] In some embodiments, tire fatty acid source(s) can include one or more purified fatty acid, such as a purified unsaturated fatty acid, in illustrative embodiments, a purified cis-unsaturated fatty acid. In some embodiments, the purified unsaturated fatty acid includes one or more oleic acid, linoleic acid, linolenic acid, ricinoleic acid, and erucic acid.

[0052] In some embodiments, tire at least one fatty acid source in total is present in a weight ratio of at least 0.1: 1.0, 0.2: 1.0, or 0.3: 1.0 relative to the at least one weak organic acid in total in a composition, for example an emulsion, herein. In some embodiments, the at least one fatty acid source in total is present in a weight ratio from 0.2: 1.0 to 4.0: 1.0 or 0.2: 1 to 1.0: 1.0 or 0.2: 1.0 to 0.5: 1.0 relative to the at least one weak organic acid in total. In some embodiments, the at least one fatty acid source in total is present in an amount of at least 0.1%, 0.5%, 1%, 3%, or 5%. In some embodiments, the at least one fatty acid source in total is present in an amount from 5 to 30% of the emulsion.

[0053] In some embodiments, the fatty acid source(s) include one or more oils herein. In some embodiments, the fatty acid source(s) include one or more purified, highly enriched, or isolated cis-unsaturated fatty acids herein. In some embodiments, the fatty acid source(s) include one or more oils, and one or more purified cis-unsaturated fatty acids. In illustrative embodiments, the fatty acid source(s) include safflower oil, and purified, highly enriched or isolated oleic acid.

[0054] Further to the above discussion, in some embodiments, an emulsion described herein comprises one or more cis-unsaturated fatty acids. In some embodiments, an emulsion described herein comprises one or more unsaturated fatty acids comprising adrenic acid, arachidonic acid, cervonic acid, vaccenic acid, dihomo-y- linolenic acid, docosadienoic acid, eicosadienoic acid, eicosapentaenoic acid, eicosatetraenoic acid, erucic acid, gadoleic acid, gondoic acid, herring acid, linoleic acid, margoleic acid, mead acid, myristoleic acid, ncrvonic acid, oleic acid, ozubondo acid, palmitoleic acid, paullinic acid, petroselenic acid, pinolenic acid, sapienic acid, sardine acid, stearidonic acid, tetracosapentaenoic acid, a-linolenic acid, y-linolenic acid, or any combination thereof. Structures and sources of cis unsaturated fatty acids described herein are described in Table 3. In some embodiments, an emulsionAttorney Docket No. LAB.003 4.W0.01described herein comprises oleic acid. In some embodiments, the oil phase of an emulsion described herein comprises from about 5% w / w to about 65% w / w of one or more unsaturated fatty acids. In some embodiments, the oil phase of an emulsion described herein comprises from about 10% w / w to about 60% w / w of one or more unsaturated fatty acids. In some embodiments, the oil phase of an emulsion described herein comprises from about 15% w / w to about 30% w / w of one or more unsaturated fatty acids. In some embodiments, the oil phase of an emulsion described herein comprises from about 15% w / w to about 20% w / w of one or more unsaturated fatty acids. In some embodiments, the oil phase of an emulsion described herein comprises about 5% w / w, about 10% w / w, about 15% w / w, about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w of one or more unsaturated fatty acids. In some embodiments, an emulsion described herein comprises from about 1% w / w to about 20% w / w of one or more unsaturated fatty acids. In some embodiments, an emulsion described herein comprises from about 2% w / w to about 10% w / w of one or more unsaturated fatty acids. In some embodiments, an emulsion described herein comprises from about 2% w / w to about 5% w / w of one or more unsaturated fatty acids. In some embodiments, an emulsion described herein comprises about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 10% w / w, about 15% w / w, about 20% w / w of one or more unsaturated fatty acids. Additional examples and details re: fatty acids and sources thereof, and percentages for fatty acids and sources thereof, in various compositions, formulations, and emulsions, and ratio with other components, for example the w eak organic acid (e.g., citric acid), are provided herein for various aspects and embodiments.Table 3: Structural and Physical Properties of Unsaturated Long-chain Fatty AcidsAtorney Docket No. LAB.003 4.W0.01"< <Atorney Docket No. LAB.003 4.W0.01>Atorney Docket No. LAB.003 4.W0.01&Attorney Docket No. LAB.003 4.W0.01

[0055] A surfactant is a molecule that typically comprises a hydrophilic head and a hydrophobic tail. Tire surfactant decreases surface tension between two liquids, stabilizing the emulsion, droplets in a continuous phase. In some embodiments, the emulsion comprises one or more surfactants. Non-ionic surfactants, emulsifiers, and detergents are typically amphiphilic compounds having both a polar, hydrophilic, and water-soluble portion and a non-polar, hydrophobic, and lipophilic portion. In some embodiments, an emulsion described herein comprises one or more non-ionic surfactants, emulsifiers, and detergents. In some embodiments, an emulsion described herein comprises lecithin, carboxylmethylcellulose, sorbitan esters, and polysorbates, including polyoxyethylene (20) sorbitan monolaurate (polysorbate 20, Tween® 20), polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40, Tween® 40), polyoxyethylene (20) sorbitan monostcaratc (polysorbate 60, Tween® 60), polyoxyethylene (20) sorbitan monooleate (polysorbate 80, Tween® 80), or any combination thereof. In some embodiments, the oil phase of an emulsion described herein comprises from about 30% w / w to about 90% w / w of a surfactant. In some embodiments, the oil phase of an emulsion described herein comprises from about 40% w / w to about 80% w / w of a surfactant. In some embodiments, the oil phase of an emulsion described herein comprises from about 50% w / w to about 75% w / w of a surfactant. In some embodiments, the oil phase of an emulsion described herein comprises from about 60% w / w to about 75% w / w of a surfactant. In some embodiments, the oil phase of an emulsion described herein comprises from about 70% w / w to about 75% w / w of a surfactant. In some embodiments, the oil phase of an emulsion described herein comprises about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w. about 55% w / w, about 60% w / w. about 65% w / w, about 70% w / w. about 75% w / w, about 80% w / w, about 85% w / w, about 90% w / w of a surfactant. In some embodiments, an emulsion described herein comprises from about 5% w / w to about 50% w / w of a surfactant. In some embodiments,Attorney Docket No. LAB.003 4.W0.01 an emulsion described herein comprises from about 10% w / w to about 40% w / w of a surfactant. In some embodiments, an emulsion described herein comprises from about 20% w / w to about 30 % w / w of a surfactant. In some embodiments, an emulsion described herein comprises from about 25% w / w to about 30% w / w of a surfactant. In some embodiments, an emulsion described herein comprises about 5% w / w, about 10% w / w, about 15% w / w, about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w of a surfactant.

[0056] In some embodiments of any of the aspects and embodiments provided herein is a composition (e.g., a formulation or an emulsion) comprising one or more non -ionic emulsifiers, and methods for making and using such compositions. Tire non-ionic emulsifier(s) typically comprises or is derived from one or more cis-unsaturated fatty acids, which in some embodiments are oleic acid, linoleic acid, linolenic acid, ricinoleic acid, and / or erucic acid. In certain illustrative embodiments the one or more non-ionic emulsifiers in compositions herein include one or more oleic acid and / or linoleic acid residues.

[0057] In illustrative embodiments, the non-ionic emulsifier(s) herein are cis-unsaturated fatty acidcontaining emulsifier(s). In some embodiments, the non-ionic emulsifier(s) herein include at least one hydrophilic region / domain (e.g., a polyoxyethylene chain) and at least one lipophilic region / domain (e.g., an oleoyl chain). In some embodiments, an emulsifier herein has predominantly lipophilic character (low HLB) and in other embodiments predominantly hydrophilic character (high HLB). As a non-limiting example, one known method to categorize emulsifiers based on their lipophilic or hydrophilic characteristic is hydrophilic-lipophilic balance (HLB). A lower HLB indicates greater hydrophobic / lipophilic character, and a higher HLB indicates greater hydrophilicity. In some embodiments, more than one emulsifier is used, and in certain embodiments, at least one emulsifier is hydrophilic and at least one emulsifier is lipophilic. The ratio indicates whether the combination of the more than one emulsifier is overall hydrophilic or lipophilic.

[0058] In some embodiments the cis-unsaturated fatty acid-containing emulsifier(s) included in compositions that are used in methods herein have reduced hydrophilic character (i.e.. low HLB). In some embodiments, the cis-unsaturated fatty acid-containing emulsifier(s) included in compositions herein include a hydrophilic region that is diminished as compared to the lipophilic region or domain, such that the emulsifier has an overall more hydrophobic character. Thus, in some embodiments, the cis-unsaturated fatty acid-containing emulsifier(s) herein are more lipophilic and thus have a lower HLB, for example, less than or equal to 6, making them suitable for water-in-oil emulsions. In some embodiments, the emulsifier is a hydrophobic emulsifier such that the HLB of the cis-unsaturated fatty acid-containing emulsifier(s) herein is in tire range of 0-3 (very hydrophobic) in illustrative embodiments in tire range of 3-6 (moderately hydrophobic)-, and in some embodiments in the range of 1-6, 1-5, 1-4, 2-4, 1-3, 2-6, 2-5, or 3-5. A non-limiting example of such an emulsifier is sorbitan monooleate (Span 80) (HLB ~4.3).Attorney Docket No. LAB.0Q3_4.WO.01

[0059] Such lipophilic emulsifier(s) in certain illustrative embodiments are used in compositions that include an agent, in some examples a therapeutic agent, that is lipophilic. Methods are known to measure and identify the lipophilic characteristic of an agent (e.g., small molecule therapeutic), such as LogP and LogD. Such lipophilic agent can have, for example, a LogP value of 1-2 (moderately lipophilic), 2-4 (lipophilic), or greater than 4 (very lipophilic), greater than 1.0, greater than 1.5, greater than 2.0, or greater than 3.0. In some embodiments, an emulsifier used in a fonnulation herein is lipophilic and an agent included in the formulation is lipophilic. Not to be limited by theory, such lipophilic emulsifier and lipophilic agent pairing may aid partitioning of the lipophilic agent into the lipid phase of droplets or particles formed in the emulsion. Non-limiting examples of the agents that are lipophilic can include corticosteroids, NSAIDs (e.g., ibuprofen, naproxen, diclofenac, Indomethacin, or celecoxib), in illustrative embodiments where the pH of the composition is 2.0 to 4.5, lipophilic amino acids, fat soluble vitamins, and antifungals (e.g., azole antifungals). Lipophilic (hydrophobic) amino acids contain nonpolar hydrocarbon or aromatic side chains that repel water and associate with lipid phases. Non-limiting examples can include alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, and tr ptophan.

[0060] In certain illustrative embodiments, the cis-unsaturated fatty acid-containing emulsifier included in compositions that are used in methods herein includes one or more hydrophilic domains (e.g., a polyoxyethylene chain) and are hydrophilic. In some embodiments, the cis-unsaturated fatty acidcontaining emulsifier(s) included in compositions herein include diminished lipophilic domains as compared to hydrophilic domains. In some embodiments, the cis-unsaturated fatty acid-containing emulsifier(s) herein has a higher HLB, for example, at least 7, at least 8, at least 9, or at least 10, making it suitable for oil-in-water emulsions. In some embodiments, the HLB of the cis-unsaturated fatty acidcontaining emulsifier(s) herein is in the range of 7-9 (borderline / wetting), 10-15 (hydrophilic), 15-18 (very hydrophilic), 10-18, 10-17, 10-16, or 10-20. In certain illustrative embodiments, the emulsifier has an HLB between 10 and 18. A non-limiting example of such an emulsifier is polysorbate 80 (Tween 80) (HLB 15.0).

[0061] Such hydrophilic emulsifier(s) with an HLB at 10 or higher, for example, in certain illustrative embodiments are used in compositions that include an agent, in some examples a therapeutic agent, that is hydrophilic. Such illustrative embodiments can further include a hydrophilic agent, for example with a LogP less than 0 (e.g., LogD at the formulation pH less than or equal to 0). Not to be limited by theory, such hydrophilic emulsifier to hydrophilic agent pairing may favor localization of the hydrophilic agent in the aqueous continuous phase or at the droplet interface. Non-limiting examples of the agents that are hydrophilic include hydrophilic amino acids, antiseptics, antiviral agents, antibiotics, antifungals, peptides, growth factors, and electrolytes. Non -limiting examples of hydrophilic amino acids includeAttorney Docket No. LAB.003 4.W0.01 those with polar or charged side chains that readily interact with water through hydrogen bonding or ionic interactions, for example serine, threonine, asparagine, glutamine, cysteine, and tyrosine, which are polar but uncharged, as well as lysine, arginine, histidine, aspartic acid, and glutamic acid, which are ionizable and carry positive or negative charges at physiological pH.

[0062] In some non-limiting embodiments, the non-ionic emulsifier can be or include one or more of an ethoxylated derivative, a sugar-based derivative, a glycerol ester, a polyglycerol ester, a propylene glycol ester, and a polyethylene glycol (PEG) ester. In some embodiments, the non-ionic emulsifier can be one or more ethoxylated derivatives, for example, ethoxylated fatty acid ester, ethoxylated fatty alcohol, ethoxylated sorbitan ester, ethoxlated glyceride, ethoxylated fatty acid amide. In some embodiments, the non-ionic emulsifier can be one or more ethoxylated fatty acid esters, for example, PEG- 10 Oleate, PEG-20 Oleate. PEG-20 Linoleate, PEG-10 Ricinoleate. In some embodiments, the non-ionic emulsifier can be one or more ethoxylated fatty alcohols, for example, Oleth-5, Oleth-lO, Oleth-20. In some embodiments, the non-ionic emulsifier can be one or more ethoxylated sorbitan esters (polysorbates), for example, polysorbate 80 (Tween 80), polysorbate 81, and polysorbate 85. In some embodiments, the non-ionic emulsifier is other than polysorbate 80 and / or other than sorbitan monooleate (Span80). In some embodiments, the non-ionic emulsifier can be one or more ethoxylated glycerides, for example. PEG-35 Castor Oil, PEG-40 Hydrogenated Castor Oil, and PEG-40 Ricinoleate. In some embodiments, the non-ionic emulsifier can be one or more ethoxylated fatty acid amides, for example, PEG-3 Oleamide, and PEG-5 Oleamide.

[0063] In some embodiments, the non-ionic emulsifier can be one or more sugar-based emulsifiers, for example, a sorbitan ester, a polysorbate, a sucrose ester, an alkyl polyglucoside, a sugar alcohol ester. In some embodiments, the non-ionic emulsifier can be one or more sorbitan esters, for example, sorbitan monooleate (Span 80), sorbitan trioleate (Span 85), and sorbitan linoleate. In some embodiments, the non-ionic emulsifier can be one or more polysorbates, for example, polysorbate 80 (Tween 80), polysorbate 81, and polysorbate 85. In some embodiments, the non-ionic emulsifier can be one or more sucrose esters, for example, sucrose oleate, and sucrose linoleate. In some embodiments, the non-ionic emulsifier can be one or more alkyl polyglucosides, for example, oleyl glucoside. In some embodiments, the non-ionic emulsifier can be one or more sugar alcohol esters, for example, sorbitol oleate, and mannitol oleate.

[0064] In some embodiments, the non-ionic emulsifier can be one or more glycerol esters, for example, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, glyceryl linoleate, glyceryl linolenate, or glyceryl erucate.

[0065] In some embodiments, tire non-ionic emulsifier can be one or more polyglycerol esters, for example, polyglyceryl-4 oleate, polyglyceryl-6 oleate, polyglyceryl- 10 oleate, polyglyceryl -4 linoleate, polyglyceryl-6 linoleate, polyglyceryl-3 ricinoleate (PGPR), polyglyceryl-6 dioleate, or polyglycery l- 10Attorney Docket No. LAB.003 4.W0.01 linoleate.

[0066] In some embodiments, the non-ionic emulsifier can be one or more propylene glycol esters, for example, propylene glycol dioleate (PGDO), propylene glycol monooleate (PGMO), propylene glycol linoleate (PG Linoleate), propylene glycol ricinoleate (PG Ricinoleate), or propylene glycol rrucate (PG Erucate).

[0067] In some embodiments, the non-ionic emulsifier can be one or more PEG esters, for example, PEG-10 oleate, PEG-20 oleate, PEG-30 oleate, PEG-12 linoleate. PEG-20 linoleate, PEG-10 ricinoleate, or PEG-20 erucate. Additional examples and details regarding non-ionic emulsifiers, and percentages for non-ionic emulsifiers in various compositions, formulations, and emulsions, and their ratio with other components, for example the weak organic acid (e.g., citric acid), are provided herein for various aspects and embodiments.

[0068] A “scaffold” compound, for the purposes of this disclosure, provides stability to a liposurfactant composition. In some embodiments, a scaffold compound generates crosslinkages in the composition. In some embodiments, an emulsion described herein comprises a scaffold compound. In some embodiments, a scaffold compound comprises glycerin or glycerol, linear pectin, amylopectin, amylose, fiber link poly carbohydrate, a polypropylene glycol, com syrup, a sugar or any combination thereof. In some embodiments, the oil phase of an emulsion described herein comprises from about 0% w / w to about 10% w / w of a scaffold compound. In some embodiments, the oil phase of an emulsion described herein comprises from about 2% w / w to about 5% w / w of a scaffold compound. In some embodiments, the oil phase of an emulsion described herein comprises about 0% w / w, about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about % w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w of a scaffold compound. In some embodiments, an emulsion described herein comprises from about 0% w / w to about 10% w / w of a scaffold compound. In some embodiments, an emulsion described herein comprises from about 1% w / w to about 5% w / w of a scaffold compound. In some embodiments, an emulsion described herein comprises about 0% w / w, about 1% w / w. about 2% w / w, about 3% w / w, about 4% w / w, about 5 % w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w of a scaffold compound.Lipophilic Agents

[0069] The following include non-limiting lipophilic agents, some of which are lipophilic therapeutic agents that can be used in compositions provided herein. In illustrative embodiments, such embodiments include a non-ionic lipophilic emulsifier, for example having an HLB in the range of 3 to 6. In some embodiments, the pH of the composition is 2.0-5.5. In some embodiments, the lipophilic therapeutic agent is a corticosteroid selected from the group consisting of dexamethasone, betamethasone, triamcinolone acetonide, budesonide, fluticasone propionate, fluticasone furoate, mometasone furoate,Attorney Docket No. LAB.003 4.W0.01 beclomethasone dipropionate, clobetasol propionate, hydrocortisone butyrate, prednicarbate, and desoximetasone. In some embodiments, the lipophilic therapeutic agent is a steroidal hormone or analogue selected from the group consisting of progesterone, medroxyprogesterone acetate, norethindrone, levonorgestrel, estradiol, ethinyl estradiol, testosterone, dihydrotestosterone, and exemestane. In some embodiments, the lipophilic therapeutic agent is a fat-soluble vitamin or analogue selected from the group consisting of retinol, retinal, retinyl palmitate, retinyl acetate, cholecalciferol (vitamin D3), ergocalciferol (vitamin D2), alpha-tocopherol (vitamin E), tocopheryl acetate, phylloquinone (vitamin KI), menaquinone-7 (vitamin K2), and coenzyme Q10 (ubiquinone). In some embodiments, the lipophilic therapeutic agent is a cannabinoid selected from the group consisting of delta-9-tetrahydrocannabinol (THC), dronabinol, cannabidiol (CBD), and cannabinol (CBN). In some embodiments, the lipophilic therapeutic agent is an immunosuppressant selected from the group consisting of cyclosporine A, tacrolimus, sirolimus (rapamycin), everolimus, and pimecrolimus. In some embodiments, the lipophilic therapeutic agent is an antibacterial selected from the group consisting of rifampin, rifabutin, rifapentine, and clofazimine. In some embodiments, tire lipophilic therapeutic agent is an anthelmintic or antiparasitic selected from tire group consisting of ivermectin, moxidectin, abamectin, and eprinomectin. In some embodiments, the lipophilic therapeutic agent is a calcium channel blocker selected from the group consisting of nifedipine, felodipine, lercanidipine, nimodipine, and nicardipine. In some embodiments, the lipophilic therapeutic agent is an antiandrogen or 5 -alpha-reductase inhibitor selected from the group consisting of bicalutamide, enzalutamide, apalutamide, finasteride, dutasteride, and abiraterone acetate. In some embodiments, the lipophilic therapeutic agent is a phosphodiesterase-5 inhibitor selected from the group consisting oftadalafiL In some embodiments, the lipophilic therapeutic agent is an anesthetic or sedative selected from the group consisting of propofol. In some embodiments, the lipophilic therapeutic agent is an antifungal selected from the group consisting of griseofulvin. In some embodiments, the lipophilic therapeutic agent is a statin in lactone prodrug fonn selected from the group consisting of simvastatin and lovastatin. In some embodiments, the lipophilic therapeutic agent is a dermatologic retinoid analogue or prodrug selected from the group consisting of retinol, retinal, retinyl palmitate, retinyl acetate, and tazarotene.

[0070] In some embodiments, a composition herein (e.g., emulsion) has a pH of 2.0-4.0, and the lipophilic agent has a logD at pH 4.0 of at least 1.0, at least 2.0, or at least 3.0. In certain embodiments the lipophilic agent is a lipid-lowering fibrate or its active acid form, such as for example, gemfibrozil, fenofibric acid, clofibric acid, and / or bezafibrate. In some embodiments, a composition herein (e.g., emulsion) has a pH of 2.0-4.5, and the lipophilic agent has a logD at pH 4.5 of at least 1.0, at least 2.0, or at least 3.0. In certain embodiments the lipophilic agent is a uricosuric, such as for example, probenecid, benzbromarone, and / or sulfinpyrazone. In some embodiments, a composition herein (e.g., emulsion) has aAttorney Docket No. LAB.003 4.W0.01 pH of 2.0-4.5, and the lipophilic agent has a logD at pH 4.5 of at least 1.0, at least 2.0, or at least 3.0. In certain embodiments the lipophilic agent is a bile acid or bile acid analogue, such as for example, deoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, cholic acid, and / or obeticholic acid. In some embodiments, a composition herein (e.g., emulsion) has a pH of 2.0-3.5, and the lipophilic agent has a logD at pH 3.0 of at least 1.0, at least 2.0, or at least 3.0. In certain embodiments the lipophilic agent is a dermatologic keratolytic or antimicrobial acid, such as for example, salicylic acid, benzoic acid, mandelic acid, azelaic acid, undecylenic acid, and / or ciclopirox. In some embodiments, a composition herein (e.g., emulsion) has a pH of 2.0-4. , and the lipophilic agent has a logD at pH 4.5 of at least 1.0, at least 2.0, or at least 3.0. In certain embodiments the lipophilic agent is a quinolone antibiotic lacking a basic side chain, such as for example, nalidixic acid, oxolinic acid, and / or cinoxacin. In some embodiments, a composition herein (e.g., emulsion) has a pH of 2.0-4.5, and the lipophilic agent has a logD at pH 4.5 of at least 1.0, at least 2.0, or at least 3.0. In certain embodiments the lipophilic agent is an antiepileptic, such as for example, valproic acid and / or its pharmaceutically acceptable prodrugs and salts. In some embodiments, a composition herein (e.g., emulsion) has a pH of 2.0-4.5, and the lipophilic agent has a logD at pH 4.5 of at least 1.0, at least 2.0, or at least 3.0. In certain embodiments the lipophilic agent is a retinoid acid or analogue, such as for example, tretinoin (all-trans-retinoic acid), isotretinoin (13-cis-retinoic acid), and / or acitretin. In some embodiments, a composition herein (e.g., emulsion) has a pH of 2.0-4.0, and the lipophilic agent has a logD at pH 4.0 of at least 1.0, at least 2.0, or at least 3.0. In certain embodiments the lipophilic agent is cinnamic acid or a cinnamic acid derivative. In some embodiments, a composition herein (e.g., emulsion) has a pH of 2.0-4.0. and the lipophilic agent has a logD at pH 4.0 of at least 1.0, at least 2.0, or at least 3.0. In certain embodiments the lipophilic agent is alpha-lipoic acid. Hydrophilic Agents

[0071] The following include non-limiting hydrophilic agents, some of which are hydrophilic therapeutic agents that can be used in compositions provided herein. In illustrative embodiments, such embodiments include a non-ionic hydrophilic emulsifier, for example having an HLB in the range of 10 to 18.

[0072] In some embodiments, a composition herein (e.g., an emulsion) has a pH of 2.0-5.5, and tire hydrophilic agent has a LogD at pH 5.5 of at most 0 (e.g., at most -0.5 or at most -1.0). In certain embodiments the hydrophilic agent is Huperzine A. In certain embodiments the hydrophilic agent is an amino acid, such as for example, alanine, valine, leucine, isoleucine, methionine, threonine, phenylalanine, tyrosine, tryptophan, histidine, lysine, arginine, proline, serine, glycine, glutamine, citrulline, and / or taurine. In some embodiments, a composition herein (e.g., an emulsion) has a pH of 2.0-5.5, and the hydrophilic agent has a LogD at pH 5.5 of at most 0 (e.g.. at most -0.5 or at most -1.0). In certain embodiments, the agent is caffeine. In certain embodiments the hydrophilic agent is an amino-acid derivative or related zwitterion, such as for example, carnitine, acetyl -L-camitine, N-acetylcysteineAttorney Docket No. LAB.003 4.W0.01 (NAC), N-acetyl-L-tyrosine, creatine, theanine, and / or gamma-aminobutyric acid (GABA). In some embodiments, a composition herein (e.g., an emulsion) has a pH of 2.0-5.5, and the hydrophilic agent has a LogD at pH 5.5 of at most 0 (e.g., at most -0.5 or at most -1.0). In certain embodiments the hydrophilic agent is a water-soluble vitamin, such as for example, vitamin C (ascorbic acid), vitamin B-l (thiamine), vitamin B-2 (riboflavin), vitamin B-3 (niacin), niacinamide (vitamin B-3), vitamin B-5 (pantothenic acid), vitamin B-6 (pyridoxine), vitamin B-7 (biotin), inositol (vitamin B-7 / B-8), vitamin B-9 (folic acid), and / or vitamin B-12. In some embodiments, a composition herein (e.g., an emulsion) has a pH of 2.0-5.5. and the hydrophilic agent has a LogD at pH 5.5 of at most 0 (e.g., at most -0.5 or at most -1.0). In certain embodiments the hydrophilic agent is a carbohydrate or polyol, such as for example, ribose and / or glycerin. In some embodiments, a composition herein (e.g., an emulsion) has a pH of 2.0-5.5, and the hydrophilic agent has a LogD at pH 5.5 of at most 0 (e.g., at most -0.5 or at most -1.0). In certain embodiments the hydrophilic agent is a nucleotide or nucleotide-containing species, such as for example, adenosine triphosphate (ATP). In some embodiments, a composition herein (e.g., an emulsion) has a pH of 2.0-5.5, and the hydrophilic agent has a LogD at pH 5.5 of at most 0 (e.g., at most -0.5 or at most -1.0). In certain embodiments the hydrophilic agent is an organic acid used as an active or functional ingredient, such as for example, citric acid and / or acetic acid. In some embodiments, a composition herein (e.g., an emulsion) has a pH of 2.0-5.5, and the hydrophilic agent is an electrolyte or ionic species that is water-soluble across this pH range (LogD not applicable). In certain embodiments the hydrophilic agent is selected from the group consisting of hydration electrolytes (e.g., sodium, potassium, magnesium, calcium, chloride, and citrate salts), choline bitartrate, and / or magnesium glycinate. In some embodiments, a composition herein (e.g., an emulsion) has a pH of 2.0-5.5, and the hydrophilic agent is a peptide or polymeric biopolymer that is water-soluble across this pH range (LogD not applicable). In certain embodiments the hydrophilic agent is selected from the group consisting of collagen peptides and / or hyaluronic acid. In some embodiments, a composition herein (e.g., an emulsion) has a pH of 2.0-5.5, and the hydrophilic agent has a LogD at pH 5.5 of at most 1.0 (e.g.. at most 0.5 or at most 0). In certain embodiments the hydrophilic agent is a neuroactive small molecule with low lipophilicity, such as for example, melatonin. In some embodiments, a composition herein (e.g., an emulsion) has a pH of 2.0-5.5, and the hydrophilic agent is a botanical powder or aqueous extract that is water-dispersible across this pH range (LogD not applicable). In certain embodiments the hydrophilic agent is selected from the group consisting of beetroot powder, aloe vera, kale powder, ginger, green tea, blueberry extract, grape seed extract, olive leaf, pea powder, and / or pomegranate powder.

[0073] In some embodiments, a composition herein (e.g., an emulsion) has a pH of 2.0-5.5, and tire hydrophilic agent has a LogD at pH 5.5 of at most 0 (e.g., at most -0.5 or at most -1.0). In certain embodiments the hydrophilic agent is a therapeutic agent. In certain embodiments the hydrophilic agent isAttorney Docket No. LAB.003 4.W0.01 an aminoglycoside antibiotic, such as for example, gentamicin, tobramycin, amikacin, streptomycin, neomycin, and / or paromomycin. In certain embodiments the hydrophilic agent is a quaternary ammonium antimuscarinic or bronchodilator, such as for example, ipratropium, tiotropium, glycopyrrolate, aclidinium, and / or umeclidinium. In certain embodiments the hydrophilic agent is a quaternary ammonium neuromuscular blocker, such as for example, rocuronium, vecuronium, pancuronium, cisatracurium, atracurium, and / or succinylcholine. In certain embodiments the hydrophilic agent is a biguanide antidiabetic, such as for example, metformin, phenformin, and / or bufonnin. In certain embodiments the hydrophilic agent is an alpha-glucosidase inhibitor, such as for example, acarbose, miglitol, and / or voglibose. In certain embodiments the hydrophilic agent is a bisphosphonate, such as for example, alendronate, risedronate, ibandronate, zoledronic acid, etidronate, and / or pamidronate. In certain embodiments the hydrophilic agent is a sulfated polysaccharide anticoagulant or related agent that is water-soluble across this pH range (LogD not applicable), such as for example, unfractionated heparin, enoxaparin, dalteparin, tinzaparin, and / or fondaparinux. In certain embodiments the hydrophilic agent is an antifolate antimetabolite, such as for example, methotrexate, pemetrexed, and / or raltitrexed. In certain embodiments the hydrophilic agent is an osmotic diuretic, such as for example, mannitol, isosorbide, and / or glycerol. In certain embodiments the hydrophilic agent is a catecholamine sympathomimetic, such as for example, epinephrine, norepinephrine, dopamine, isoproterenol, and / or dobutamine. In certain embodiments the hydrophilic agent is a histamine H2 receptor antagonist, such as for example, cimetidine, ranitidine, famotidine, and / or nizatidine. In certain embodiments the hydrophilic agent is a polyaminocarboxylate metal chelator, such as for example, edetate disodium (EDTA), calcium disodium EDTA, diethylenetriaminepentaacetic acid (DTPA), and / or deferoxamine. In certain embodiments the hydrophilic agent is a water-soluble iodinated radiographic contrast medium, such as for example, iohexol, iopamidol, ioversol, iopromide, and / or diatrizoate. In certain embodiments the hydrophilic agent is a gadolinium MRI contrast agent that is water-soluble across this pH range (LogD not applicable), such as for example, gadoterate meglumine, gadobutrol, gadoteridol, gadopentetate dimeglumine, and / or gadodiamide. In certain embodiments the hydrophilic agent is a peptide or protein therapeutic that is water-soluble across this pH range (LogD not applicable), such as for example, insulin, glucagon, grow th honnone, interferons, erythropoietin, and / or monoclonal antibodies. In certain embodiments the hydrophilic agent is an oligonucleotide therapeutic that is water-soluble across this pH range (LogD not applicable), such as for example, nusinersen, inotersen, patisiran (siRNA), and / or pegaptanib. In certain embodiments the hydrophilic agent is a quaternary ammonium acetylcholinesterase inhibitor, such as for example, neostigmine and / or pyridostigmine. In certain embodiments the hydrophilic agent is a betalactam antibiotic excluding lipophilic ester prodrugs such as pivampicillin and cefuroxime axetil, such as for example, ampicillin, amoxicillin, penicillin G, piperacillin, ticarcillin, cephalexin, cefazolin.Attorney Docket No. LAB.003 4.W0.01 cefotaxime, ceftriaxone, imipenem, meropenem, and / or aztreonam.Maximum Saturated Fatty Acids

[0074] It has been surprisingly observed that increasing amounts of saturated fatty acids above certain threshold amounts in formulations and emulsions herein, has an increasingly negative / deleterious impact on absorption of agents therein through the skin into the blood stream. Accordingly, in some embodiments of compositions, formulations, and emulsions herein, the fatty acid source(s) comprising a combination of one or more oils, and one or more purified cis-unsaturated fatty acids in total include less than 20%, 15%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% w / w of saturated fatty acids. In some embodiments, the non -ionic emulsifier herein is not considered as a fatty acid source for the purpose of calculating total fatty acids herein. In some embodiments, the non-ionic emulsifier is considered as a fatty acid source for calculating total fatty acids herein. In such embodiments, the fatty acid source(s) comprise a combination of one or more oils, one or more purified cis-unsaturated fatty acids, and tire non-ionic emulsifier, and in total include less than 20%, 15%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%. 3%, 2%, or 1% w / w of saturated fatty acids. In some embodiments, tire at least one fatty acid source, the non-ionic emulsifier, and non-fatty acid hydrocarbons (which optionally are present in certain embodiments) present in the emulsion in total comprise less than or equal to 25%, 22%, 20%, 15.0%, 12%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% w / w of saturated fatty acids and saturated non-fatty acid hydrocarbons. In illustrative embodiments, the fatty acid contribution from the one or more non-ionic emulsifiers is included in the percent determination. In certain embodiments the non-fatty acid hydrocarbons are one or more of those specifically disclosed herein.

[0075] In some cases, the fatty acid source(s) comprising a combination of one or more oils, one or more purified cis-unsaturated fatty acids, and / or the non-ionic emulsifier in total include less than 20%, 15%, 12%, 10%, 9%, 8%. 7%, 6%, or 5% w / w of saturated non-fatty acid hydrocarbons. In some cases, for the comparison of saturated fatty acids or saturated non-fatty acid hydrocarbons in the emulsions herein relative to total hydrocarbon content in the emulsions, the fatty acids coming from the at least one fatty acid source, and the non-ionic emulsifier is considered, along with the non-fatty acid hydrocarbons from other components / ingredients in the emulsion. In some cases, the saturated fatty acids, and / or the saturated non-fatty acid hydrocarbons is compared to the total amount of fatty acids from the fatty acid source, and the fatty acids from the non-ionic emulsifier, and the contribution of non-fatty acid hydrocarbons present in the emulsion, for example, C7, Cs, C9, C10, or longer non-fatty acid hydrocarbons present in tire emulsion. Therefore, in some cases, the at least one fatty acid source, and / or the non-ionic emulsifier, and the non-fatty acid hydrocarbons present in the emulsion, in some embodiments, C10, Cn, C12, C13, C14, C15 or longer non-fatty acid hydrocarbons in total comprise less than or equal to 25%, 22%, 20%, 15.0%, 12%, 10%, 9%, 8%, 7%, 6%, or 5% w / w of saturated fatty acids and saturated non-fatty acidAttorney Docket No. LAB.0Q3_4.WO.01 hydrocarbons.

[0076] In illustrative embodiments, the non-fatty acid hydrocarbons herein are saturated non-fatty acid hydrocarbons or are non-fatty acid hydrocarbons that include saturated hydrocarbons. Non-limiting examples of components / ingredients that are the non-fatty acid hydrocarbons or that include saturated non-fatty acid hydrocarbons are squalane, mineral hydrocarbons or petroleum -derived hydrocarbons, for example, one or more of petrolatum (white petrolatum), mineral oil (paraffmum liquidum), microcrystalline wax, ozokerite, and ceresin. Other sources of the non-fatty acid hydrocarbons or that include non-fatty acid saturated hydrocarbons can include one or more of synthetic isoalkanes, natural saturated hydrocarbons, saturated fatty alcohols, hydrogenated oils, and silicone hydrocarbons. Nonlimiting examples of synthetic isoalkanes can include isohexadecane, isododecane, isoeicosane, and hydrogenated polydecene. Non-limiting examples of natural saturated hydrocarbons can include beeswax, carnauba wax, candelilla wax, paraffin wax, and lanolin wax. Non-limiting examples of saturated fatty alcohols can include cetyl alcohol (Cl 6), stearyl alcohol (Cl 8), and cetearyl alcohol (C16-C18 mix). Non-limiting examples of hydrogenated oils can include hydrogenated castor oil, hydrogenated coconut oil, and hydrogenated polyisobutene. Non-limiting examples of silicone hydrocarbons can include dimethicone, cyclopentasiloxane, cyclohexasiloxane, andtrimethylsiloxysilicate.Delivery of Additional Compounds

[0077] Tire biphasic aspect of emulsions described herein provides for delivery of additional compounds or additional agents with varying solubility profiles in a single formulation. In some embodiments, emulsions described herein comprise one or more additional compounds or additional agents having solubility in water. In some embodiments, emulsions described herein comprise one or more additional compounds having solubility in oil. In some embodiments, emulsions described herein comprise one or more additional compounds having solubility in water and one or more additional compounds having solubility in oil. In some embodiments, emulsions described herein provide for codelivery of one or more additional compounds in cooperation with agents to increase systemic nitric oxide. The discussion and teaching herein regarding emulsifier and agent lipophilicity or hydrophilicity is useful in this regard.

[0078] In some embodiments, an additional compound described herein is a nutritional supplement. In some embodiments, an additional compound described herein is a systemic medication. In some embodiments, an additional compound described herein is a targeted therapy. In some embodiments, an additional compound described herein acts on the cardiovascular, respirator}’, gastrointestinal, tire nervous system, or any combination thereof. In some embodiments of any of the aspects and embodiments herein that comprise an emulsion, and / or formulation that comprises one or more additional compounds or additional agents, the one or more additional compounds or additional agents can include acetyl-1-Attorney Docket No. LAB.003 4.W0.01 carnitine (ale), alanine, alpha lipoic acid, arginine, artichoke extract, ashwagandha, bacopa powder, bamboo extract powder, basil powder, beet powder, xanthan gum. calcium beta-hydroxy-beta-methylbutyrate (HMB), glutathione, calcium carbonate, blueberry extract, aloe vera, choline bitartrate, collagen protein peptides, collagen powder, citrulline, citrulline malate, curcumin powder, creatine, CoQlO, kale powder, folic acid, gingko biloba, glutamine, glycerin, ginger, glycine, grape seed extract, green tea, inositol (vitamins B7 / B8), histidine, jojoba, pomegranate powder, magnesium glycinate, leucine, lysine, lecithin (sun flower), niacinamide (vitamin B3), nutmeg powder, niacin, methionine, NALT (acetyl tyrosine), NAC, lutein, olive leaf, pea powder, periwinkle, phenylalanine, potassium, for example potassium citrate, proline, ribose, DAA (d-aspartic acid), serine, hyaluronic acid, taurine, threonine, try ptophan, tunneric, theanine, valine (amino acid), valerian root powder, zinc oxide, vitamin A. vitamin B complex, vitamin B-L vitamin B-2, vitamin B-5, vitamin B-6 (pyridoxine), vitamin B-7&8, vitamin B-9 (folic acid), vitamin B-12, vitamin C (ascorbic acid), ascorbyl glucoside, vitamin D-3 (cholecalciferol), vitamin E, vitamin K-2, ginseng, isoleucine, almond oil, broccoli seed oil, collagen liquid, avocado oil, chamomile liquid, vitamin E oil, glycerin (conditioning), grapefruit seed, grape seed oil, gotu kola oil, kava liquid, virgin algae oil (fish oil), jojoba extract oil (organic), lavender oil, macadamia nut oil, meadowfoam seed oil. peppennint oil. maracuja oil (passionfruit), primrose oil, pomegranate oil, BCAA, GABA, collagen oil, virgin algae oil, ashwagandha powder, collagen peptides, guarana powder, and huperzine. In some cases, the one or more additional compounds or additional agents can comprise acetyl-l-camitine (ale), alanine, alpha lipoic acid, arginine, artichoke extract, ashwagandha, bacopa powder, bamboo extract powder, basil powder, beet powder, calcium carbonate, blueberry extract, aloe vera, choline bitartrate, collagen protein peptides, collagen powder, citrulline, citrulline malate, curcumin powder, creatine, CoQlO, kale powder, folic acid, gingko biloba, glutamine, glycerin, ginger, glycine, grape seed extract, green tea, inositol (vitamins B7 / B8), histidine, jojoba, pomegranate powder, magnesium glycinate, leucine, lysine, lecithin (sun flower), niacinamide (vitamin B3). nutmeg powder, niacin, methionine, NALT (acetyl tyrosine). NAC, lutein, olive leaf, pea powder, periwinkle, phenylalanine, potassium, for example, potassium citrate, proline, ribose, DAA (d-aspartic acid), serine, hyaluronic acid, taurine, threonine, try ptophan, turmeric, theanine, valine (amino acid), valerian root powder, zinc oxide, vitamin A, vitamin B complex, vitamin B-l, vitamin B-2, vitamin B-5, vitamin B-6 (pyridoxine), vitamin B-7&8. vitamin B-9 (folic acid), vitamin B-12, vitamin D-3 (cholecalciferol), vitamin E, vitamin K-2, ginseng, isoleucine, almond oil, broccoli seed oil, collagen liquid, avocado oil, chamomile liquid, vitamin E oil, glycerin (conditioning), grapefruit seed, grape seed oil, gotu kola oil, kava liquid, virgin algae oil (fish oil), jojoba extract oil (organic), lavender oil, macadamia nut oil, meadowfoam seed oil. peppennint oil. maracuja oil (passionfruit), primrose oil, pomegranate oil, BCAA, GABA, collagen oil. virgin algae oil, ashwagandha powder, collagen peptides,Attorney Docket No. LAB.003 4.W0.01 guarana powder, menthol and huperzine. In some cases, the emulsion herein can comprise ascorbic acid and one or more of the agents as disclosed herein. In some cases, the emulsion as disclosed herein can include at least 0.05%, 0.1%, 0.2%, or 0.3% of the one or more agents disclosed herein. For example, the weight percentage ranges of the one or more additional compounds or additional agents disclosed herein can be in the range of 0.05-5%, 0.05-4%, 0.05-3%, or 0.05-2% of the weight of the transdermal formulation as disclosed herein. In some cases, tire molecular weight of the one or more additional compounds or the additional agents in the emulsion is less than 2000MW. 1800MW, 1500MW. or 1400MW. For example, the molecular weight of the one or more agents is in the range of 100 MW to 1500 MW, 100 MW to 1400 MW, or 100 MW to 1350 MW. In some embodiments of any of the aspects and embodiments herein that comprise an emulsion, and / or formulation, the emulsion, and / or fonnulation comprise one or more additional compounds or additional agents as disclosed herein. In some cases, the one or more additional compounds or additional agents can include one or more of magnesium oxide, zinc oxide, chromium, Banaba leaf extract, Rhodiola root extract, inositol, berberine HC1, Gardenia fruit extract, Salacia bark extract, apple fruit extract, Banaba leaf extract standardized to 18% crosolic acid, Rhodiola root extract standardized to 3% rosavins and 1% salidrosides, Gardenia fruit extract (10:1), Salacia extract (6:1), apple extract standardized to 75% polyphenols, ButyraGen® (tributyrin complex (tributyrin 100 mg / guar fiber 20 mg)), SolarPlast® (Spinach leaf extract), BIOHM-FX R) 4-strain probiotic blend (Lactobacillus acidophilus 16 axg™, Saccharomyces boulardii 16 mxg™, Lactobacillus rhanmosus 18 fx™, Bifidobacterium breve 19 bx™, amylase) 1 Billion CFU, BPL1®HT (postbiotic) B. lactis CECT 8145, rosemary extract, acacia fiber, microcrystalline cellulose, protease blend protease and peptidase, ginger rhizome extract standardized to 5% gingerols, cellulase, beta glucanase, cinnamon bark extract, diastase, alpha galactosidase, lactase, lipase, Bacillus subtilis DEI 11 (1 billion CFU), glucoamylase, xylanase, hemicellulose, galactomannan fiber (Sunfiber®), inulin (from Helianthus tuberosus), Capros® Amla fruit extract (Phyllanthus emblica), vitamin B-l (thiamine), vitamin B-2 (riboflavin), vitamin B-3 (niacin or niacinamide), vitamin B-6 (pyridoxine hydrochloride), folate, vitamin B-l 2, biotin, pantothenic acid, Cascara Sagrada (Rhamnus purshiana, bark), Milk Thistle extract (80% Silymarin) (Silybum marianum L, fruit), L-theanine, Burdock extract 4: 1 (Arctium lappa, root), Dandelion extract, 4: 1 (Taxacum mongolicum, root), Slippery elm extract 4: 1 (Ulmus rubra, bark), Marshmallow’ extract (Althaea officinalis, root), Citrus bioflavonoid 80% (Citrus aurantim, fruit), Black pepper extract (95% Piperine) (Piper nigrum, fruit) as Bioperine, bamboo extract (Bambusa vulgaris, shoot), rice hull concentrate, rice bran, and combinations thereof.Method of Manufacturing

[0079] Provided herein are methods of manufacturing emulsions for delivery of supplements to increase a systemic nitric oxide level as described herein. In some embodiments, methods of manufacture compriseAttorney Docket No. LAB.003 4.W0.01stirring an oil phase into an aqueous phase to generate the emulsion. In some embodiments, methods of manufacture comprise stirring an aqueous phase into an oil phase to generate the emulsion. It will be understood that such methods are not limiting, as other methods for creating emulsions can be used to make emulsions provided herein.

[0080] In some embodiments, generating an aqueous phase of an emulsion described herein comprises the steps (a) combining dry, water soluble components, (b) stirring one or more organic acids and water to generate an aqueous composition, (c) stirring the dry, water soluble components into tire aqueous composition to make an aqueous phase. In some embodiments, an aqueous composition is generated at about 25 degrees C. In some embodiments, an aqueous composition is generated at a temperature greater than 25 degrees C. In some embodiments, an aqueous composition is generated at about 37 degrees C, about 38 degrees C, about 39 degrees C, about 40 degrees C, about 41 degrees C, about 42 degrees C. In some embodiments, an aqueous phase is generated at about 25 degrees C. In some embodiments, an aqueous phase is generated at a temperature greater than 25 degrees C. In some embodiments, an aqueous phase is generated at about 37 degrees C, about 38 degrees C, about 39 degrees C, about 40 degrees C, about 41 degrees C, about 42 degrees C. In some embodiments, an aqueous composition is generated by stirring at about 200 RPM, about 400 RM, about 500 RPM, about 1000 RPM, about 1500 RPM, about 2000 RPM, about 2500 RPM, about 3000 RPM. In some embodiments, an aqueous phase is generated with stirring at about 500 RPM, about 1000 RPM, about 1500 RPM, about 2000 RPM, about 2500 RPM, about 3000 RPM. In some embodiments, the stirring is for about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, or about 10 minutes. In some embodiments, an aqueous composition is generated by stirring at about 38 degrees C and about 500 RPM for about 5 minutes. In some embodiments, an aqueous composition is generated by stirring at about 40 degrees C and about 500 RPM for about 5 minutes. In some embodiments, an aqueous phase is generated by stirring at about 38 degrees C and about 500 RPM for about 5 minutes. In some embodiments, an aqueous phase is generated by stirring at about 40 degrees C and about 500 RPM for about 5 minutes.

[0081] In some embodiments, generating an oil phase of an emulsion described herein comprises stirring the oil, the one or more fatty acids, the scaffold, and the surfactant to generate an oil phase. In some embodiments, an oil phase is generated at about 25 degrees C. In some embodiments, an oil phase is generated at a temperature greater than 25 degrees C. In some embodiments, an oil phase is generated at about 37 degrees C, about 38 degrees C, about 39 degrees C, about 40 degrees C, about 41 degrees C, about 42 degrees C. In some embodiments, an oil phase is generated by stirring at about 500 RPM, about 1000 RPM, about 1500 RPM, about 2000 RPM, about 2500 RPM, about 3000 RPM. In someAttorney Docket No. LAB.003 4.W0.01embodiments, the stirring is for about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, or about 10 minutes. In some embodiments, an oil phase is generated by stirring at about 25 degrees C and about 1000 RPM for about 5 minutes. In some embodiments, an oil phase is generated by stirring at about 38 degrees C and about 1000 RPM for about 5 minutes. In some embodiments, an oil phase is generated by stirring at about 40 degrees C and about 1000 RPM for about 5 minutes.

[0082] In some embodiments, an emulsion is generated by stirring a first phase into a second phase, combining the phases to form an emulsion. In some embodiments, the first phase is an oil phase and the second phase is an aqueous phase. In some embodiments, the first phase is an aqueous phase and the second phase is an oil phase. In some embodiments, the combining is over about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, or about 60 seconds. In some embodiments, the combining is at about 25 degrees C, about 26 degrees C, about 27 degrees C, about 28 degrees C, about 29 degrees C, about 30 degrees C, about 31 degrees C, about 32 degrees C, about 33 degrees C, about 34 degrees C, about 35 degrees C, about 36 degrees C, about 37 degrees C, about 38 degrees C, about 39 degrees C, about 40 degrees C, about 41 degrees C. about 42 degrees C. In some embodiments, the stirring is at about 500 RPM, about 1000 RPM, about 1500 RPM, about 2000 RPM, about 2500 RPM. In some embodiments, the stirring speed is increased during the combining. In some embodiments, tire stirring is increased after addition of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% of the second phase. In some embodiments, the stirring speed is increased twice, three times, four times, or five times during the combining. In some embodiments, the stirring speed is increased continuously during the combining. In some embodiments, a first about 35% of the first phase is added to the second phase, stirring at about 500 RPM. In some embodiments, a second about 35% of the first phase is added to the second phase with stirring at about 1000 RPM. In some embodiments, a final about 30% of the first phase is added to the second phase with stirring at about 1500. In some embodiments, a final about 30% of the first phase is added to the second phase with stirring at about 2000 RPM. In some embodiments, a final about 30% of the first phase is added to the second phase with stirring at about 2500 RPM.

[0083] In some embodiments, the generated emulsion is stirred for about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes. In some embodiments, the generated emulsion is stirred at about 25 degrees C, about 26 degrees C, about 27 degrees C, about 28 degrees C, about 29 degrees C, about 30 degrees C, about 31 degrees C, about 32 degrees C, about 33 degrees C. about 34 degrees C, about 35 degrees C, about 36 degrees C, about 37 degrees C, about 38 degrees C, about 39 degrees C, about 40 degrees C, about 41 degrees C,Attorney Docket No. LAB.003 4.W0.01 about 42 degrees C. In some embodiments, the generated emulsion is stirred for about 5 minutes at 38 degrees C. In some embodiments, the generated emulsion is stirred for about 5 minutes at 40 degrees C. In some embodiments, the generated emulsion is stirred for about 30 minutes at 38 degrees C. In some embodiments, the generated emulsion is stirred for about 30 minutes at 40 degrees C.

[0084] The generated emulsion comprises a pH of from about 1.5 to about 3.5, or from 2.0 to 5.5, 2.5 to 5.5, 3.0 to 5.5, 3.5 to 5.5, 4.0 to 5.5 or 4.5 to 5.5. In some embodiments, the generated emulsion comprises a pH of about 1.5, about 1.6, about 1.7. about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5. Other pH ranges for emulsions of aspects and embodiments are provided herein. In some embodiments, tire pH of one or more phases of the emulsion are adjusted prior to combining. In some embodiments, the pH is adjusted after generation of the emulsion. The generated emulsion comprises a viscosity at 25 degrees C of from about 1800 cPa to about 4000 cPa. In some embodiments, the generated emulsion comprises a viscosity at 25 degrees C of about 1800 cPa, about 1900 cPa, about 2000 cPa, about 2100 cPa, about 2200 cPa, about 2300 cPa, about 2400 cPa, about 2500 cPa, about 2600 cPa, about 2700 cPa, about 2800 cPa. about 2900 cPa, about 3000 cPa, about 3100 cPa, about 3200 cPa. about 3300 cPa, about 3400 cPa, about 3500 cPa. about 3600 cPa, about 3700 cPa, about 3800 cPa, about 3900 cPa, about 4000 cPa.Muscle Preservation and Therapeutic Application

[0085] Provided herein are methods and uses of improving or ameliorating a condition, disease, or side effect of a treatment comprising increasing a nitric oxide level in a subject, wherein the method comprises topical administration of a composition comprising a NO-increasing agent herein, in illustrative embodiments a precursor of nitric oxide. Accordingly, provided herein are methods for delivering at least one systemic nitric oxide -increasing agent to tire blood stream of a subject, comprising administering any of the transdermal compositions, systems, or emulsions herein to a mucus membrane, or in illustrative embodiments the skin of the subject, wherein the systemic nitric oxide level is increased in the subject afterthe administering. For example, at 2, 4, 6, 8, 10, 12, 18, 24, 28, 32, and 36 hours after such administration. Details regarding frequency and amount of dosing are provided elsewhere herein.

[0086] In another aspect, provided herein is a method of preventing or reducing muscle mass loss that is correlated to treatment with a weight loss therapeutic agent, a caloric restrictive diet, a nutritional deficient intake protocol diet (fad diet), a medically or medicinally influenced or activated malnutritional condition, or a dietary intake condition. In illustrative embodiments, the subject is being treated with a GLP-1 agonist. Such method typically involves topical administration of a transdermal composition (e.g., a transdermal emulsion) provided herein to a mucus membrane, or in illustrative embodiments, the skin of the subject. Details regarding frequency and amount of dosing are provided elsewhere herein.Attorney Docket No. LAB.0Q3_4.WO.01

[0087] As supported by Example 20 herein, systemic NO-increasing emulsions delivered topically appear to preserve muscle loss in a subject taking a weight loss therapeutic. This result is consistent with the effects of increased systemic NO on muscle. Nitric oxide promotes relaxation of vascular smooth muscle and subsequent dilation, which may augment mechanisms contributing to muscle performance, hypertrophy, and strength. Increased NO bioavailability minimizes or prevents loss of muscle mass or promotes muscle mass gain. By activating soluble guanylate cyclase in vascular smooth muscle, NO increases cGMP and causes vasodilation, improving skeletal-muscle perfusion during activity.Furthermore, higher habitual nitrate intake in humans associates with better muscle function and lower odds of sarcopenia, outcomes aligned with preserving muscle mass and strength. As such NO-increasing emulsions herein can be referred to as weight loss metabolic companion emulsions or weight loss therapeutic (e.g., GLP-1 agonist) companion emulsions.

[0088] Accordingly, topical application of a composition or emulsion described herein to a subject having an affliction or having a condition that causes loss of muscle mass, provides for an increase in systemic nitric oxide, which is believed to minimize and possibly even reverse, loss of muscle mass. Tirus, in some embodiments of any method herein, the subject is afflicted by or otherwise has a condition that causes loss of muscle mass. In some embodiments, the subject is taking an agent, such as a therapeutic agent that causes loss of muscle mass. In some embodiments, the subject is experiencing, or experienced within 30, 14, 7, or 1 day before the administering, weight loss, cachexia, or muscle atrophy. In some cases, the condition comprises muscle mass loss, muscle fatigue, high blood pressure (hypertension), low / reduced blood oxygen, or any combination thereof.

[0089] With respect to blood pressure, or hypertension, in some embodiments of any method herein that involves administering a NO-increasing emulsion herein to a subject, the subject suffers from, or suffered from high blood pressure before tire administering. In some embodiments, the systolic blood pressure of the subject is reduced by at least 10, 20, 25, 30, 40 or 50 mmHg, or between 10 and 50, 40, 30, or 25 mmHg after the administering compared to before the administering. The administering in such embodiments can be a single administration or can be multiple administrations according to any dosing amount and frequency herein. As such in some embodiments, the systolic blood pressure of the subject is reduced by between 10 and 50 mmHg at 1, 2, 4, 8, 12, 18, or 24 hours after the last administering compared to before the first administering, and wherein the administering is daily dosing for at least 5, 7, 14, or 28 days, or 1, 2, 3, 6, 9, or 12 months.

[0090] In non -limiting examples, methods herein involve administering compositions (e.g., emulsions) provided herein to a mammalian subject that is undergoing one or more weight loss therapies, protocols, and / or methods. Subjects undergoing weight loss therapies and / or methods typically experience muscle mass loss as an undesirable side effect. Thus, compositions (e.g., emulsions) disclosed herein can be usedAttorney Docket No. LAB.003 4.W0.01 by a mammalian subject undergoing one or more weight loss therapies and / or methods disclosed herein to reduce weight loss that is often associated with such weight loss therapies. Accordingly, administration of the emulsion to the subject can reduce the level of muscle mass loss suffered by the subject. The reduction in level of muscle mass loss suffered by the subject can be absolute, or relative to the amount of fat mass loss.

[0091] Weight loss methods practiced by subjects topically administering compounds (e.g., emulsion) herein, can include any such method that is known to. or believed to cause muscle mass loss, including disproportionate muscle mass loss vs. overall body mass loss, at least in some subjects. For example, such weight loss methods can include calorie-restricted diets, time -restricted eating, nutritional fad protocols, nutritionally deficient protocols, pre-operative liver-shrinking diets, and protein-sparing modified fasts. Weight loss methods can include weight loss therapies that involve the use of obesity and weight-loss therapeutics, including therapies grouped by function and / or other categories. Non-limiting examples of weight loss therapies by functional targets or other categories include incretin-based, amylin pathway, sympathomimetic anorectics, central appetite modulators, gastrointestinal agents / devices, and rare-disease targeted therapies. Weight loss can also occur in mammalian subjects due to medical or medicinal influence including from diseases such as. in non-limiting examples, endocrine / metabolic, gastrointestinal / malabsorption, chronic organ disease, cancer and cancer cachexia, infection, inflammation, neurologic / psychiatric, medication / substance-related, post-surgical disorders and critical illness. Weight loss therapies and / or methods can include prescribed and / or recommended administration, dosing amounts, and dosing timing protocols. Prescription weight loss therapies are typically administered, at the dosage amount and time, per the prescribed recommendation of a medical doctor. Weight loss methods can be administered, at the dosage amount and time, per the prescribed recommendation of a medical doctor, and can also be performed or carried out at the discretion of the subject.

[0092] In some cases, the condition is a side effect of a treatment with a GLP- 1 agonist. In some cases, the condition is a side effect of a treatment with a GIP agonist. In some cases, the condition is a side effect of a treatment with dual GLP-l / GIP agonist.

[0093] Treatment with a glucagon-like peptide- 1 (GLP-1) agonist, also known as an incretin mimetic, can be used to treat type 2 diabetes and obesity. Exemplary GLP-1 agonists include dulaglutide (Trulicity®), exenatide extended release (Bydureon bcise®), exenatide (Byetta®), semaglutide (Ozempic®, Wegovy®, Rybelsus®), liraglutide (Victoza®, Saxenda®), or lixisenatide (Adlyxin®). Common side effects associated with use of GLP- Is include nausea, vomiting, and diarrhea. Additionally, the significant weight loss associated with use of GLP-1 agonists can contribute to loss of muscle mass. Increasing nitric oxide levels in the body improves circulation and reduces symptoms associated with GLP-1 treatment,Attorney Docket No. LAB.003 4.W0.01 including loss of muscle mass.

[0094] Treatment with dual glucagon-like peptide- 1 / glucose-dependent insulinotropic polypeptide (GLP-1 / G1P) receptor agonists, also known as incretin co-agonists, is used to treat type 2 diabetes and obesity. These can be the treatments of subjects that perform methods that include topically administering compositions (e.g., emulsions) provided herein. Exemplary GLP-l / GIP co-agonists can include tirzepatide (e.g., Mounjaro®, Zepbound®). Common side effects associated with use of GLP-l / GIP co-agonists include nausea, vomiting, and diarrhea. Additionally, the significant weight loss associated with use of GLP-l / GIP co-agonists can contribute to loss of muscle mass. Increasing nitric oxide levels in the body improves circulation and reduces symptoms associated with GLP-l / GIP co-agonist treatment, including loss of muscle mass.

[0095] For the purposes of this disclosure, therapeutic application comprises use in the treatment of a disease, disorder, or condition; use to counteract side effects of a separate therapy; use to counteract symptoms of a condition; use to increase or induce a desirable feature or condition; use to decrease or remove an undesirable feature or condition; or any combination thereof.

[0096] In some embodiments, emulsions described herein have therapeutic application. In some embodiments, an emulsion having a therapeutic application is an emulsion as described herein comprising a composition to increase a systemic nitric oxide level in the body. In some embodiments, an emulsion having a therapeutic application is an emulsion as described herein comprising a composition to increase a systemic nitric oxide level in the body and one or more additional compounds as described herein.

[0097] In some embodiments, a therapeutic application is provided by application of an emulsion described herein providing for an increase in systemic nitric oxide. In some embodiments, a therapeutic application is provided by application of an emulsion described herein providing for an increasing in systemic nitric oxide further comprising one or more additional compounds as described herein.

[0098] Therapeutic applications of emulsions as described herein comprise, without limitation, reduces side effects of GLP-1 and / or dual GLP-l / GIP treatments; retain muscle mass from treatment with GLP-1 and / or dual GLP-l / GIP; retain muscle mass from weight loss; retain muscle mass due to wasting disease; support age-related muscular degeneration; relieve menstrual cramps; relieve menopausal symptoms; benefit fertility; relieve cancer symptoms; relieve symptoms following chemotherapy; restore strength and structure to hair; restore hair color; regenerate lost hair follicles; improve skin color, tone, clarity, surface, pores, and hydration; clear and suppress acne; increase levels of oxygen and blood flow capacity in a subject with asthma; reduce blood pressure, reduce heart rate, reduce body temperature, and increase blood oxygen in a subject with cardiovascular disease (CVD); reduce blood pressure, reduce heart rate, reduce body temperature, and increase blood oxygen in a subject with chronic obstructive pulmonary disease (COPD); reduce blood pressure, reduce heart rate, reduce body temperature, and increase bloodAttorney Docket No. LAB.003 4.W0.01oxygen in a subject with emphysema; reduce blood pressure, reduce heart rate, reduce body temperature, increase blood oxygen, and increase blood flow to the brain in subjects with dementia; reduce blood pressure, reduce heart rate, reduce body temperature, increase blood oxygen, and increase blood flow to limbs in subjects with neuropathy; reduce blood pressure, reduce heart rate, reduce body temperature, increase blood oxygen, and increase blood flow to organs in subjects with diabetes; reduce blood pressure, reduce heart rate, reduce body temperature, increase blood oxygen, and increase blood flow to organs in subjects undergoing dialysis; improve appearance of fingernails and toenails; kill nail fungus; eliminate jet lag: increase endurance, improve performance, and reduce recovery time in body building, exercise, and sports; improve outcomes with IV treatments; improve healing outcomes after surgery ; increase gut microbiota; increase oral microbiota; increase immunity’ in treatment of colds, flu, COVID-19, or RSV; or increase delivery and absorption of supplements.Dosage and Administration

[0099] Emulsions described herein in illustrative embodiments, arc for topical application. In some embodiments, topical application comprises contacting an emulsion to a body surface. In some embodiments, topical application comprises contacting a skin or mucous membrane. In some embodiments, the emulsion is applied as a paste, an ointment, a cream, a lotion, a foam, a gel, a spray, or a patch.

[0100] Hie emulsions provided herein in some embodiments, are topically applied in a single dose. In some embodiments, an emulsion described herein is applied in multiple doses. In some embodiments, the multiple doses are topically applied concurrently or sequentially. In some embodiments, the multiple doses are applied to the same area of skin or mucous membrane or to different areas of skin or mucus membrane. In some embodiments, a dose comprises about 0.2 g, about 0.3 g, about 0.4 g, about 0.5 g, about 0.6 g, about 0.7 g. about 0.8 g, about 0.9 g, about 1.0 g, about 1.1 g. about 1.2 g, about 1.3 g, about 1.4 g, about 1.5 g, about 1.6 g, about 1.7 g, about 1.8 g, about 1.9 g, about 2.0 g, about 2.1 g, about 2.2 g, about 2.3 g, about 2.4 g, about 2.5 g, about 2.6 g, about 2.7 g, about 2.8 g, about 2.9 g, about 3.0 g, about 3.1 g, about 3.2 g, about 3.3 g, about 3.4 g, about 3.5 g, about 3.6 g, about 3.7 g, about 3.8 g, about 3.9 g, about 4.0 g, about 4.1 g, about 4.2 g, about 4.3 g, about 4.4 g, about 4.5 g, about 4.6 g, about 4.7 g, about 4.8 g, about 4.9 g. about 5.0 g, about 0.5 g to 10 g, 0.5 g to 5 g, 0.5 g to 2.5 g, or 1 g to 2.5 g of an emulsion provided herein.

[0101] Emulsions provided herein, providing an increase in systemic nitric oxide levels, can be applied topically, or administered, at various timepoints and / or intervals, in non-limiting examples, at the time the weight loss therapies and / or methods are administered and / or perfonned. In non-limiting examples, the emulsions can be administered to the subject within I, 2, 5, 10, 20, 30, 60, or 120 minutes before or after the weight loss therapies and / or methods are administered and / or performed. In non-limiting examples,Attorney Docket No. LAB.003 4.W0.01the emulsions can be administered to the subject within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours before or after the weight loss therapies and / or methods are administered and / or performed. In non-limiting examples, the emulsions can be administered to the subject within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days before or after the weight loss therapies and / or methods are administered and / or performed. In non-limiting examples emulsions can be administered more than once daily, or in illustrative examples, once daily. In nonlimiting examples emulsions can be administered every 1, 2, 3, 4, 5, 10, 12, 14, or 16 hours. In nonlimiting examples, emulsions can be administered every 1, 2, 3, 4. 5, 6, 7, 8, 9, or 10 days. In some embodiments, the weight loss therapy is administered once per year, twice per year, once per month, once every two weeks, weekly, or daily. In some embodiments, an emulsion herein is provided while the weight loss therapy is present at detectable levels within the subject. In some embodiments, an emulsion herein is provided while the weight loss therapy is present at therapeutic levels within the subject.

[0102] Emulsions provided herein can be administered at a dose, in non-limiting examples, between 0.20 and 3.00 oz. Emulsions provided herein can be administered at a dose, in non-limiting examples, of 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.50. 1.55, 1.60, 1.65, 1.70, 1.75, 1.80. 1.85, 1.90, 1.95, 2.00, 2.05, 2.10, 2.15, 2.20. 2.25, 2.30, 2.35, 2.40, 2.45. 2.50. 2.55, 2.60, 2.65, 2.70, 2.75. 2.80. 2.85, 2.90, 2.95, or 3.00 oz. In non-limiting examples, the emulsions can be dosed between 0.20 oz and 1.80 oz, 0.25 oz and 1.75 oz, 0.30 oz and 1.70 oz, 0.35 oz and 1.65 oz, 0.40 oz and 1.60 oz, 0.45 oz and 1.55 oz, 0.50 oz and 1.50 oz, 0.55 oz and 1.45 oz, 0.60 oz and 1.40 oz, 0.65 oz and 1.35 oz, 0.70 oz and 1.30 oz, 0.75 oz and 1.25 oz, 0.80 oz and 1.20 oz, 0.85 oz and 1.15 oz, 0.90 oz and 1.10 oz, or 0.95 oz and 1.05 oz. In nonlimiting examples, the emulsions can be dosed between 0.20 oz on the low end and 1.00, 1.05, 1.10, 1.15, 1.20, and 1.25 oz on the high end; or between 0.25 oz on the low end and 1.00, 1.05, 1.10, 1.15, 1.20, and 1.25 oz on tire high end; or between 0.30 oz on the low end and 1.00, 1.05, 1.10, 1.15, 1.20, and 1.25 oz on the high end; or between 0.35 oz onthe low end and 1.00, 1.05, 1.10, 1.15, 1.20, and 1.25 oz onthe high end; or between 0.40 oz on the low end and 1.00. 1.05. 1.10, 1.15, 1.20, and 1.25 oz on the high end: or between 0.45 oz on the low end and 1.00, 1.05, 1.10, 1.15, 1.20, and 1.25 oz on the high end; or between 0.50 oz on the low7end and 1.00, 1.05, 1.10, 1.15, 1.20, and 1.25 oz on the high end; or between 0.55 oz on tire low end and 1.00, 1.05, 1.10, 1.15, 1.20, and 1.25 oz on the high end; or between 0.60 oz on the low end and 1.00, 1.05. 1.10, 1.15, 1.20, and 1.25 oz on the high end: or between 0.65 oz on the low end and 1.00, 1.05, 1.10, 1.15, 1.20, and 1.25 oz on the high end; or between 0.70 oz on the low end and 1.00, 1.05, 1.10, 1.15, 1.20, and 1.25 oz on the high end; or between 0.75 oz on the low end and 1.00, 1.05, 1.10, 1.15, 1.20, and 1.25 oz on the high end; or betw een 0.80 oz on tire low end and 1.00, 1.05, 1.10, 1.15, 1.20, and 1.25 oz on the high end; or between 0.85 oz on the low end and 1.00, 1.05, 1.10, 1.15, 1.20, and 1.25 oz on the high end; or between 0.90 oz on the low' end and 1.00, 1.05, 1.10, 1.15,Attorney Docket No. LAB.003 4.W0.01 1.20, and 1.25 oz on the high end; or between 0.95 oz on the low end and 1.00, 1.05, 1.10, 1.15, 1.20, and 1.25 oz on the high end.

[0103] In non-limiting examples, the emulsions can be dosed between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 1.00 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 1.05 oz on tire high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 1.10 oz on the high end; or between 0.20. 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 1.15 oz on the high end: or between 0.20, 0.25, 0.30, 0.35, 0.40. and 0.45 oz on the low end and 1.20 oz on the high end: or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 1.25 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 1.30 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 1.35 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 1.40 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 1.45 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 1.50 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 1.55 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 1.60 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 1.65 oz on the high end; or between 0.20, 0.25, 0.30, 0.35. 0.40, and 0.45 oz on the low end and 1.70 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 1.75 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 1.80 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 1.85 oz on the high end: or between 0.20, 0.25, 0.30, 0.35, 0.40. and 0.45 oz on the low end and 1.90 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 1.95 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 2.00 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 2.05 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 2.10 oz on the high end; or between 0.20, 0.25, 0.30. 0.35, 0.40, and 0.45 oz on the low end and 2.15 oz on tire high end: or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 2.20 oz on the high end: or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 2.25 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 2.30 oz on tire high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 2.35 oz on the high end; or between 0.20, 0.25, 0.30, 0.35. 0.40, and 0.45 oz on the low end and 2.40 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 2.45 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 2.50 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 2.55 oz on the high end: or between 0.20, 0.25, 0.30, 0.35, 0.40. and 0.45 oz on the low end and 2.60 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 2.65 oz on theAttorney Docket No. LAB.003 4.W0.01 high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 2.70 oz on the high end; or between 0.20, 0.25. 0.30, 0.35, 0.40, and 0.45 oz on the low end and 2.75 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 2.80 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 2.85 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 2.90 oz on the high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 2.95 oz on tire high end; or between 0.20, 0.25, 0.30, 0.35, 0.40, and 0.45 oz on the low end and 3.00 oz on the high end.

[0104] In non-limiting examples, emulsions can be administered at a dose of between 5g and 60g.Emulsions disclosed herein can be administered at a dose, in non-limiting examples, of 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0. 18.5, 19.0, 19.5, 20.0, 20.5. 21.0, 21.5, 22.0, 22.5, 23.0, 23.5. 24.0, 24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5, 30.0, 30.5, 31.0, 31.5, 32.0, 32.5, 33.0, 33.5, 34.0, 34.5, 35.0, 35.5, 36.0, 36.5, 37.0, 37.5, 38.0, 38.5, 39.0, 39.5, 40.0, 40.5, 41.0, 41.5, 42.0, 42.5, 43.0, 43.5, 44.0, 44.5, 45.0, 45.5, 46.0, 46.5, 47.0, 47.5, 48.0, 48.5, 49.0, 49.5, 50.0, 50.5, 51.0, 51.5, 52.0, 52.5, 53.0, 53.5, 54.0, 54.5, 55.0, 55.5, 56.0, 56.5, 57.0, 57.5, 58.0, 58.5. 59.0, 59.5, or 60.0g. In non-limiting examples, the emulsions can be dosed between 5.0 g on the low end and 30.0, 32.5, 35.0. 37.5. 40.0, and 42.5 g on the high end; or between 7.5 g on the low end and 30.0, 32.5, 35.0, 37.5, 40.0, and 42.5 g on the high end; or between 10.0 g on tire low end and 30.0, 32.5, 35.0, 37.5, 40.0, and 42.5 g on the high end; or between 12.5 g on the low end and 30.0, 32.5, 35.0, 37.5, 40.0, and 42.5 g on the high end; or between 15.0 g on the low end and 30.0, 32.5, 35.0. 37.5. 40.0, and 42.5 g on the high end; or between 17.5 g on the low end and 30.0, 32.5, 35.0, 37.5, 40.0, and 42.5 g on the high end; or between 20.0 g on the low end and 30.0, 32.5, 35.0, 37.5, 40.0, and 42.5 g on the high end; or between 22.5 g on the low end and 30.0, 32.5, 35.0, 37.5, 40.0, and 42.5 g on the high end; or between 25.0 g on the low end and 30.0, 32.5, 35.0, 37.5, 40.0, and 42.5 g on the high end; or between 27.5 g on the low end and 30.0, 32.5, 35.0, 37.5, 40.0, and 42.5 g on the high end. In non-limiting examples, the emulsions can be dosed between 5.0. 7.5, 10.0. 12.5. 15.0, and 17.5 g on the low end and 30.0 g on the high end: or between 5.0, 7.5, 10.0, 12.5, 15.0, and 17.5 g on the low end and 32.5 g on the high end; or between 5.0, 7.5, 10.0, 12.5, 15.0, and 17.5 g on the low end and 35.0 g on tire high end; or between 5.0, 7.5, 10.0, 12.5, 15.0, and 17.5 g on the low end and 37.5 g on the high end: or between 5.0. 7.5, 10.0. 12.5, 15.0, and 17.5 g on the low end and 40.0 g on the high end: or between 5.0, 7.5, 10.0, 12.5, 15.0, and 17.5 g on the low end and 42.5 g on the high end; or between 5.0, 7.5, 10.0, 12.5, 15.0, and 17.5 g on the low end and 45.0 g on the high end; or between 5.0, 7.5, 10.0, 12.5, 15.0, and 17.5 g on the low end and 47.5 g on the high end; or between 5.0, 7.5, 10.0, 12.5, 15.0, and 17.5 g on the low end and 50.0 g on the high end; or between 5.0, 7.5. 10.0, 12.5, 15.0, and 17.5 g on the low end and 52.5 g on the high end; or between 5.0, 7.5, 10.0, 12.5, 15.0, and 17.5 g on the low endAttorney Docket No. LAB.003 4.W0.01 and 55.0 g on the high end; or between 5.0, 7.5, 10.0, 12.5, 15.0, and 17.5 g on the low end and 57.5 g on the high end; or between 5.0, 7.5, 10.0, 12.5, 15.0, and 17.5 g on tire low end and 60.0 g on the high end.

[0105] Administration of the emulsions disclosed herein can include, in non-limiting examples, topical application to a portion of the body, or area of skin or mucous membrane, of the subject or to the hill body. Tire emulsion dosage amount can be applied to one or more portions, or treatment areas, of the subject, or the full body. Emulsions provided herein are believed to deliver tire one or more agents therein rapidly through the skin to the bloodstream. Thus, following topical application of an emulsion herein, at least one agent in the emulsion enters the blood stream within 60, 90, 120, 180, 240, 300, 360, 420, 480, 540, or 600 seconds, or 15, 30 or 60 minutes after administration to the skin of the subject. In illustrative embodiments, at least one agent enters the bloodstream within 10, 5, or 1 minute after administration to the skin of the subject.

[0106] the emulsion can be left in place for 1, 2, 3, 4, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 300, 360, 420, 480, 540, or 600 seconds. In non-limiting examples, tire emulsions can be left in place between 1 second on the low end and 30, 35, 40, 45, 50, and 55 seconds on tire high end; or between 6 seconds on the low end and 30, 35, 40, 45, 50, and 55 seconds on the high end; or between 11 seconds on the low end and 30, 35, 40, 45, 50. and 55 seconds on the high end; or between 16 seconds on the low end and 30. 35.40, 45, 50, and 55 seconds on the high end; or between 21 seconds on the low end and 30, 35, 40, 45, 50, and 55 seconds on tire high end; or between 26 seconds on the low end and 30, 35, 40, 45, 50, and 55 seconds on the high end. In non-limiting examples, the emulsions can be left in place between 1, 5, 10, 15, 20, and 25 seconds on the low end and 30 seconds on the high end; or between 1, 5, 10, 15, 20, and 25 seconds on the low end and 35 seconds on the high end; or between 1, 5, 10, 15, 20, and 25 seconds on the low end and 40 seconds on the high end; or between 1, 5, 10, 15, 20, and 25 seconds on the low end and 45 seconds on tire high end; or between 1, 5, 10, 15, 20, and 25 seconds on the low7end and 50 seconds on the high end; or between 1, 5, 10, 15, 20, and 25 seconds on the low end and 55 seconds on the high end; or between 1, 5, 10, 15, 20, and 25 seconds on the low end and 60 seconds on the high end. In non-limiting examples, the emulsion can be wiped off, rinsed off, or removed, in illustrative examples, after a time period disclosed herein. In non-limiting examples, the emulsion can be left on tire subject and / or not wiped off, rinsed off, or removed. A single administration of the emulsions can include a single application or two or more aliquots distributed across the selected portion(s), or treatment area(s). or area of skin or mucous membrane of the subject. In non-limiting examples, a single administration of the emulsions to the subject can include between 1 application on the low7end and 25, 30, 35, 40, 45, and 50 applications on the high end; or betw een 6 applications on the low end and 25, 30, 35, 40, 45, and 50 applications on the high end; or between 11 applications on the low end and 25, 30, 35, 40, 45, and 50 applications on the high end; or between 16 applications on the low end and 25, 30, 35, 40, 45, and 50Attorney Docket No. LAB.003 4.W0.01 applications on the high end; or between 21 applications on the low end and 25, 30, 35, 40, 45, and 50 applications on the high end. In non-limiting examples, a single administration of the emulsions to tire subject can include between 1, 5, 10, 11, and 20 applications on the low end and 25 applications on the high end; or between 1, 5, 10, 11, and 20 applications on the low end and 30 applications on the high end; or between 1, 5, 10, 11, and 20 applications on the low end and 35 applications on the high end; or between 1, 5, 10, 11, and 20 applications on the low end and 40 applications on the high end; or between I, 5. 10. 11, and 20 applications on the low end and 45 applications on tire high end; or between 1, 5, 10, I I, and 20 applications on the low end and 50 applications on the high end.

[0107] The foregoing description and accompanying drawings set forth a number of representative embodiments attire present time. Various modifications, additions, and alternative designs will, of course, become apparent to those skilled in the art in light of the foregoing teachings without departing from the scope hereof, which is indicated by the following claims rather than by the foregoing description. All changes and variations that fall within the meaning and range of equivalency of the claims are to be embraced within their scope.EXEMPLARY EMBODIMENTS

[0108] Provided in this Exemplary Embodiments section are non-limiting exemplary aspects and embodiments provided herein and further discussed throughout this specification. For the sake of brevity and convenience, all of the aspects and embodiments disclosed herein, and all of the possible combinations of the disclosed aspects and embodiments are not listed in this section. Additional embodiments and aspects are provided in other sections herein. Furthermore, it will be understood that embodiments are provided that are specific embodiments for many aspects and that can be combined with any other embodiment, for example as discussed in this entire disclosure. It is intended in view of the full disclosure herein, that any individual embodiment recited below or in this full disclosure can be combined w ith any aspect recited below7or in this full disclosure where it is an additional element that can be added to an aspect or because it is a narrow er element for an element already present in an aspect. Such combinations are sometimes provided as non-limiting exemplary combinations and / or are discussed more specifically in other sections of this detailed description.

[0109] In one aspect, provided herein is a transdermal composition in the form of an emulsion, comprising: at least one weak organic acid comprising citric acid present in total in an amount from 0.2% to 45.0% w / w of tire emulsion; at least one agent, wherein the at least one agent in total is present in a weight ratio from 0.1 : 1.0 to 3.0: 1.0 relative to the at least one weak organic acid in total; water, present inAttorney Docket No. LAB.003 4.W0.01a weight ratio from 0.5:1 to 45: 1 relative to the at least one weak organic acid in total; at least one fatty acid source comprising at least one cis unsaturated fatty acid selected from oleic acid and linoleic acid, wherein the at least one fatty acid source in total is present in a weight ratio from 0.2: 1.0 to 4.0: 1.0 relative to the at least one weak organic acid in total: and at least one non-ionic emulsifier comprising one or more cis unsaturated fatty' acids, wherein the at least one non-ionic emulsifier in total is present in a weight ratio from 1.0: 1.0 to 5.0: 1.0 relative to the at least one weak organic acid in total, wherein the transdennal composition has a pH in the range of 2.0 to 5.5. wherein total fatty acids, and / or CIO or longer non-fatty acid hydrocarbons if present in the emulsion, comprise less than or equal to a total of 15.0% w / w of saturated fatty acids and / or saturated CIO or longer non-fatty acid hydrocarbons, wherein the non-ionic emulsifier comprises polysorbate 80, wherein the agent comprises arginine, citrulline, citrulline malate, beetroot, or any combination thereof, and wherein the transdermal composition is capable of delivering the at least one agent to the blood stream of a subject when applied to the skin of the subject and increasing systemic nitric oxide level in the subject.

[0110] In one aspect, provided herein is a multi-component transdennal system, comprising: (a) an aqueous phase comprising: at least one weak organic acid in total present in an amount from 1.0% to 75.0% w / w of the aqueous phase; at least one agent, wherein the at least one agent in total present in the aqueous phase is present in a weight ratio from 0.1 : 1.0 to 3.0: 1.0 relative to the at least one weak organic acid in total present in the aqueous phase; and water, present in the aqueous phase in a weight ratio from 0.5 : 1.0 to 45 : 1.0 relative to the at least one weak organic acid in total present in the aqueous phase, wherein the aqueous phase has a pH in tire range of 2.0 to 5.5: (b) an oil phase comprising: at least one fatty acid source comprising at least one cis unsaturated fatty acid selected from oleic acid and linoleic acid, wherein the at least one fatty acid source in total present in the oil phase is present in a weight ratio from 0.2: 1.0 to 30: 1.0 relative to the at least one weak organic acid in total present in the aqueous phase; and at least one non-ionic emulsifier comprising one or more cis unsaturated fatty acids, wherein the at least one non-ionic emulsifier in total present in the oil phase is present in a weight ratio from 0.5 : 1.0 to 25: 1.0 relative to the at least one weak organic acid in total present in the aqueous phase, wherein the non-ionic emulsifier comprises or is derived from one or more oleic acid residues and / or one or more linoleic acid residues, wherein tire combination of the aqueous phase and the oil phase equals 100% w / w of the emulsion, and wherein the transdermal system is capable of forming a transdermal emulsion having total fatty acids and / or CIO or longer hydrocarbons that comprise less than or equal to a total of 15.0% w / w of saturated fatty acids and / or saturated CIO or longer non-fatty acid hydrocarbons, wherein the agent comprises arginine, citrulline, citrulline malate, beetroot, or any combination thereof, and wherein the transdermal emulsion is capable of delivering the at least one agent to the blood stream of a subject when applied to the skin of the subject and increasing systemic nitric oxide level in the subject.Attorney Docket No. LAB.003 4.W0.01

[0111] In some embodiments of any of the aspects and embodiments herein that include a multicomponent transdermal system, wherein the at least one weak organic acid comprises citric acid. In some embodiments of any of the aspects and embodiments herein that include a multi-component transdermal system, wherein the at least one non-ionic emulsifier comprises polysorbate 80.

[0112] In some embodiments, provided herein is a method for delivering tire at least one agent to the blood stream of a subject, comprising administering atransdennal composition (e.g., emulsion) provided herein to the skin of the subject, wherein the systemic nitric oxide level is increased in the subject at 2, 4, 6, 8, 10, 12. 18, 24, 28, 32, and / or 36 hours after such administration, typically as compared to the systemic nitric oxide level measured prior to administration of the transdermal composition (e.g., emulsion). In some embodiments of any of the aspects and embodiments herein that include a method for delivering the at least one agent to the bloodstream of a subject, the at least one weak organic acid comprises citric, acid and in illustrative embodiments the at least one non-ionic emulsifier comprises polysorbate 80. In some embodiments of any of the aspects and embodiments herein that include a method for delivering the at least one agent to tire blood stream of a subject, wherein the subject is being treated with a GLP-1 agonist.

[0113] In some embodiments of any of the aspects and embodiments herein that include an emulsion for topical administration, the oil comprising linoleic acid is safflower oil. In some embodiments, the subject is being treated with a GLP-1 agonist, in some embodiments within one week from the administering. In some embodiments, the agent comprises a nitric oxide pathway nitrogenous agent, a nitric oxide supporting agent, or a nitric oxide adjunct, or a combination thereof. In some embodiments, the agent further comprises creatine, glutamine, norvaline, ornithine, histidine, beta-alanine, agmatine, betaine, L- theanine, glutathione, or any nitrate, or any combination thereof.

[0114] In one aspect, provided herein is an emulsion for topical administration comprising: a) an aqueous phase comprising: citric acid, or a salt thereof, in an amount that is about 15% to about 35% w / w of the emulsion: water in an amount that is about 15% to about 35% w / w of the emulsion: and glacial acetic acid, or a salt or ion thereof, in an amount that is about 0% to about 2% w / w of the emulsion; and an agent that is about 15% to about 25% w / w of the emulsion, wherein the agent comprises ascorbic acid or it’s derivative and arginine, citrulline, citrulline malate, any plant-based nitrate source, in illustrative embodiments beetroot, or any combination thereof; and b) an oil phase comprising: an oil in amount that is about 3% to about 15% w / w of the emulsion, wherein the oil comprises less than 15% saturated fatty acids, and wherein the oil comprises linoleic acid, an unsaturated fatty acid in an amount that is about 1% to about 20% w / w of the emulsion, wherein the unsaturated fatty acid comprises oleic acid; glycerin in an amount that is about 0.0% to about 7% w / w of the emulsion; and polysorbate 80 that is about 5% to aboutAttorney Docket No. LAB.003 4.W0.01about 75% w / w of the aqueous phase and about 25% to about 45% w / w of the oil phase, and wherein topical administration of the composition to the skin of a subject provides for a relative increase in a systemic nitric oxide level in the subject as compared to a systemic nitric oxide level measured prior to administration of the composition.

[0115] In one aspect, provided herein is a method for making a transdermal emulsion, comprising: (a) making an aqueous phase by combining aqueous phase components comprising: at least one weak organic acid, wherein the at least one weak organic acid in total is present in an amount from 35% to 65.0% w / w of the aqueous phase; at least one agent, wherein the at least one agent in total is present in an amount from 1.0% to 25.0% w / w of the aqueous phase; and water, present in an amount from 15.0% to 95.0% w / w of the aqueous phase; (b) making an oil phase by combining oil phase components comprising: at least one fatty acid source comprising at least one cis unsaturated fatty acid selected from oleic acid and linoleic acid, wherein the at least one fatty acid source in total is present in an amount from 15.0% to 65.0% w / w of the oil phase; and at least one non-ionic emulsifier comprising one or more cis unsaturated fatty acids, wherein the at least one non-ionic emulsifier in total is present in an amount from 40% to 80% w / w of the oil phase; (c) combining the aqueous phase and oil phase to form a formulation; and (d) mixing the formulation, thereby forming tire transdermal emulsion, wherein the non-ionic emulsifier comprises or is derived from one or more cis-oleic acid residues and / or one or more cis-linoleic acid residues, wherein the transdermal emulsion comprises 50% to 90% w / w of the aqueous phase, and 10% to 50% w / w of the oil phase and has total fatty acids and / or CIO or longer hydrocarbons that comprise less than or equal to a total of 15.0% w / w of saturated fatty acids, and / or saturated CIO or longer non-fatty acid hydrocarbons, wherein the combination of the aqueous phase and the oil phase equals 100% w / w of the transdermal emulsion, wherein the at least one agent comprises any nitric oxide-increasing agent provided herein. For example, tire agent can be arginine, citrulline, citrulline malate, and a plant-derived nitrate source, for example beetroot, or a combination thereof. In one embodiment the agent comprises creatine, glutamine, leucine, norvaline, ornithine, histidine, beta- alanine, phenylalanine, agmatine, betaine, L-theanine, glutathione, or any nitrate or any nitrite, any nitro, or any nitroso or salt thereof, or any combination thereof. The transdermal emulsion is typically capable of delivering the agent to the blood stream of a subject when applied to the skin of the subject and increasing systemic nitric oxide level in the subject.

[0116] In one aspect, provided herein is a transdermal composition in the form of an emulsion comprising at least one weak organic acid; at least one agent; water, in illustrative embodiments, present in a weight ratio from 0.5: 1 to 45: 1 relative to the at least one weak organic acid in total; at least one fatty¬ acid source comprising at least one cis unsaturated fatty acid selected from oleic acid and linoleic acid; and at least one non-ionic emulsifier comprising one or more cis unsaturated fatty acids. In someAttorney Docket No. LAB.003 4.W0.01embodiments, the non-ionic emulsifier comprises or is derived from one or more oleic acid residues and / or one or more linoleic acid residues. In some embodiments, the at least one weak organic acid is present in total in an amount from 0.2% to 45.0% w / w of the emulsion. In some embodiments of any of the aspects and embodiments herein that include a transdermal composition, the at least one agent in total is present in a weight ratio from 0.1 : 1.0 to 3.0: 1.0 relative to the at least one weak organic acid in total. In some embodiments of any of the aspects and embodiments herein that include a transdermal composition, the at least one fatty acid source in total is present in a weight ratio from 0.2: 1.0 to 4.0: 1.0 relative to the at least one weak organic acid in total. In some embodiments of any of the aspects and embodiments herein that include a transdermal composition, the at least one non-ionic emulsifier in total is present in a weight ratio from 1.0: 1.0 to 5.0: 1.0 relative to the at least one weak organic acid in total. In some embodiments of any of the aspects and embodiments herein that include a transdermal composition, the transdennal composition has a pH in the range of 2.0 to 5.5. In some embodiments of any of the aspects and embodiments herein that include a transdermal composition, total fatty acids and / or CIO or longer non-fatty acid hydrocarbons, if present in the emulsion, comprise less than or equal to a total of 15.0% w / w of saturated fatty acids and / or saturated CIO or longer non-fatty acid hydrocarbons. In some embodiments of any of the aspects and embodiments herein that include a transdermal composition, the transdermal composition is capable of delivering the at least one agent to the bloodstream of a subject when applied to the skin of the subject.

[0117] In another aspect, provided herein is a multi-component transdennal system comprising:(a) an aqueous phase comprising at least one weak organic acid, at least one agent, and water: and (b) an oil phase comprising at least one fatty acid source comprising at least one cis unsaturated fatty acid selected from oleic acid and linoleic acid, and at least one non-ionic emulsifier comprising one or more cis unsaturated fatty acids.

[0118] In some embodiments, the non-ionic emulsifier comprises or is derived from one or more oleic acid residues and / or one or more linoleic acid residues. In some embodiments, tire transdermal system is capable of forming a transdermal emulsion having total fatty acids and / or Cio or longer hydrocarbons that comprise less than or equal to a total of 15.0% w / w of saturated fatty acids and / or saturated Cio or longer non-fatty acid hydrocarbons. In some embodiments of any of the aspects and embodiments herein that include a multi-component transdermal system, the at least one weak organic acid is in total present in an amount from 1.0% to 75.0% w / w of the aqueous phase. In some embodiments, the water is present in the aqueous phase in a weight ratio from 0.5: 1.0 to 45: 1.0 relative to the at least one weak organic acid in total present in the aqueous phase

[0119] In some embodiments of any of the aspects and embodiments herein that include a multicomponent transdermal system, the at least one agent in total present in the aqueous phase is present in aAttorney Docket No. LAB.003 4.W0.01weight ratio from 0.1 : 1.0 to 3.0: 1.0 relative to the at least one weak organic acid in total present in the aqueous phase.

[0120] In some embodiments of any of the aspects and embodiments herein that include a multicomponent transdermal system, the aqueous phase has a pH in the range of 2.0 to 5.5, 3.0 to 5.5, 3.5 to 5.5, or 4.0 to 5.5.

[0121] In some embodiments of any of the aspects and embodiments herein that include a multicomponent transdermal system, the at least one fatty acid source in total present in tire oil phase is present in a weight ratio from 0.2: 1.0 to 30: 1.0 relative to the at least one weak organic acid in total present in the aqueous phase.

[0122] In some embodiments of any of tire aspects and embodiments herein that include a multicomponent transdermal system, the at least one non-ionic emulsifier in total present in the oil phase is present in a weight ratio from 0.5 : 1.0 to 25 : 1.0 relative to the at least one weak organic acid in total present in the aqueous phase.

[0123] In some embodiments of any of tire aspects and embodiments herein that include a multicomponent transdermal system, the combination of the aqueous phase and the oil phase equals 100% w / w of the emulsion.

[0124] In some embodiments of any of the aspects and embodiments herein that include a multicomponent transdermal system, the transdermal emulsion is capable of delivering the at least one agent to the bloodstream of a subject when applied to the skin of the subject.

[0125] In another aspect, provided herein is a transdermal composition in the fonn of an emulsion comprising at least one weak organic acid; at least one agent; water; at least one non-ionic emulsifier comprising one or more cis unsaturated fatty acids; and at least one fatty acid source comprising at least one cis unsaturated fatty acid selected from oleic acid and linoleic acid.

[0126] In some embodiments of any of the aspects and embodiments herein that include a transdennal composition, the at least one weak organic acid in total is present in an amount from 0.2% to 45.0% w / w of the emulsion.

[0127] In some embodiments of any of tire aspects and embodiments herein that include a transdermal composition, each agent of the at least one agent has a molecular weight less than or equal to 2,000 Da.

[0128] In some embodiments of any of the aspects and embodiments herein that include a transdennal composition, the at least one agent in total is present in an amount from 1.0% to 20.0% w / w of the emulsion.

[0129] In some embodiments of any of tire aspects and embodiments herein that include a transdermal composition, water is present in an amount from 10.0% to 85.0% w / w of the emulsion.

[0130] In some embodiments of any of the aspects and embodiments herein that include a transdermalAttorney Docket No. LAB.003 4.W0.01composition, the at least one non-ionic emulsifier in total is present in an amount from 3.0% to 35.0% w / w of the emulsion.

[0131] In some embodiments of any of the aspects and embodiments herein that include a transdermal composition, the at least one fatty acid source in total is present in an amount from 5.0% to 25.0% w / w of the emulsion.

[0132] In some embodiments of any of the aspects and embodiments herein that include a transdennal composition, the transdermal composition has a pH in the range of 2.0 to 5.5, 3.0 to 5.5. 3.5 to 5.5, or 4.0 to 5.5.

[0133] In some embodiments of any of tire aspects and embodiments herein that include a transdermal composition, total fatty’ acids and Cio or longer hydrocarbons in the emulsion comprise less than or equal to 15.0% w / w of saturated fatty acids and / or saturated Cio or longer non-fatty acid hydrocarbons.

[0134] In some embodiments of any of the aspects and embodiments herein that include a transdermal composition, the transdermal composition is capable of delivering at least one of the at least one agent to the bloodstream of a subject when applied to the skin of the subject.

[0135] In another aspect, provided herein is a multi-component transde mial system comprising:(a) an aqueous phase comprising at least one weak organic acid, at least one agent, and water: and (b) an oil phase comprising at least one fatty acid source comprising at least one cis unsaturated fatty acid selected from oleic acid and linoleic acid, and at least one non-ionic emulsifier comprising one or more cis unsaturated fatty acids;wherein the non-ionic emulsifier comprises or is derived from one or more cis-oleic acid residues and / or one or more cis-linoleic acid residues, and wherein the oil phase and the aqueous phase are capable of forming a transdermal emulsion comprising 50% to 90% w / w of the aqueous phase and 10% to 50% w / w of tire oil phase, having total fatty acids and / or C io or longer hydrocarbons that together comprise less than or equal to a total of 15.0% w / w of saturated fatty acids and / or saturated Cio or longer non-fatty acid hydrocarbons.

[0136] In some embodiments of any of the aspects and embodiments herein that include a multicomponent transdennal system, the at least one weak organic acid in total is present in an amount from 35% to 65.0% w / w of the aqueous phase.

[0137] In some embodiments of any of the aspects and embodiments herein that include a multicomponent transdermal system, the at least one agent in total is present in an amount from 1.0% to 25.0% w / w of the aqueous phase.

[0138] In some embodiments of any of tire aspects and embodiments herein that include a multicomponent transdermal system, water is present in an amount from 15.0% to 95.0% w7w of the aqueous phase.Attorney Docket No. LAB.003 4.W0.01

[0139] In some embodiments of any of the aspects and embodiments herein that include a multicomponent transdermal system, the at least one fatty acid source in total is present in an amount from 15.0% to 65.0% w / w of the oil phase.

[0140] In some embodiments of any of tire aspects and embodiments herein that include a multicomponent transdermal system, the at least one non-ionic emulsifier in total is present in an amount from 40% to 80% w / w of the oil phase.

[0141] In some embodiments of any of the aspects and embodiments herein that include a composition, a multi-component transdermal system and / or an emulsion, the combination of the aqueous phase and the oil phase equals 100% w / w of the emulsion.

[0142] In one aspect, provided herein is an emulsion for topical administration comprising:an aqueous phase comprising: citric acid, or a salt thereof, in an amount that is 15% to 35% w / w of the emulsion;water in an amount that is 15% to 35% w / w of the emulsion; andglacial acetic acid, or a salt or ion thereof, in an amount that is 0% to 2% w / w of the emulsion; an agent that is 15% to 25% w / w of the emulsion, wherein the agent comprises ascorbic acid or its derivative and arginine, citrulline, citrulline malate, beetroot, creatine, glutamine, leucine, norvaline. ornithine, histidine, beta-alanine, phenylalanine, agmatine, betaine, L-theanine, glutathione, or any nitrate or any nitrite, any nitro, or any nitroso or salt thereof, or any combination thereof; andan oil phase comprising:an oil in amount that is 3% to 15% w / w of tire emulsion, wherein the oil comprises less than 15% saturated fatty acids;an unsaturated fatty acid in an amount that is 1% to 20% w / w of the emulsion; glycerin in an amount that is 0.0% to 7% w / w of the emulsion; andpolysorbate 80 that is 5% to 50% wAv of the emulsion,wherein the emulsion comprises from 55% to 75% w / w of the aqueous phase and 25% to 45% w / w of the oil phase, and wherein topical administration of the composition to the skin of a subject provides for a relative increase in a systemic nitric oxide level in the subject as compared to a systemic nitric oxide level prior to administration of the composition. In some embodiments of any of the aspects and embodiments herein that include an emulsion for topical administration, the nitric oxide level is imputed from a measure of salivary nitrite.

[0143] In another aspect, provided herein is a transdermal composition in the form of an emulsion, comprising at least one weak organic acid present in total in an amount from 0.2% to 45.0% w / w of the emulsion; at least one agent, wherein the at least one agent in total is present in a weight ratio from 0.1 : 1.0 to 3.0: 1.0 relative to the total weak organic acid: water present in a weight ratio from 0.5 : 1.0 toAttorney Docket No. LAB.003 4.W0.0145: 1.0 relative to the total weak organic acid; at least one fatty acid source comprising at least one cisunsaturated fatty acid selected from oleic acid and linoleic acid, wherein the fatty acid source in total is present in a weight ratio from 0.2: 1.0 to 4.0: 1.0 relative to the total weak organic acid; and at least one non-ionic emulsifier comprising one or more cis-unsaturated fatty acids, wherein the non-ionic emulsifier in total is present in a weight ratio from 1.0: 1.0 to 5.0: 1.0 relative to tire total weak organic acid. In some embodiments , the transdermal composition has a pH in the range of 2.0 to 5.5; total fatty acids and / or CIO or longer non-fatty acid hydrocarbons, if present, comprise less than or equal to 15.0% w / w saturated fatty acids and / or saturated hydrocarbons; and the non-ionic emulsifier comprises or is derived from oleic acid residues and / or linoleic acid residues. In some embodiments, the agent comprises one or more of arginine, citrulline, citrulline malate, beetroot, creatine, glutamine, leucine, norvaline, ornithine, histidine, beta-alanine, phenylalanine, agmatine, betaine, L-theanine, glutathione, or any nitrate, nitrite, nitro, or nitroso compound or salt thereof, or any combination thereof. In some embodiments, the transdermal composition is capable of delivering the at least one agent to the bloodstream of a subject when applied to the skin, thereby increasing systemic nitric oxide levels in the subject.

[0144] In some embodiments of any of the aspects and embodiments herein that include a transdennal composition, the agent further comprises ascorbic acid or a derivative thereof.

[0145] In another aspect, provided herein is a multi-component transdermal system, comprising:(a) an aqueous phase including at least one weak organic acid in total present in an amount from 1.0% to 75.0% w / w of the aqueous phase; at least one agent, wherein the at least one agent in total is present in the aqueous phase at a weight ratio from 0.1 : 1.0 to 3.0: 1.0 relative to the total weak organic acid; and water present in a weight ratio from 0.5 : 1.0 to 45 : 1.0 relative to the total weak organic acid, wherein the aqueous phase has a pH in the range of 2.0 to 5.5; and(b) an oil phase including at least one fatty acid source comprising at least one cis-unsaturated fatty acid selected from oleic acid and linoleic acid, wherein the total fatty acid source is present in an amount from 0.2: 1.0 to 30: 1.0 relative to the total weak organic acid; and at least one non-ionic emulsifier comprising one or more cis-unsaturated fatty acids, wherein the total non-ionic emulsifier is present in an amount from 0.5: 1.0 to 25: 1.0 relative to the total weak organic acid. In some embodiments, the non-ionic emulsifier comprises or is derived from one or more oleic acid residues and / or linoleic acid residues. In some embodiments, the combination of the aqueous phase and oil phase equals 100% w / w of the emulsion. In some embodiments, the transdermal system is capable of fonning a transdermal emulsion having total fatty acids and / or CIO or longer hydrocarbons that comprise less than or equal to 15.0% w / w of saturated fatty' acids and / or saturated hydrocarbons. In some embodiments, the agent comprises one or more of arginine, citrulline, citrulline malate, beetroot, creatine, glutamine, leucine, norvaline, ornithine, histidine, beta-alanine, phenylalanine, agmatine, betaine, L-theanine, glutathione, or any nitrate, nitrite.Attorney Docket No. LAB.003 4.W0.01nitro, or nitroso compound or salt thereof, or any combination thereof. In some embodiments, tire transdermal emulsion formed thereby is capable of delivering the at least one agent to the bloodstream of a subject upon topical application, increasing systemic nitric oxide levels in the subject.

[0146] In some embodiments of any of tire aspects and embodiments herein that include a multicomponent transdermal system, the agent further comprises ascorbic acid or a derivative thereof.

[0147] In another aspect, provided herein is a transdermal composition in tire form of an emulsion, comprising at least one weak organic acid, wherein the total weak organic acid is present in an amount from 0.2% to 45.0% w / w of the emulsion; at least one agent, wherein each agent has a molecular weight less than or equal to 2,000 Da, and the total agent amount is from 1.0% to 20.0% w / w of the emulsion; water in an amount from 10.0% to 85.0% w / w of the emulsion; at least one non-ionic emulsifier comprising one or more cis-unsaturated fatty acids in an amount from 3.0% to 35.0% w / w of the emulsion; and at least one fatty acid source comprising one or more cis-unsaturated fatty acids selected from oleic acid and linoleic acid in an amount from 5.0% to 25.0% w / w of the emulsion. In some embodiments, the transdermal composition has a pH in the range of 2.0 to 5.5, and total fatty acids and / or CIO or longer hydrocarbons comprise less than or equal to 15.0% w / w of saturated fatty acids and / or saturated non-fatty acid hydrocarbons. In some embodiments, the agent comprises one or more of arginine, citrulline, citrulline malate, beetroot, creatine, glutamine, leucine, norvaline, ornithine, histidine, beta-alanine, phenylalanine, agmatine, betaine, L-theanine, glutathione, or any nitrate, nitrite, nitro, or nitroso compound or salt thereof, or any combination thereof. In some embodiments, the transdermal composition is capable of delivering at least one of the agents to the bloodstream of a subject when applied to the skin, thereby increasing systemic nitric oxide levels in the subject.

[0148] In some embodiments of any of tire aspects and embodiments herein that include a transdermal composition, the agent further comprises ascorbic acid or a derivative thereof.

[0149] In another aspect, provided herein is a multi-component transde mial system, comprising:(a) an aqueous phase including at least one weak organic acid present in total in an amount from 35% to 65.0% w / w of the aqueous phase; at least one agent present in an amount from 1.0% to 25.0% w / w of the aqueous phase; and water present in an amount from 15.0% to 95.0% w / w of the aqueous phase; and (b) an oil phase including at least one fatty acid source comprising one or more cis-unsaturated fatty acids selected from oleic acid and linoleic acid, wherein the total fatty acid source is present in an amount from 15.0% to 65.0% w / w of the oil phase, and at least one non-ionic emulsifier comprising one or more cis-unsaturated fatty acids in an amount from 40% to 80% w / w of the oil phase. In some embodiments, the non-ionic emulsifier comprises or is derived from one or more cis-oleic acid residues and / or one or more cis-linoleic acid residues. In some embodiments, the oil phase and aqueous phase are capable of fonning a transdennal emulsion comprising 50% to 90% w / w of the aqueous phase and 10% to 50% w / w of the oilAttorney Docket No. LAB.003 4.W0.01 phase. In some embodiments, the transdermal emulsion has total fatty acids and / or Cw or longer hydrocarbons that comprise less than or equal to 15.0% w / w of saturated fatty acids and / or saturated hydrocarbons. In some embodiments, the combination of the aqueous phase and oil phase equals 100% w / w of the emulsion. In some embodiments, the agent comprises one or more of arginine, citrulline, citrulline malate, beetroot, creatine, glutamine, leucine, norvaline, ornithine, histidine, beta-alanine, phenylalanine, agmatine, betaine, L-theanine, glutathione, or any nitrate, nitrite, nitro, or nitroso compound or salt thereof, or any combination thereof. In some embodiments, the transdermal emulsion is capable of delivering the agent to the bloodstream of a subject upon application to the skin and increasing systemic nitric oxide levels in the subject.

[0150] In some embodiments of any of tire aspects and embodiments herein that include a multicomponent transdermal system, the agent further comprises ascorbic acid or a derivative thereof.

[0151] In some embodiments of any of the aspects and embodiments herein that include an emulsion, the oil comprises fish oil, safflower oil, high-oleic oil, grapeseed oil, rapeseed oil, flaxseed oil, hemp oil, walnut oil, poppyseed oil, com oil, soybean oil, cottonseed oil, peanut oil, hemp oil, wheatgerm oil, rice bran oil, pistachio oil, canola oil, egg yolk, linseed oil, sunflower oil, avocado oil, sesame oil, olive oil, canola oil. or any combination thereof.

[0152] In some embodiments of any of the aspects and embodiments herein that include an emulsion, the oil comprises safflower oil.

[0153] In some embodiments of any of tire aspects and embodiments herein that include an emulsion, the oil comprises less than 20%. 15%. 10%, 5%, 4%, 3%, or 2% saturated fatty acids.

[0154] In some embodiments of any of the aspects and embodiments herein that include an emulsion, a transdermal composition, or a multi-component transdermal system, the unsaturated fatty acid comprises palmitoleic acid, oleic acid, myristoleic acid, linoleic acid, arachidonic acid, or any combination thereof.

[0155] In some embodiments of any of the aspects and embodiments herein that include an emulsion, a transdermal composition, or a multi-component transdermal system, tire unsaturated fatty acid comprises oleic acid.

[0156] In some embodiments of any of tire aspects and embodiments herein that include an emulsion, a transdermal composition, or a multi-component transdermal system, the agent comprises ascorbic acid and citrulline, in some embodiments, in a 1: 1 ratio.

[0157] In some embodiments of any of the aspects and embodiments herein that include an emulsion, a transdermal composition, or a multi-component transdermal system, the agent comprises ascorbic acid, citrulline, and arginine in a 1: 1: 1-0.25 ratio.

[0158] In some embodiments of any of the aspects and embodiments herein that include an emulsion, a transdermal composition, or a multi-component transdermal system, tire formulation further comprises anAttorney Docket No. LAB.003 4.W0.01 additional compound. In some embodiments, the additional compound comprises a nutritional supplement, a systemic medication, a targeted therapy, or any combination thereof.

[0159] In another aspect, provided herein is an emulsion comprising an aqueous phase comprising 23-27 g citric acid, 23-27 g water, 0.2-0.3 g glacial acetic acid, 6-7 g citrulline, and 6-7 g ascorbic acid per 100 g of emulsion; and an oil phase comprising 6-7 g safflower oil, 2.5-3.5 g oleic acid, 0.5-1.5 g glycerin, and 23-27 g polysorbate 80 per 100 g of emulsion. The emulsion comprises 60-70% of the aqueous phase and 30-40% of the oil phase.

[0160] In some embodiments of any of the aspects and embodiments herein that include an emulsion, the nitric oxide level is imputed from a measure of salivary nitric oxide.

[0161] In another aspect, provided herein is an emulsion for topical administration comprising an aqueous phase including 2327 g citric acid, 23-27 g water, 0.2-0.3 g glacial acetic acid. 3.5-4.5 g citrulline, 3.5-4.5 g arginine, and 3.5-4.5 g ascorbic acid per 100 g of emulsion; and an oil phase including 6-7 g safflower oil, 2.5-3.5 g oleic acid, 0.5-1.5 g glycerin, and 23-27 g polysorbate 80 per 100 g of emulsion.

[0162] In some embodiments of any of the aspects and embodiments herein that include an emulsion, the oil comprises one or more of fish oil, safflower oil, high -oleic oil, grapeseed oil. rapeseed oil, flaxseed oil, hemp oil, walnut oil, poppyseed oil, com oil, soybean oil, cottonseed oil, peanut oil, wheatgerm oil, rice bran oil, pistachio oil, canola oil, egg yolk, linseed oil, sunflower oil, avocado oil, sesame oil, olive oil, or any combination thereof.

[0163] In some embodiments of any of the aspects and embodiments herein that include an emulsion, the oil comprises safflower oil.

[0164] In some embodiments of any of tire aspects and embodiments herein that include an emulsion, the oil comprises less than 20% saturated fatty acids.

[0165] In some embodiments of any of the aspects and embodiments herein that include an emulsion, a transdennal composition, or a multi-component transdermal system, tire unsaturated fatty acid comprises palmitoleic acid, oleic acid, myristoleic acid, linoleic acid, arachidonic acid, or any combination thereof.

[0166] In some embodiments of any of the aspects and embodiments herein that include an emulsion, a transdermal composition, or a multi-component transdermal system, the unsaturated fatty acid comprises oleic acid.

[0167] In some embodiments of any of the aspects and embodiments herein that include an emulsion, a transdermal composition, or a multi-component transdermal system, the agent comprises ascorbic acid and citrulline in a 1 : 1 ratio.

[0168] In some embodiments of any of the aspects and embodiments herein that include an emulsion, a transdennal composition, or a multi-component transdermal system, tire agent comprises ascorbic acid,Attorney Docket No. LAB.003 4.W0.01 citrulline, and arginine in a 1: 1: 1-0.25 ratio.

[0169] In some embodiments of any of the aspects and embodiments herein that include an emulsion, a transdennal composition, or a multi-component transdermal system, tire composition further comprises an additional compound. In some embodiments, the additional compound comprises a nutritional supplement, a systemic medication, a targeted therapy, or any combination thereof.

[0170] In another aspect, provided herein is an emulsion comprising an aqueous phase including, per 100 g of emulsion, 23-27 g citric acid, 23-27 g water. 0.2-0.3 g glacial acetic acid, 6-7 g citrulline, and 6-7 g ascorbic acid; and an oil phase including, per 100 g of emulsion, 6-7 g safflower oil, 2.5-3.5 g oleic acid, 0.5-1.5 g glycerin, and 23-27 g polysorbate 80. The emulsion comprises 60-70% of the aqueous phase and 30-40% of the oil phase. Topical administration of the composition to the skin of a subject provides a relative increase in systemic nitric oxide level as compared to a systemic nitric oxide level prior to administration.

[0171] In some embodiments of any of tire aspects and embodiments herein that include an emulsion, the nitric oxide level is imputed from a measure of salivary nitric oxide.

[0172] In another aspect, provided herein is an emulsion for topical administration comprising an aqueous phase including, per 100 g of emulsion, 23-27 g citric acid, 23-27 g water. 0.2-0.3 g glacial acetic acid, 3.5-4.5 g citrulline, 3.5-4.5 g arginine, and 3.5-4.5 g ascorbic acid; and an oil phase including, per 100 g of emulsion, 6-7 g safflower oil, 2.5-3.5 g oleic acid, 0.5-1.5 g glycerin, and 23-27 g polysorbate 80. Tire emulsion comprises 60-70% of the aqueous phase and 30-40% of the oil phase. Topical administration to the skin of a subject provides a relative increase in systemic nitric oxide level in the subject as compared to a systemic nitric oxide level prior to administration.

[0173] In some embodiments of any of tire aspects and embodiments herein that include an emulsion, the nitric oxide level is imputed from a measure of salivary nitric oxide.

[0174] In another aspect, provided herein is a method of generating an emulsion for topical administration comprising generating an aqueous composition that includes 30 to 60% w / w citric acid, 30 to 60% w / w water, and 0 to 2% w / w glacial acetic acid; stirring the aqueous composition at 500 to 2500 RPM for 2 to 15 minutes at 30-45 °C; further adding to the aqueous composition 5 to 40% w / w of an agent comprising arginine, citrulline, citrulline malate, beetroot, creatine, glutamine, leucine, norvaline, ornithine, histidine, beta-alanine, phenylalanine, agmatine, betaine, L-theanine, glutathione, or any nitrate or nitrite, nitro or nitroso compound or salt thereof, or any combination thereof, and 5 to 15% w / w ascorbic acid; stirring the aqueous composition at 500 to 2500 RPM for 2 to 15 minutes at 30-45 °C; generating an oil-based composition comprising 0 to 50% w / w oil, 10 to 50% w / w unsaturated fatty acid, 0 to 10% w / w glycerin, and 30 to 90% w / w polysorbate 80; stirring the oil -based composition at 500 RPM for 2 to 15 minutes at 20-30 °C: adding the oil-based composition to the aqueous composition overAttorney Docket No. LAB.003 4.W0.01at least 30 seconds and concurrently stirring the aqueous composition at 500 RPM and increasing to 2500 RPM at 30-45 °C to fonn an emulsion comprising 40 to 70% w / w of the aqueous composition and 30 to 60% w / w of the oil-based composition; and further stirring the emulsion for a combined total of 2 to 30 minutes in steps (g) and (h). In some embodiments, the emulsion is stirred at 2000 to 3500 RPM for 2 to 15 minutes at 30-45 °C. Topical administration of the resulting composition to the skin of a subject provides a relative increase in systemic nitric oxide level as compared to a systemic nitric oxide level measured prior to administration.

[0175] In some embodiments of any of the aspects and embodiments herein that include a method of generating an emulsion, the nitric oxide level is imputed from a measure of salivary nitric oxide.

[0176] In some embodiments of any of tire aspects and embodiments herein that include a method of generating an emulsion or applying a composition, tire oil comprises one or more of fish oil, safflower oil, high-oleic oil, grapeseed oil, rapeseed oil, flaxseed oil, hemp oil, walnut oil, poppyseed oil, com oil, soybean oil, cottonseed oil, peanut oil, wheatgerm oil, rice bran oil, pistachio oil, canola oil, egg yolk, linseed oil, sunflower oil, avocado oil, sesame oil, olive oil, or any combination thereof.

[0177] In some embodiments of any of the aspects and embodiments herein that include a method of generating an emulsion or applying a composition, the oil comprises safflower oil.

[0178] In some embodiments of any of the aspects and embodiments herein that include a transdermal composition, the at least one weak organic acid is present in total in an amount from 1.0% to 50.0% w / w of tire emulsion.

[0179] In some embodiments of any of the aspects and embodiments herein, the at least one weak organic acid is present in total in an amount from 2.0% to 45.0% w / w of the emulsion.

[0180] In some embodiments of any of the aspects and embodiments herein, the at least one weak organic acid is present in total in an amount from 0.1% to 10.0% w / w of the emulsion.

[0181] In some embodiments of any of the aspects and embodiments herein, the at least one weak organic acid comprises citric acid.

[0182] In some embodiments of any of the aspects and embodiments herein that include a multicomponent transdermal system, the at least one weak organic acid is present in total in an amount from 25% to 75% w / w of the aqueous phase.

[0183] In some embodiments of any of the aspects and embodiments herein, the at least one weak organic acid is present in total in an amount from 35% to 65% w / w of the aqueous phase.

[0184] In some embodiments of any of the aspects and embodiments herein, the at least one w eak organic acid is present in total in an amount from 0.2% to 10% w / w of the aqueous phase.

[0185] In some embodiments of any of the aspects and embodiments herein, the at least one weak organic acid comprises citric acid.Attorney Docket No. LAB.003 4.W0.01

[0186] In some embodiments of any of the aspects and embodiments herein that include a transdermal composition or a multi-component transdermal system, at least one agent of the at least one agent has a molecular weight of equal to or less than 2,500, 2,000, 1,500, or 1,000 Da.

[0187] In some embodiments of any of tire aspects and embodiments herein that include a transdermal composition, the total fatty acids and / or Cw or longer non-fatty acid hydrocarbons in the emulsion, from fatty acids present in the at least one non-ionic emulsifier and the at least one fatty acid source, together comprise less than or equal to 15.0% w / w of saturated fatty acids and / or saturated non-fatty acid hydrocarbons.

[0188] In some embodiments of any of the aspects and embodiments herein, the total fatty acids and / or CIO or longer non-fatty acid hydrocarbons in the emulsion comprise less than or equal to 10.0% w / w of saturated fatty acids and / or saturated non-fatty acid hydrocarbons.

[0189] In some embodiments of any of the aspects and embodiments herein, the total fatty acids and / or CIO or longer non-fatty acid hydrocarbons in the emulsion comprise less than or equal to 5.0% w / w of saturated fatty acids and / or saturated non-fatty acid hydrocarbons.

[0190] In some embodiments of any of the aspects and embodiments herein that include a transdennal composition, the agent comprises arginine, citrulline, citrulline malate, beetroot, creatine, glutamine, leucine, norvaline, ornithine, histidine, beta-alanine, phenylalanine, agmatine, betaine, L-theanine, glutathione, or any nitrate, nitrite, nitro, or nitroso compound or salt thereof, or any combination thereof.

[0191] In some embodiments of any of the aspects and embodiments herein, the agent further comprises ascorbic acid or its derivative.

[0192] In some embodiments of any of the aspects and embodiments herein that include a multicomponent transdennal system, the system is capable of forming an emulsion in which the total fatty acids derived solely from fatty acids in the at least one non-ionic emulsifier and the at least one fatty acid source comprise less than or equal to 15.0% w / w of saturated fatty acids.

[0193] In some embodiments of any of the aspects and embodiments herein, the total fatty acids derived from fatty acids in the at least one non-ionic emulsifier and the at least one fatty acid source comprise less than or equal to 10.0% w / w of saturated fatty acids.

[0194] In some embodiments of any of the aspects herein, tire multi-component transdermal system, or transdennal system, is capable of forming an emulsion in which the total fatty acids derived from the fatty acids in the at least one non-ionic emulsifier, the at least one fatty acid source, and any CIO or longer non-fatty acid hydrocarbons present in the emulsion together comprise less than or equal to 15.0% w / w of a total of saturated fatty acids and saturated non-fatty acid hydrocarbons.

[0195] In some embodiments of any of the aspects herein, the total fatty acids derived from the fatty acids in the at least one non-ionic emulsifier, the at least one fatty acid source, and any CIO or longer nonAttorney Docket No. LAB.003 4.W0.01 fatty acid hydrocarbons present in tire emulsion together comprise less than or equal to 10.0% w / w of a total of saturated fatty acids and saturated non-fatty acid hydrocarbons.

[0196] In some embodiments of any of the aspects and embodiments herein that include a multicomponent transdermal system or a transdermal composition, the at least one non-ionic emulsifier in total is present in a weight ratio from 1.0: 1.0 to 4.0: 1.0 relative to tire at least one weak organic acid in total.

[0197] In some embodiments of any of the aspects and embodiments herein, the at least one non-ionic emulsifier in total is present in a weight ratio from 2.0: 1.0 to 4.0: 1.0 relative to the at least one weak organic acid in total.

[0198] In another aspect, provided herein is a method for delivering at least one agent to the bloodstream of a subject, comprising administering a transdermal composition or emulsion as described in any of the aspects and embodiments herein to the skin of the subject, wherein at least one of the one or more agents penetrates the skin, and in illustrative embodiments enters the bloodstream of the subject within 24, 12, 8, 6, 4, 2, or 1 hour, or within 30, 15, 10, or 5 minutes after such administration. In another aspect, provided herein is a method for delivering at least one agent to the bloodstream of a subject, comprising administering a transdermal composition or emulsion as described in any of the aspects and embodiments herein to a mucus membrane or the skin of the subject, wherein the systemic nitric oxide level in the subject is increased at 4, 6, 12, 24, or 36 hours after such administration.

[0199] In some embodiments of any of tire aspects and embodiments herein that include a method of delivering an agent, the administering is performed once or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24, 30, 45, 60, 90, 120, 180, or 360 times, every 1, 2, 3. 4, 6, 8, 12, or 24 hours, or once or twice per day, week, or month. Such administering can be repeated for up to, or in illustrative embodiments at least 7, 14, 21, or 28 days, or 1, 2, 3, 6, 9, or 12 months.

[0200] In some embodiments of any of tire aspects and embodiments herein that include a method for increasing systemic nitric oxide levels, the administering is perfonned at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24, 30, 45, 60. 90. 120, 180. or 360 times, every 1, 2, 3, 4. 6, 8, 12, or 24 hours, or once or twice per day, week, or month.

[0201] In some embodiments, the subject is experiencing, or experienced within 30, 14, 7, or 1 day before the administering, weight loss, cachexia, or muscle atrophy . In some cases, tire condition comprises muscle mass loss, muscle fatigue, high blood pressure, reduced blood oxygen, or any combination thereof. With respect to blood pressure, in some embodiments of any method herein that involves administering a NO-increasing emulsion herein to a subject, the subject suffers from, or suffered from high blood pressure before tire administering. In some embodiments, the systolic blood pressure of the subject is reduced by at least 10, 20, 25, 30, 40 or 50 mmHg, or between 10 and 50, 40, 30, or 25 mmHg after the administering compared to before the administering. Hie administering in suchAttorney Docket No. LAB.003 4.W0.01 embodiments can be a single administration or can be multiple administrations according to any dosing amount and frequency herein. As such in some embodiments, the systolic blood pressure of the subject is reduced by between 10 and 50 mmHg at 1, 2, 4, 8, 12, 18, or 24 hours after the most recent or last administering compared to before the first administering, and wherein the administering is daily dosing for at least 5, 7, 14, or 28 days, or 1, 2, 3, 6, 9, or 12 months. In some embodiments, before the time of the first administering includes 120. 60, 50, 40, 30, 20, 10, 5, 2, or 1 minutes before, or at the time of the first administering.

[0202] In some embodiments, the administering of the transdermal composition or emulsion is performed in an amount of at least 0.1 oz, 1.0 oz, 5.0 oz, 10.0 oz, 20.0 oz, 50.0 oz, between 0.1 oz and 10.0 oz, 0.1 oz and 5.0 oz, 0.5 and 1.5 oz, in illustrative embodiments, between 0.75 and 1.25 oz, or 1 oz. In some embodiments, the administering comprises contacting at least one area of the skin of the subject one or more times. In some embodiments, at least one agent, of the at least one agent, penetrates the skin within 10, 20, or 30 seconds, or 1, 2, 3, 4, 5, 10, 15, or 20 minutes after the administering. In some embodiments, the agent comprises citrulline, citrulline malate, or a combination thereof to provide a total citrulline, and wherein the amount of total citrulline applied to the skin of the subject is at least 0.1 g, 0.5 g, 1.0 g. 2.5 g. 5.0 g, 10.0 g. 20.0 g, between 0.1 g and 20.0 g. 0.3 g and 10.0 g, in illustrative embodiments between 0.1 g and 5.0 g, or 0.2 and 3.0 g. In some embodiments, the agent comprises a plant-based nitrate source, in illustrative embodiments beetroot, or a combination thereof to provide a total nitrate source, and wherein tire amount of total nitrate source applied to the skin of the subject is at least 0.1 g, 0.5 g, 1.0 g, 2.5 g, 5.0 g, 10.0 g, 20.0 g, between 0.1 g and 20.0 g, 0.1 g and 10.0 g, in illustrative embodiments between 0.1 g and 5.0 g. In some embodiments, the agent comprises a plantbased nitrate source, in illustrative embodiments beetroot, or a combination thereof to provide a total nitrate source, and wherein the total percentage of the total nitrate source in the emulsion is at least 0.5%, 1.0%, 5.0%, 10.0%, 20.0%, 35.0%, between 0.25% and 20.0%, 0.25% and 10.0%, in illustrative embodiments 0.25% and 7.5%. In some embodiments, the agent comprises citrulline, citrulline malate, or a combination thereof to provide a total citrulline, and wherein the total percentage of total citrulline in the emulsion is at least 0.5%, 1.0%, 5.0%, 10.0%, 20.0%, 35.0%, between 0.5% and 20.0%, 0.75% and 10.0%, in illustrative embodiments 1.0% and 7.5%. In some embodiments, the total amount of citrulline malate applied to the skin of the subject is at least 0.1 g. 0.5 g. 1.0 g, 2.5 g, 5.0 g, 10.0 g, 20.0 g. between 0.1 g and 20.0 g, 0.1 g and 10.0 g, in illustrative embodiments between 0.1 g and 5.0 g, or 0.3 g and 2.0 g. In some embodiments, the agent comprises citrulline malate 1:2, or in illustrative embodiments citrulline malate 1: 1 or citrulline malate 2: 1, or a combination thereof, and wherein the total percentage of citrulline malate in the emulsion is at least 0.5%, 1.0%, 5.0%, 10.0%, 20.0%, 35.0%, between 0.5% and 20.0%. 0.75% and 10.0%, in illustrative embodiments 1.0% and 7.5%. In some embodiments, the agentAttorney Docket No. LAB.003 4.W0.01 comprises arginine, and wherein tire amount of arginine applied to the skin of the subject is at least 0.1 g, 0.5 g, 1.0 g, 2.5 g, 5.0 g. 10.0 g, 20.0 g, between 0.1 g and 20.0 g, 0.1 g and 10.0 g, 0.1 g and 4.0 g, in illustrative embodiments between 0.2 g and 2.0 g. In some embodiments, the agent comprises arginine, and wherein the total percentage of arginine in the emulsion is at least 0.5%, 1.0%, 5.0%, 10.0%, 20.0%, 35.0%, between 0.1% and 20.0%, 0.1% and 10.0%, in illustrative embodiments 0.1% and 5.0%, or 0.25% and 2.0%.

[0203] In some embodiments, the subject suffers from low blood oxygen, and the subjects blood oxygen increases by 1-10, 2-8, or 4-6% afterthe administering compared to before the administering. The administering in such embodiments can be a single administration or can be multiple administrations according to any dosing amount and frequency herein. As such in some embodiments, the blood oxygen (SpO2) of the subject is reduced by between 2-8% or 4-6% at 1. 2, 4, 8, 12, 18, or 24 hours afterthe most recent or last administering compared to before the first administering, and wherein the administering is daily dosing for at least 5, 7, 14, or 28 days, or 1, 2, 3, 6, 9, or 12 months. In some embodiments, before the time of the first administering includes 120, 60, 50, 40, 30, 20, 10, 5, 2, or 1 minutes before, or at the time of the first administering.

[0204] In some embodiments of any of the aspects and embodiments herein that include a method of administration, the blood pressure of the subject decreases within 120, 60, 30, 20, or 15 minutes afterthe administering.

[0205] In some embodiments of any of tire aspects and embodiments herein that include a method of administration, the transdermal composition or emulsion comprises an ion, and the blood level of the ion in the subject increases following administration.

[0206] In some embodiments, the transdermal composition or emulsion comprises an ion selected from potassium, sodium, chloride, bicarbonate, calcium, magnesium, or phosphate, and the level of the selected ion in the blood of the subject increases follow ing administration.

[0207] In some embodiments of any of the aspects and embodiments that include a transdermal formulation, a transdermal composition, a method, a multi-component system or a multi-component transdermal system, the total fatty acids, and Cio, Cm, C20, or longer non-fatty acid hydrocarbons if present in tire emulsion in total, comprise less than or equal to 25%, 20%, 15.0%, 10%, 9.0%, 8.0%, 7.0%, 6.0%. 5.0%, 4.0%, or 3.0% w / w of saturated fatty acids and / or saturated Cm, C15, C20 or longer non-fatty acid hydrocarbons. In some embodiments, the dermatological system is capable of forming an emulsion having total fatty acids and / or Cm or longer hydrocarbons present in the emulsion that comprise less than or equal to 25%, 20%, 15.0%, 10.0%, 9.0%, 8.0%, 7.0%, 6.0%, 5.0%, 4.0%, or 3.0% w / w of saturated fatty acids and / or saturated Cm or longer non-fatty acid hydrocarbons. In some embodiments, the dermatological system is capable of forming an emulsion having total fatty acids from only fatty acidsAttorney Docket No. LAB.003 4.W0.01 in the at least one non-ionic emulsifier and the at least one fatty acid source in total, that comprise less than or equal to 25%, 20%, 15.0%, 10.0%, 9.0%, 8.0%, 7.0%. 6.0%, 5.0%, 4.0%, or 3.0% w / w of saturated fatty acids. In some embodiments, the dermatological system is capable of fonning an emulsion having total fatty acids and / or Cio or longer hydrocarbons present in the emulsion that comprise less than or equal to 25%, 20%, 15.0%, 10.0%, 9.0%, 8.0%, 7.0%, 6.0%, 5.0%, 4.0%, or 3.0% w / w of saturated fatty acids and / or saturated Cio or longer non-fatty acid hydrocarbons. In some embodiments, the dermatological system is capable of forming an emulsion having total fatty acids from fatty acids in the at least one non-ionic emulsifier and the at least one fatty acid source, and saturated non-fatty acid hydrocarbons from the Cio or longer hydrocarbons present in the emulsion that in total comprise less than or equal to atotal of 25%, 20%, 15.0%, 10.0%, 9.0%, 8.0%, 7.0%, 6.0%, 5.0%, 4.0%, or 3.0% w / w of saturated fatty acids and saturated Cio or longer non-fatty acid hydrocarbons in the emulsion. In some embodiments, the at least one weak organic acid in total is present in a weight ratio from 0.02:0.9 to 2.0:0.9 relative to the aqueous phase.

[0208] In some embodiments or any of tire aspects and embodiments that include an agent, the agent has a molecular weight of equal to or less than 10.000 Daltons (D), 5,000 D, 2,500 D, 2,000 D, 1,500 D, 1,000 D, or 500 D or a therapeutic agent between 200 and 1,000 D or between 200 and 500 D.

[0209] In another aspect, provided herein is a method for delivering at least one agent to the bloodstream of a subject, comprising administering a transdermal composition or emulsion as described in any of the aspects and embodiments herein to the skin of the subject, wherein the agent enters the bloodstream of the subject within 24, 12, 8, 6, 4, 2, or 1 hour after such administration.

[0210] In some embodiments of any of the aspects and embodiments herein that include a method of delivering an agent, the administering is performed at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24, 30, 45, 60, 90, 120, 180, or 360 times, every 1, 2, 3, 4, 6, 8, 12, or 24 hours, or once or twice per day, week, or month.

[0211] In some embodiments of any of the aspects and embodiments herein that include a method of delivery, the transdermal composition or emulsion comprises an ion, and the blood level of the ion in the subject increases following administration.

[0212] In some embodiments of any of tire aspects and embodiments herein that include a method of delivery, the transdennal composition or emulsion comprises an ion selected from potassium, sodium, chloride, bicarbonate, calcium, magnesium, and phosphate, and the level of the ion in the blood of the subject increases following administration.

[0213] In another aspect, provided herein is a method for delivering at least one agent to the bloodstream of a subject, comprising administering a transdermal composition or emulsion as described in any of the aspects and embodiments herein to the skin of the subject, wherein the agent enters the bloodstream of the subject within 24, 12, 8, 6, 4, 2, or 1 hour after such administration.Attorney Docket No. LAB.003 4.W0.01

[0214] In some embodiments of any of the aspects and embodiments herein that include a method of delivering an agent, the administering is performed at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24. 30, 45, 60, 90, 120, 180, or 360 times, every 1, 2, 3, 4, 6, 8, 12, or 24 hours, or once ortwice per day, week, or month.

[0215] In some embodiments of any of tire aspects and embodiments herein that include a method of delivery, the transdermal composition or emulsion comprises an ion, and the blood level of the ion in the subject increases following administration.

[0216] In some embodiments of any of the aspects and embodiments herein that include a method of delivery, the transdermal composition or emulsion comprises an ion selected from potassium, sodium, chloride, bicarbonate, calcium, magnesium, and phosphate, and the level of the ion in the blood of the subject increases following administration.

[0217] In one aspect, provided herein is a method of preventing or reducing muscle mass loss that is correlated to treatment with a weight loss therapy, in illustrative embodiments, a GLP- 1 agonist comprising topical administration of a transdermal composition (e.g., a transdermal emulsion) provided herein.

[0218] In some embodiments of any of the aspects or embodiments herein, the subject is experiencing, afflicted with, or has, one or more of the following conditions: a wasting disease; age-related muscular degeneration; menstrual cramps; menopausal symptoms: infertility; cancer symptoms; cancer drug sideeffects, symptoms following chemotherapy; loss of strength and structure to hair; grayed hair color; lost hair follicles; desire to improve skin color, tone, clarity, surface, pores, and hydration; acne; asthma, reduced oxygen and / or blood flow capacity for example in a subject with asthma; elevated heart rate, a fever, a desire to decrease body temperature, cardiovascular disease (CVD); chronic obstructive pulmonary disease (COPD); emphysema; dementia; neuropathy; diabetes; undergoing dialysis; a desire to improve appearance of their fingernails and toenails; nail fungus; jet lag; a desire to increase endurance, a desire to improve overall or sports-related performance, a desire to reduce recovery time in body building, exercise, and sports: undergoing an IV treatment; is about to undergo, or has undergone surgery with the past, or next 1 , 2, 3, 4, 7, 10, 14, or 28 days, or 1 month; a desire to increase gut microbiota; a desire to increase oral microbiota; a desire to increase immunity in treatment of colds, a flu, COVID-19, RSV; a desire to increase delivery and absorption of supplements; or reduced blood flow.

[0219] In some embodiments, the transdermal composition comprises an aqueous phase comprising citric acid, or a salt thereof; water; optionally glacial acetic acid, or a salt or ion thereof; an agent; and an oil phase comprising an oil, an unsaturated fatty acid, glycerin, and polysorbate 80. In some embodiments, citric acid is in an amount that is 15% to 35% w / w of tire aqueous phase. In some embodiments, water is in an amount that is 15% to 35% w / w of the aqueous phase. In some embodiments, glacial acetic acid is in an amount that is 0% to 2% w / w of the aqueous phase. In some embodiments, theAttorney Docket No. LAB.003 4.W0.01 agent is 15% to 25% w / w of the aqueous phase. In some embodiments, the agent comprises ascorbic acid or its derivative and arginine, citrulline, citrulline malate, beetroot, creatine, glutamine, leucine, norvaline, ornithine, histidine, beta-alanine, phenylalanine, agmatine, betaine, L-theanine, glutathione, or any nitrate or any nitrite, any nitro, or any nitroso or salt thereof, or any combination thereof. In some embodiments, the agent comprises arginine, citrulline, citrulline malate, and / or a plant-based nitrate source, in illustrative embodiments, beetroot, or combinations thereof.

[0220] In some embodiments, the oil is 3% to 15% w / w of the oil phase, and the oil comprises less than 15% saturated fatty acids. In some embodiments, the unsaturated fatty acid is in an amount that is 1% to 20% w / w of the oil phase. In some embodiments, polysorbate 80 is 5% to 50% w / w of the oil phase. In some embodiments, tire aqueous phase and the oil phase are combined to fomr the transdennal composition comprising from 55% to 75% w / w of the aqueous phase and 25% to 45% w / w of the oil phase. In some embodiments, topical administration of the transdermal composition to the skin of a subject provides for a relative increase in a systemic nitric oxide level in the subject as compared to a systemic nitric oxide level prior to administration of tire composition. In some embodiments of any of the aspects and embodiments herein that include a method, the nitric oxide level is imputed from a measure of salivary nitric oxide.

[0221] In another aspect, provided herein is a method of preventing or reducing muscle mass loss that is correlated to treatment with a GLP-1 agonist of a subject, comprising topically administering a transdermal composition in the form of an emulsion to the skin of the subject, wherein the transdermal composition comprises at least one weak organic acid, at least one agent, water, at least one fatty acid source comprising at least one cis unsaturated fatty acid selected from oleic acid and linoleic acid, and at least one non-ionic emulsifier comprising one or more cis unsaturated fatty acids. In some embodiments, the at least one weak organic acid is present in total in an amount from 0.2% to 45.0% w / w of the emulsion. In some embodiments, the at least one agent in total is present in a weight ratio from 0.1 : 1.0 to 3.0: 1.0 relative to the at least one weak organic acid in total. In some embodiments, water is present in a weight ratio from 0.5: 1 to 45: 1 relative to the at least one weak organic acid in total. In some embodiments, the at least one fatty acid source in total is present in a weight ratio from 0.2: 1.0 to 4.0: 1.0 relative to the at least one weak organic acid in total. In some embodiments, the at least one non-ionic emulsifier in total is present in a weight ratio from 1.0: 1.0 to 5.0: 1.0 relative to the at least one weak organic acid in total. In some embodiments, the transdermal composition has a pH in the range of 2.0 to 5.5. In some embodiments, total fatty acids and / or CIO or longer non-fatty acid hydrocarbons if present in the emulsion comprise less than or equal to a total of 15.0% w / w of saturated fatty acids and / or saturated CIO or longer non-fatty acid hydrocarbons. In some embodiments, the non-ionic emulsifier comprises or is derived from one or more oleic acid residues and / or one or more linoleic acid residues. In someAttorney Docket No. LAB.003 4.W0.01embodiments, the at least one agent comprises arginine, citrulline, citrulline malate, beetroot, creatine, glutamine, leucine, norvaline, ornithine, histidine, beta-alanine, phenylalanine, agmatine, betaine, L-theanine, glutathione, or any nitrate or any nitrite, any nitro, or any nitroso or salt thereof, or any combination thereof. In some embodiments, the topically administering of the emulsion to the skin of a subject provides for a relative increase in a systemic nitric oxide level in the subject as compared to a systemic nitric oxide level prior to the topically administering. In some embodiments of any of tire aspects and embodiments herein that include a method, the agent further comprises ascorbic acid or its derivative.

[0222] In another aspect, provided herein is a method of preventing or reducing muscle mass loss that is correlated to treatment with a GLP-1 agonist of a subject, comprising topically administering an emulsion to the skin of the subject, wherein the emulsion is fonned using a multi-component transdermal system, comprising an aqueous phase comprising at least one weak organic acid, at least one agent, and water, and an oil phase comprising at least one fatty acid source comprising at least one cis unsaturated fatty acid selected from oleic acid and linoleic acid, and at least one non-ionic emulsifier comprising one or more cis unsaturated fatty acids, wherein the non-ionic emulsifier comprises or is derived from one or more oleic acid residues and / or one or more linoleic acid residues. In some embodiments, the at least one agent in total present in the aqueous phase is present in a weight ratio from 0.1 : 1.0 to 3.0: 1.0 relative to the at least one weak organic acid in total present in the aqueous phase. In some embodiments, the aqueous phase has a pH in the range of 2.0 to 5.5. In some embodiments, the at least one fatty acid source in total present in the oil phase is present in a weight ratio from 0.2: 1.0 to 30: 1.0 relative to the at least one weak organic acid in total present in the aqueous phase. In some embodiments, the at least one non-ionic emulsifier in total present in the oil phase is present in a weight ratio from 0.5 : 1.0 to 25 : 1.0 relative to the at least one weak organic acid in total present in the aqueous phase. In some embodiments, the combination of the aqueous phase and the oil phase equals 100% w / w of the emulsion. In some embodiments, the transdermal system is used to generate a transdermal emulsion having total fatty acids and / or CIO or longer hydrocarbons that comprise less than or equal to a total of 15.0% w / w of saturated fatty acids and / or saturated CIO or longer non-fatty acid hydrocarbons. In some embodiments, the agent comprises arginine, citrulline, citrulline malate, beetroot, creatine, glutamine, leucine, norvaline, ornithine, histidine, beta-alanine, phenylalanine, agmatine, betaine, L-theanine, glutathione, or any nitrate or any nitrite, any nitro, or any nitroso or salt thereof, or any combination thereof, and wherein the topically administering of the emulsion to the skin of a subject provides for a relative increase in a systemic nitric oxide level in the subject as compared to a systemic nitric oxide level prior to topically administering. In some embodiments of any of the aspects and embodiments herein that include a method, the agent further comprises ascorbic acid or its derivative.

[0223] In another aspect, provided herein is a method of preventing or reducing muscle mass loss that isAttorney Docket No. LAB.003 4.W0.01correlated to treatment with a GLP-1 agonist of a subject, comprising topically administering a transdennal composition in the form of an emulsion to the skin of the subject, wherein the transdermal composition comprises at least one weak organic acid, at least one agent, water, at least one non-ionic emulsifier comprising one or more cis unsaturated fatty acids, and at least one fatty acid source comprising at least one cis unsaturated fatty acid selected from oleic acid and linoleic acid, wherein the transdennal composition has a pH in the range of 2.0 to 5.5. In some embodiments, the at least one organic acid in total is present in an amount from 0.2% to 45.0% w / w of the emulsion. In some embodiments, each agent of the at least one agent is less than or equal to 2,000 mw and the at least one agent in total is present in an amount from 1.0% to 20.0% w / w of the emulsion. In some embodiments, water is present in an amount from 10.0% to 85.0% w / w of the emulsion. In some embodiments, the at least one non-ionic emulsifier in total is present in an amount from 3.0% to 35.0% w / w of the emulsion. In some embodiments, the at least one fatty acid source in total is present in an amount from 5.0% to 25.0% w / w of the emulsion. In some embodiments, total fatty acids and CIO or longer hydrocarbons in the emulsion comprise less than or equal to 15.0% w / w of saturated fatty acids and / or saturated CIO or longer non-fatty acid hydrocarbons. In some embodiments, the agent comprises arginine, citrulline, citrulline malate, beetroot, creatine, glutamine, leucine, norvalmc. ornithine, histidine, beta-alanine, phenylalanine, agmatine, betaine, L-theanine, glutathione, or any nitrate or any nitrite, any nitro, or any nitroso or salt thereof, or any combination thereof, wherein the topically administering of the emulsion to the skin of the subject provides for a relative increase in a systemic nitric oxide level in the subject as compared to a systemic nitric oxide level prior to the topically administering. In some embodiments of any of the aspects and embodiments herein that include a method, the agent further comprises ascorbic acid or its derivative.

[0224] In another aspect, provided herein is a method of preventing or reducing muscle mass loss that is correlated to treatment with a GLP-1 agonist of a subject, comprising topically administering an emulsion to the skin of the subject, wherein the emulsion is formed using a multi-component transdermal system comprising an aqueous phase comprising at least one weak organic acid, at least one agent, and water, and an oil phase comprising at least one fatty acid source comprising at least one cis unsaturated fatty acid selected from oleic acid and linoleic acid, and at least one non-ionic emulsifier comprising one or more cis unsaturated fatty acids, wherein the non-ionic emulsifier comprises or is derived from one or more cisoleic acid residues and / or one or more cis-linoleic acid residues. In some embodiments, the at least one weak organic acid in total is present in an amount from 35% to 65.0% w / w of the aqueous phase. In some embodiments, tire at least one agent in total is present in an amount from 1.0% to 25.0% w / w of tire aqueous phase. In some embodiments, water is present in an amount from 15.0% to 95.0% w / w of the aqueous phase. In some embodiments, the at least one fatty acid source in total is present in an amountAttorney Docket No. LAB.003 4.W0.01 from 15.0% to 65.0% w / w of the oil phase. In some embodiments, the at least one non-ionic emulsifier in total is present in a amount from 40% to 80% w / w of the oil phase. In some embodiments, the oil phase and the aqueous phase are capable of forming atransdermal emulsion comprising 50% to 90% w / w of the aqueous phase and 10% to 50% w / w of the oil phase and having total fatty acids and / or CIO or longer hydrocarbons that comprise less than or equal to a total of 15.0% w / w of saturated fatty acids and / or saturated CIO or longer non-fatty acid hydrocarbons. In some embodiments, the aqueous phase and the oil phase are combined to fonn the emulsion such that their combination in total equals 100% w / w of the emulsion. In some embodiments, the agent comprises arginine, citrulline, citrulline malate, beetroot, creatine, glutamine, leucine, norvaline, ornithine, histidine, beta-alanine, phenylalanine, agmatine, betaine, L-theanine, glutathione, or any nitrate or any nitrite, any nitro, or any nitroso or salt thereof, or any combination thereof, and wherein the topically administering of the emulsion to the skin of a subject provides for a relative increase in a systemic nitric oxide level in the subject as compared to a systemic nitric oxide level prior topically administering. In some embodiments of any of the aspects and embodiments herein that include a method, the agent further comprises ascorbic acid or its derivative.

[0225] In some embodiments of any of the aspects and embodiments herein that include a method, the transdennal composition or the transdennal emulsion is capable of delivering the agent to the bloodstream of a subject when applied to the skin of the subject for at least 60 seconds, 2, 4, 5, 6, 8, 10, 12, 15, 18, or 20 minutes.

[0226] In some embodiments of any of tire aspects and embodiments herein that include a method, the at least one non-ionic emulsifier comprises polysorbate 80.

[0227] In some embodiments of any of the aspects and embodiments herein that include a method, the at least one agent comprises citrulline malate and ascorbic acid.

[0228] In some embodiments of any of tire aspects and embodiments herein that include a method, the at least one fatty acid source comprises safflower oil.

[0229] In some embodiments of any of the aspects and embodiments herein that include a method, the at least one fatty acid source comprises safflower oil and oleic acid.

[0230] In some embodiments of any of tire aspects and embodiments herein that include a method, the oil phase and the aqueous phase are capable of forming a transdennal emulsion comprising 50% to 90% w / w of the aqueous phase, and 10% to 50% w / w of the oil phase.

[0231] In some embodiments of any of the aspects and embodiments herein that include a method, the emulsion comprises no CIO or longer saturated hydrocarbons that are not fatty acids.

[0232] In some embodiments of any of tire aspects and embodiments herein that include a method, the non-ionic emulsifier is selected from the group consisting of an ethoxylated derivative, a sugar-based derivative, a glycerol ester, a polyglycerol ester, a propylene glycol ester, and a polyethylene glycolAttorney Docket No. LAB.003 4.W0.01 (PEG) ester.

[0233] In some embodiments of any of the aspects and embodiments herein that include a method, the ethoxylated derivative is selected from the group consisting of ethoxylated fatty acid esters, ethoxylated sorbitan esters, ethoxylated glycerides, and ethoxylated fatty acid amides.

[0234] In some embodiments of any of tire aspects and embodiments herein that include a method, the weight ratio of the non-ionic emulsifier is at least 1.0: 1.0 relative to the weak organic acid.

[0235] In some embodiments of any of the aspects and embodiments herein that include a method, the emulsion does not comprise a crosslinker.

[0236] In some embodiments of any of tire aspects and embodiments herein that include a method, the crosslinker comprises hydroxypropyl methylcellulose (HPMC).

[0237] In some embodiments of any of the aspects and embodiments herein that include a method, the at least one non-ionic emulsifier is a lipophilic non-ionic emulsifier having a hydrophilic -lipophilic balance (HLB) in the range of 3-6.

[0238] In some embodiments of any of tire aspects and embodiments herein that include a method, the at least one agent comprises at least one lipophilic agent having a LogP of greater than 1.5.

[0239] In some embodiments of any of the aspects and embodiments herein that include a method, the at least one non-ionic emulsifier is sorbitan monooleate (span 80).

[0240] In some embodiments of any of tire aspects and embodiments herein that include a method, the at least one non-ionic emulsifier is a hydrophilic non-ionic emulsifier having a hydrophilic-lipophilic balance (HLB) in the range of 10-20.

[0241] In some embodiments of any of the aspects and embodiments herein that include a method, the at least one agent comprises at least one hydrophilic agent having a LogP less than 0.

[0242] In some embodiments of any of tire aspects and embodiments herein that include a method, the at least one non-ionic emulsifier is polysorbate 80.

[0243] In some embodiments of any of the aspects and embodiments herein that include a method, the emulsion comprises a crosslinker having less than or equal to a w / w ratio of 0.3 : 1 with respect to the at least one weak organic acid in total.

[0244] In some embodiments of any of tire aspects and embodiments herein that include a method, the emulsion comprises a crosslinker having a w / w ratio in the range of 0.01 : 1 to 0.3 : 1 with respect to the at least one weak organic acid in total.

[0245] In another aspect, provided herein is a method of improving or ameliorating a condition, disease, or side effect of a treatment comprising increasing a nitric oxide level in a subject, wherein the method comprises topical administration of a composition comprising a precursor of nitric oxide.

[0246] In some embodiments of any of the aspects and embodiments herein that include a method, theAttorney Docket No. LAB.003 4.W0.01 condition, disease, or side effect of a treatment is a side effect of a treatment with a GLP-1 agonist.

[0247] In some embodiments of any of method or use aspects and embodiments herein that recite treatment with a GLP-1 agonist, a side-effect of a GLP-1 agonist, that the subject is taking a GLP-1 agonist, that the subject has detectable or therapeutic levels of a GLP-1 agonist, or otherwise recite a GLP-1 agonist, the GLP-1 is an FDA-approved GLP-1, such as dulaglutide, exenatide, semaglutide, liraglutide, lixisenatide, tirzepatide, or any combination thereof, as non-limiting examples.

[0248] In one aspect, provided herein is an emulsion comprising an aqueous phase wherein each 100 g emulsion comprises: 23-27 g citric acid; 23-27 g water; 0.2-0.3 g glacial acetic acid; 6-7 g citrulline: and 6-7 g ascorbic acid; and an oil phase, wherein each 100 g emulsion comprises: 6-7 g safflower oil; 2.5-3.5 g oleic acid; 0.5-1.5 g glycerin; and 23-27 g polysorbate 80, wherein the emulsion comprises about 60-70% of the aqueous phase and about 30-40% of the oil phase, wherein topical administration of the composition to the skin of a subject provides for a relative increase in a systemic nitric oxide level in the subject as compared to a systemic nitric oxide level measured prior to administration of the composition. In some embodiments, the nitric oxide level is imputed from a measure of salivary nitric oxide.

[0249] In one aspect, provided herein is an emulsion for topical administration comprising: an aqueous phase, wherein each 100 g emulsion comprises: 23-27 g citric acid; 23-27 g water; 0.2-0.3 g glacial acetic acid: 3.5-4.5 g citrulline: 3.5-4.5 g arginine; and 3.5-4.5 g ascorbic acid; and an oil phase, wherein each 100 g emulsion comprises: 6-7 g safflower oil; 2.5-3.5 g oleic acid; 0.5-1.5 g glycerin; and 23-27 g polysorbate 80, wherein the emulsion comprises about 60-70% of the aqueous phase and about 30-40% of the oil phase, wherein topical administration of the composition to the skin of a subject provides for a relative increase in a systemic nitric oxide level in the subject as compared to a systemic nitric oxide level measured prior to administration of the composition. In some embodiments, the nitric oxide level is imputed from a measure of salivary nitrite.

[0250] In one aspect, provided herein is a method of generating an emulsion for topical administration, comprising: (a) generating an aqueous composition, wherein the aqueous composition comprises: (i) about 30% to about 60% w / w citric acid: (ii) about 30% to about 60% w / w water; and (iii) about 0% to about 2% w / w glacial acetic acid; (b) stirring the aqueous composition at from about 500 to about 2500 RPM for about 2 to about 15 minutes at 30 to 45 degrees C; (c) further adding to the aqueous composition: (i) about 5% to about 40% w / w of an agent comprising arginine, citrulline, citrulline malate, beetroot, creatine, glutamine, leucine, norvaline, ornithine, histidine, beta-alanine, phenylalanine, agmatine, betaine, L-theanine, glutathione, or any nitrate or any nitrite, any nitro, or any nitroso or salt thereof, or any combination thereof; and (ii) about 5% to about 15% w / w ascorbic acid; (d) stirring the aqueous composition at from about 500 to about 2500 RPM for about 2 to about 15 minutes at 30 to 45 degrees C; (e) generating an oil-based composition comprising: (i) about 0% to about 50% w / w an oilAttorney Docket No. LAB.003 4.W0.01 comprising less than 5% saturated fatty’ acids; (ii) about 10% to about 50% w / w an unsaturated fatty acid; (iii) about 0% to about 10% w / w glycerin: and (iv) about 30% to about 90% w / w polysorbate 80; (f) stirring the oil-based composition at about 500 RPM for 2 to about 15 minutes at 20 to 30 degrees C; (g) adding the oil-based composition to the aqueous composition over at least 30 seconds and concurrently stirring the aqueous composition at about 500 and rapidly increasing to about 2500 RPM and 30 to 45 degrees C, thereby fanning an emulsion, wherein the emulsion comprises from about 40% to about 70% w / w of the aqueous composition and about 30% to about 60% w / w of the oil-based composition; (h) further stirring the emulsion for a combined total of about 2 to about 30 minutes in steps (g) and (h); (i) stirring the emulsion at about 2000 to about 3500 RPM for 2 to about 15 minutes at 30 to 45 degrees C, wherein topical administration of the composition to the skin of a subject provides for a relative increase in a systemic nitric oxide level in the subject as compared to a systemic nitric oxide level measured prior to administration of the composition. In some embodiments, the nitric oxide level is imputed from a measure of salivary nitric oxide. In some embodiments of any? of the aspects and embodiments herein that include a method of generating an emulsion for topical administration, wherein the oil comprises less than 15%, 10%, 5%, 4%, 3% or 2% saturated fatty acid.

[0251] In one aspect, provided herein is a method of generating an emulsion for topical administration, comprising: (a) generating an aqueous composition, wherein each 100 g aqueous composition comprises: (i) 45-55 g citric acid; (ii) 45-55 g water; and (iii) 0.0-1 g glacial acetic acid; (b) stirring the aqueous composition at about 1000 RPM for about 5 minutes at about 38 degrees C; (c) further adding to each 100 g of aqueous composition: (i) 8-12 g citrulline; (ii) 8-12 g ascorbic acid (d) stirring the aqueous composition at about 1000 RPM for about 5 minutes at about 38 degrees C; (e) generating an oil-based composition, wherein each 100g oil-based composition comprises: (i) 16-20 g safflower oil; (ii) 7-9 g oleic acid; (iii) 2-4 g glycerin; and (iv) 70-74 g polysorbate 80; (f) stirring the oil-based composition at about 1000 RPM for about 5 minutes at about 25 degrees C: (g) adding the oil -based composition to the aqueous composition over at least 30 seconds, concurrently stirring the aqueous composition at about 1000 RPM, increasing to 2500 RPM and about 38 degrees C, thereby generating an emulsion, wherein the emulsion comprises from about 40% to about 70% w / w of the aqueous composition and about 30% to about 60% w / w of tire oil-based composition; (h) further stirring the emulsion for a combined total of about 5 minutes in steps (g) and (h): (i) stirring the emulsion at about 2500 RPM for about 5-30 minutes at about 38 degrees C, wherein topical administration of the composition to the skin of a subject provides for a relative increase in a systemic nitric oxide level in the subject as compared to a systemic nitric oxide level measured prior to administration of the composition. In some embodiments, the nitric oxide level is imputed from a measure of salivary nitric oxide.

[0252] In some embodiments, provided herein is a method of treating a condition comprising low nitricAttorney Docket No. LAB.003 4.W0.01 oxide in a subject, the method comprising atopical administration of an emulsion, wherein topical administration of the composition to the skin of a subject provides for a relative increase in a systemic nitric oxide level in the subject as compared to a systemic nitric oxide level measured prior to administration of the composition. In some emobimdnets, the nitric oxide level is imputed from a measure of salivary nitric oxide. In illustrative embodiments of this and any method that includes administering an emulsion to a subject, the emulsion is any of the emultions provided herein, or any emulsion that is prepared using any of the multi-component systems, fonnulations or compositions herein.

[0253] In illustrative embodiments for any of the methods provided herein that include administering an emulsion provided herein to a subject, an increase in systemic nitric oxide level is observed after such administered as compared to before such administering. In some embodiments, the increase in systemic nitric oxide level is observed, detected, and / or maintained for at least 6, 8. 10, 12, 16, 24, 30, and 36 hours. In some embodiments, the increase in systemic nitric oxide level is observed, detected, and / or maintained for between 6 hours on the low end and 20, 22, 24, 26, 28, 30, and 36 hours on the high end; or between 8 hours on tire low end and 20, 22, 24, 26, 28, 30, and 36 hours on the high end; or between 10 hours on the low end and 20, 22, 24, 26, 28, 30, and 36 hours on the high end; or between 12 hours on the low end and 20, 22, 24, 26, 28, 30. and 36 hours on the high end; or between 14 hours on the low end and 20, 22, 24, 26, 28, 30, and 36 hours on the high end; or between 16 hours on the low end and 20, 22, 24, 26, 28, 30, and 36 hours on the high end.

[0254] In some embodiments, the increase in systemic nitric oxide level is observed, detected, and / or maintained for between 6. 8, 10. 12. 14, and 16 hours on the low end and 20 hours on the high end; or between 6, 8, 10, 12, 14, and 16 hours on the low end and 22 hours on the high end; or between 6, 8, 10, 12, 14, and 16 hours on the low end and 24 hours on the high end; or between 6, 8, 10, 12, 14, and 16 hours on the low end and 26 hours on the high end; or between 6, 8, 10, 12, 14, and 16 hours on the low end and 28 hours on the high end; or between 6, 8, 10, 12, 14, and 16 hours on the low end and 30 hours on the high end: or between 6. 8, 10, 12. 14. and 16 hours on the low end and 32 hours on the high end; or between 6, 8, 10, 12, 14, and 16 hours on the low end and 34 hours on the high end; or between 6, 8, 10, 12, 14, and 16 hours on the low end and 36 hours on the high end. In some embodiments, the increase in systemic nitric oxide level is observed, detected, and / or maintained for between 6 hours and 36 hours, 10 hours, and 30 hours. 12 hours and 28 hours, or 18 hours and 24 hours.

[0255] In some embodiments of any of the aspects and embodiments herein that include the emulsion, wherein the additional compound is one or more additional agent selected from the group consisting of acctyl-l-carnitinc (ale), alanine, alpha lipoic acid, arginine, artichoke extract, ashwagandha, bacopa powder, bamboo extract powder, basil powder, beet powder, calcium carbonate, blueberry extract, aloe vera, choline bitartrate, collagen protein peptides, collagen powder, citrulline, citrulline malate, curcuminAttorney Docket No. LAB.003 4.W0.01 powder, creatine, CoQlO, kale powder, folic acid, gingko biloba, glutamine, glycerin, ginger, glycine, grape seed extract, green tea, inositol (vitamins B7 / B8), histidine, jojoba, pomegranate powder, magnesium glycinate, leucine, lysine, lecithin (sun flower), niacinamide (vitamin B3), nutmeg powder, niacin, methionine, NALT (acetyl tyrosine), NAC, lutein, olive leaf, pea powder, periwinkle, phenylalanine, potassium, proline, ribose, DAA (d-aspartic acid), serine, hyaluronic acid, taurine, threonine, tryptophan, turmeric, theanine, valine (amino acid), valerian root powder, zinc oxide, vitamin A. vitamin B complex, vitamin B-L vitamin B-2, vitamin B-5, vitamin B-6 (pyridoxine), vitamin B-7&8. vitamin B-9 (folic acid), vitamin B-l 2, vitamin C (ascorbic acid), ascorbyl glucoside, vitamin D-3 (cholecalciferol), vitamin E, vitamin K-2, ginseng, isoleucine, almond oil, broccoli seed oil, collagen liquid, avocado oil, chamomile liquid, vitamin E oil, glycerin (conditioning), grapefruit seed, grape seed oil, gotu kola oil, kava liquid, virgin algae oil (fish oil), jojoba extract oil (organic), lavender oil, macadamia nut oil, meadowfoam seed oil, peppermint oil, maracuja oil (passionfruit), primrose oil, pomegranate oil, BCAA, GABA, collagen oil, virgin algae oil, ashwagandha powder, collagen peptides, guarana powder, huperzine, and combinations thereof.

[0256] In some embodiments of any of the aspects and embodiments herein that include the emulsion, wherein the additional compound is one or more additional agent selected from the group consisting of magnesium oxide, zinc oxide, chromium, Banaba leaf extract, Rhodiola root extract, inositol, berberine HC1, Gardenia fruit extract, Salacia bark extract, apple fruit extract, tributyrin complex (tributyrin 100 mg / guar fiber 20 mg), spinach leaf extract), probiotic blend comprising Lactobacillus acidophilus, Saccharomyces boulardii, Lactobacillus rhamnosus. Bifidobacterium breve, and amylase, B. lactis CECT 8145, rosemary extract, acacia fiber, microcrystalline cellulose, protease blend protease and peptidase, ginger rhizome extract, cellulase, beta glucanase, cinnamon bark extract, diastase, alpha galactosidase, lactase, lipase, Bacillus subtilis DEI 11, glucoamylase, xylanase, hemicellulose, galactomannan fiber, inulin. Amla fruit extract (Phyllanthus emblica), vitamin B-l (thiamine), vitamin B-2 (riboflavin), vitamin B-3 (niacin or niacinamide), vitamin B-6 (pyridoxine hydrochloride), folate, vitamin B-12, biotin, pantothenic acid, Cascara Sagrada (Rhamnus purshiana, bark). Milk Thistle extract (Silybum marianum L, fruit), L-theanine, Burdock extract (Arctium lappa, root), Dandelion extract (Taxacum mongolicum, root), Slippery elm extract (Ulmus rubra, bark), Marshmallow extract (Althaea officinalis, root), Citrus bioflavonoid (Citrus aurantiin, fruit), Black pepper extract (Piper nigrum, fruit), bamboo extract (Bambusa vulgaris, shoot), rice hull concentrate, rice bran, and combinations thereof.

[0257] In one aspect, provided herein is a method of preventing or reducing muscle mass loss that is correlated to treatment with a GLP-1 agonist comprising topical administration of a composition comprising: an aqueous phase comprising: citric acid, or a salt thereof, in an amount that is about 15% to about 35% w / w of the emulsion; water in an amount that is about 15% to about 35% w / w of the emulsion;Attorney Docket No. LAB.003 4.W0.01 and glacial acetic acid, or a salt or ion thereof, in an amount that is about 0% to about 2% w / w of the emulsion; an agent that is about 15% to about 25% w / w of tire emulsion, wherein the agent comprises ascorbic acid or it's derivative and arginine, citrulline, citrulline malate, beetroot, creatine, glutamine, leucine, norvaline, ornithine, histidine, beta-alanine, phenylalanine, agmatine, betaine, L-theanine, glutathione, or any nitrate or any nitrite, any nitro, or any nitroso or salt thereof, or any combination thereof; an oil phase comprising: an oil in amount that is about 3% to about 15% w / w of the emulsion, wherein the oil comprises less than 15% saturated fatty acids; an unsaturated fatty acid in an amount that is about 1% to about 20% w / w of the emulsion; glycerin in an amount that is about 0.0% to about 7% w / w of the emulsion; and polysorbate 80 that is about 5% to about 50% w / w of the emulsion, wherein aqueous phase and the oil phase are combined in an emulsion comprising from about 55% to about 75% w / w of the aqueous phase and about 25% to about 45% w / w of the oil phase, wherein topical administration of the composition to the skin of a subject provides for a relative increase in a systemic nitric oxide level in the subject as compared to a systemic nitric oxide level measured prior to administration of the composition, and wherein the nitric oxide level is imputed from a measure of salivary nitric oxide.

[0258] In some embodiments of any of the aspects and embodiments herein that include a method of preventing or reducing muscle mass loss that is correlated to treatment with a GLP-1 agonist comprising topical administration of a composition herein: the oil comprises less than 2% saturated fatty acid. In some embodiments of any of the aspects and embodiments herein that include a method of preventing or reducing muscle mass loss that is correlated to treatment with a GLP-1 agonist, wherein a condition that involves, or is otherwise experiencing muscle mass loss, muscle fatigue, high blood pressure, reduced blood oxygen, or any combination thereof.

[0259] In one aspect, provided herein is a method of improving or ameliorating a condition, disease, or side effect of a treatment comprising increasing a nitric oxide level in a subject, wherein the method comprises topical administration of a composition comprising a precursor of nitric oxide, and wherein the nitric oxide level is determined imputed from a measure of salivary nitric oxide.

[0260] The following non-limiting examples are provided purely by way of illustration of exemplary' embodiments, and in no way limit the scope and spirit of the present disclosure.EXAMPLESExample 1: Manufacture of Emulsion

[0261] An emulsion, also referred to as an emulsified formulation, was generated by combining an acidic composition with oil, water and surfactant. A first component was made by combining 340 ml (374 g) citric acid powder, 800 ml (640 g) apple cider vinegar, and 60 ml (44.4 g) beetroot powder. A secondAttorney Docket No. LAB.003 4.W0.01 component was made by combining 700 ml polysorbate 80 (742 g), 700 ml (700 g) distilled water, and, 350 ml (308 g) macadamia oil, and 350 ml (308g) maracuja oil. Hie first and second components were poured together and mixed for 60 - 180 minutes at 70-85°F to fonn the emulsion. The pH was checked to confirm acidity of pH 4.5-5.5. Viscosity was confirmed at 2,000-3,000 centipoise (cP). The emulsion was poured into a fine micro-mesh filter (mesh #325 / 44 microns) suspended over a 150 oz vat. The emulsion was incubated at room temperature without agitation for 24-36 hours. Surface impurities were skimmed of liquid surface using a 44 micron micro mesh filter.Example 2: Application of an Emulsion

[0262] As a non-limiting example, 0.35 oz dose of an emulsion, as described in Example 1, is applied to an area of skin of a subject. The area of skin to which the emulsion is applied is overlaid with ionized water, in liquid or gas form.Example 3: Observational Study with Metabolic Emulsion

[0263] This Example provides evidence for the therapeutic benefits of a metabolic transdermal delivery formulation through in vivo data presented in Tables 3 and 4 that demonstrate improvements in three key indicia of human health: weight, heart rate, and blood pressure follow ing administration of an emulsion as disclosed herein. Five (5) participants applied to their umbilicus (navel area) approximately 0.35 oz of a Metabolic emulsion twice daily for 21 consecutive days. Each participant’s weight, heart rate, and blood pressure 'ere measured on days 0, 7, 14, and 21 and Blood Pressure and Heart Rate were measured.

[0264] Table 4

[0265] Table 5Attorney Docket No. LAB.003 4.W0.01Example 4: Observational Study with an Emulsion

[0266] This Example provides evidence for the therapeutic benefits of an emulsion as disclosed herein though in vivo data that demonstrates cognitive improvements in five (5) participants from 60 to 79 years of age and with no previous diagnosis of dementia who applied to the nape (nucha) of the neck and around the entirety of the neck area, approximately 0.25 oz of tire Focus™ emulsion (or Placebo Control), as described in Table 6, once daily for 28 consecutive days.

[0267] Table 6: Representative Components within Distinct Transdermal Delivery Formulations TRANSDERMAL DELIVERY FORMULATION&Attorney Docket No. LAB.003 4.W0.01TRANSDERMAL DELIVERY FORMULATION- - absent from an emulsion++ present in an emulsiont-+++ unique to (or at an elevated concentration relative to “core”) in an emulsion

[0268] Improved cognitive function and performance were demonstrated through studies performed by BrainCheck. Inc. (Austin, TX). Two protocols are used during the study: (1) TNS Studies’ FOCUS Serum, (2) BrainCheck’s online cognitive assessment.

[0269] Baseline testing is captured using BrainCheck’s online cognitive assessment tool. BrainCheck performed an online cognitive assessment one each participant and provided testing results.

[0270] The results of this study are presented in Table 7 and FIGs. 1A-1F. The average change in Total Score from baseline to Test 3, as reported by BrainCheck, was 10% (data not shown). Improvements in executive function were demonstrated by a 27% improvement from baseline for Stroop Color Interference measurements of the ability of a human subject or domestic, veterinary, or agricultural animal to inhibit reactions and control impulses.

[0271] As depicted in FIGs. 1A-1F, all test groups show an increase in score over baseline. Test subjects in the 51-60 age range showed tire greatest improvement in Total Score, 19.5%. Attention improved by 29%, Mental Flexibility improved by 4% (Ages 71-80), Executive Function (digital symbol substitution) improved by 15.5% (Ages 41-50), Executive Function (stroop) improved by 44% (Ages 41- 50), Immediate Memory improved by 16.6% (Ages 51-60), and Delayed Memory improved by 27% (Ages 71-80).

[0272] Table 7Attorney Docket No. LAB.003 4.W0.01Example 5: Observational Study with an Emulsion

[0273] This Example provides evidence for the therapeutic benefits of an emulsion as disclosed hereinAttorney Docket No. LAB.003 4.W0.01 though in vivo data that demonstrates cognitive improvements in eight (8) participants from 34 to 72 years of age and with no previous diagnosis of dementia who applied to the nape of the neck area approximately 0.25 oz of a Focus™ emulsion (or Placebo Control), as described in Table 6. once daily for 28 consecutive days.

[0274] Improved cognitive function and performance were demonstrated through studies performed using RC21X by Home Base Impairment Company. Inc. (Coraopolis, PA). Two protocols were used during the study: (1) TNS Studies' FOCUS Serum, and (2) RC21X’s ROBERTO mobile application.

[0275] Baseline testing was captured using RC21X’s ROBERTO mobile application. RC21X provided testing results on each participants’ test.

[0276] with the Roberto App (RC21X, Coraopolis, PA). Testing scores were tracked and indicators of improvement were assessed in the following areas: (1) mental focus, (2) hand / eye coordination, (3) eye tracking, (4) auditory and visual recognition & recollection, and (5) reduction in stress and mental fatigue.100% of Study Participants reported improved or less stress during the Study. 83% of Study Participants’ sleep was improved. 66% of Study Participants reported feeling calmer while on the Serum.

[0277] Hie results of this study are presented in Table 8. Improvements in average scores across five (5) of the six (6) tests were demonstrated from baseline to the last test performed. Visual discrimination and impulse control (Base-Stealing Game) showed the greatest overall improvement as an average of all participant scores. The 61 - 70 age group demonstrated improvement in four (4) of the five (5) tests. Visual memory delayed recall (Video Recognition) demonstrated a 38% increase in the 41 - 50 age group. Audio memory delayed recall (Audio Recognition), Bilateral finger motor speed (Finger Tapping). Working memory and visual attention (Shape Memory) and Visual discrimination and impulse control (Base-Stealing Game) demonstrated 56%, 46%, 126% and 375% respectively, improvement from baseline to last test in the 61-70 age group. Working memory / visual attention (Number Memory'), a 29% improvement, was demonstrated in the 71 - 80 age group.

[0278] Table 8. Results of ROBERTO test.Attorney Docket No. LAB.003 4.W0.01Example 6: Characterization of an Emulsion

[0279] Emulsions were characterized using emulsion droplet size and zeta sizer analysis. Three batches of emulsion (designated batch 1, 2, and 3) were generated as described in Example 1. Emulsions were held for 24 hours at 37-45 degrees C. Duplicate samples (designated A and B) were taken from each batch for testing.

[0280] Zetasizer analysis

[0281] Samples were diluted in HPLC-grade water at 1:200 and 1:400. Additionally, to compare results from samples diluted in local (Mobile, AL) tap water, a sample from Batch A was prepared by dilutingAttorney Docket No. LAB.003 4.W0.01 1 : 1 in tap water, then further diluted in tap water or HPLC-grade water to a final dilution of 1 :200 or 1:400.

[0282] Sizing measurements were made using a Zetasizer Nano series instrument (Malvern Panalytical Inc., Westborough, MA). Three measurements were carried out for each sample. Eleven runs or cycles were completed for each replicate. Each run had a duration of 10 seconds. Zetasizer settings were as follows:

[0283] Temperature: 25 °C

[0284] Material: Nanoparticles

[0285] Material refractive index (RI): 1.00

[0286] Dispersant name: Water

[0287] Dispersant RI: 1.330

[0288] Viscosity (cP): 0.8888

[0289] Equilibration time: 1 min

[0290] Cell Description: Disposable sizing cuvette

[0291] Zetapotential analysis and count rate

[0292] Zeta potential and count rate were measured using a Zetaview® instrument (Particle Metrix, Ammersee, Germany). Samples were diluted 1:100,000 in water. Analysis was performed with the following settings:

[0293] Temperature: 25 °C

[0294] Electrolyte: Water

[0295] Laser: 488 nm

[0296] Filter Wavelength: Scatter

[0297] Cell S / N: ZNTA

[0298] Sensed Electric Field: 3.39 V / cm (pulse)

[0299] Measurement Mode: Stationary 3 cycles

[0300] Size, countrate, and zeta potential data are shown in Table 9.Table 9: Characterization data from batches of emulsionsAtorney Docket No. LAB.003 4.W0.01Attorney Docket No. LAB.003 4.W0.01

[0301] Line graphs showing size distribution in the sub-2 micron range of each sample preparation are provided in FIGs. 2A-2N. As shown in the figures, all samples comprised a population of emulsion droplets with a diameter from about 10 nm to about 300 nm.Example 7: Manufacture of a Molecular Application Platform Emulsion

[0302] A Molecular Application Platform (MAP) emulsion is generated by preparing separate aqueous and oil phases. The aqueous phase is made by combining 80 g citric acid (CAS 77-92-9, MilliporeSigma, Burlington, MA) with 80 g water (CAS 7732-18-5, MilliporeSigma, Burlington, MA) and 0.8 g glacial acetic acid (CAS 64-19-7, MilliporeSigma, Burlington, MA). Tire composition is heated to 40 degrees C and stirred at 500 RPM for 5 min. 20 g citrulline and 20 g ascorbic acid are combined as dry powders and added to the water mixture at 40 degrees C and stirred for 5 minutes at 500 RPM.

[0303] The oil phase is made by combining 20g safflower oil (CAS 8001-23-8, MilliporeSigma, Burlington, MA) with 9g oleic acid (CAS 112-80-1, MilliporeSigma, Burlington, MA), 3.17g glycerinAttorney Docket No. LAB.003 4.W0.01 (CAS 56-81-5, Millipore Sigma, Burlington, MA), and 80g polysorbate 80 (CAS 9005-65-6) at 25 degrees C. Tire oil-based composition is mixed for 5 min at 1000 RPM.

[0304] The oil phase is drizzled into the aqueous phase. After adding about one third of the oil phase, the mixing speed is increased to 1000 RPM. After two thirds of the oil phase are added, the mixing speed is increased to between 1500-2500 RPM. The emulsion is stirred at 40 degrees C for an additional 5-30 minutes. pH and viscosity are measured after stirring the emulsion.Example 8: Systemic Delivery of Caffeine by Topical Application

[0305] Systemic delivery of active agents in an exemplary beetroot / caffeine emulsion according to the present disclosure was demonstrated, to achieve increased nitric oxide levels out to over 24 hours as a demonstration of a systemic NO-increasing emulsion. A test emulsion having the components of Table 10 was prepared. The fonnulation for this emulsion included beetroot powder as a nitric oxide precursor, macadamia oil as a source of oleic acid, maracuja oil as a source of linoleic acid, apple cider vinegar as a source of acetic acid, and polysorbate 80 as the emulsifier.

[0306] Hie fonnulation was prepared by adding the components in the following order: Distilled water, macadamia oil, maracuja oil, beetroot powder, apple cider vinegar and citric acid powder. Then these components were mixed for 20 minutes in a KitchenAid mixer at approximately 600 rpm, before adding polysorbate 80 to the formulation. After addition of polysorbate 80 to the formulation, an emulsion w as prepared using a standard operating procedure as follows: The formulation was mixed using the KitchenAid mixer at approximately 600 rpm for 4 to 6 hours, with stoppages for cooling (approx. 2 stoppages) to form the test emulsion with the Table 10 components. The mixing was performed without temperature control.

[0307] A 13% w / w caffeine composition / emulsion / NO supplement was generated by adding 0.65 g caffeine powder to 4.35 g to the emulsion comprising the Table 10 components.

[0308] Table 10. Delivery EmulsionAttorney Docket No. LAB.0Q3_4.WO.01

[0309] 2.47 g of the 13% caffeine emulsion, representing 321 mg caffeine was applied to the skin over the abdomen of a subject following 8 hours of fasting. Blood pressure, heart rate, blood oxygen, and salivary nitric oxide content were tracked for 12-1 / 2 hours. Salivary nitric oxide was tested using nitric oxide indicator strips (Changchun Mcrydi Bio-Tech Co., Ltd., Changchun, Jilin, China). Nitric oxide indicator strips were compared to a color gauge representing the values as in Table 11.

[0310] Table 11. Detected NO values with NO Indicator Strips

[0311] Hie measured levels for various physiological parameters are shown in Table 12.

[0312] Table 12: Physiologic assessments after application of the emulsion with beetroot and caffeine"Attorney Docket No. LAB.0Q3_4.WO.01

[0313] FIG. 3 is a line graph depiction of the results from Table 12 with more quantitative details re: NO levels and comments regarding results for various physiological parameters. As observed, and as a proof-of-concept demonstration of the systemic deliver)’ capability of the emulsions provided herein, a number of physiological parameters were affected by administration of the beetroot / caffeine emulsion that included beetroot as a plant-based, nitrate source, nitric oxide-promoting agent and caffeine as an agent or additional compound, with known physiological effects.

[0314] Notably, the physical effects of caffeine delivery, “buzz” and headache, were observed and coincide with an elevated blood pressure and heart rate (Table 12), consistent with the emulsion delivering systemic caffeine to the subject. On the other hand, shortly after administration of the beetroot / caffeine emulsion, both systolic and diastolic blood pressure, as well as heart rate after an early, short-lived minor increase, decreased such that by 14 minutes after administration, tire decrease was observed. Such blood pressure and heart rate decrease supports that active agent(s) in addition to caffeine are being delivered with topical administration of the emulsion. Similar reduced heart rate and blood pressure has been observed by the inventors during similar time periods after administration for multiple subjects who have topically administered various test emulsions that include one or more hydrophilic nitric oxide promoting agents such as beetroot powder, citrulline, or citrulline malate, a source of oleic acid, a source of linoleic acid, citric acid, and polysorbate 80 as the emulsifier (data not shown). It is also noteworthy that blood oxygen remained steady throughout the time periods tested.

[0315] As shown in the table and FIG. 3, NO levels increased to “High” within 22 minutes. This level was maintained for four hours. As shown in Table 12, NO levels were still elevated above baseline at 1526 minutes (25:26) after administration. This demonstrates systemic delivery of nitric oxide-increasing compounds in the beetroot agent (i.e. load components) in the emulsion. Elevated nitric oxide levels maintained after 24 hours suggesting that daily, or 2 times, or 2 to 4 times a day dosing would be effective to maintain elevated nitric oxide levels over multiple days.Attorney Docket No. LAB.003 4.W0.01 Example 9: Nitric Oxide Generation with Daily Dosage of an Emulsion

[0316] An emulsion was prepared using the following components: citric acid, water, acetic acid, citrulline malate, ascorbic acid, arginine, creatine, beetroot, EEA, caffeine, safflower oil, oleic acid, glycerin, and Tween 80. The components in the emulsion were prepared using the following amounts: 80g citric acid, 80g water, 0.8g acetic acid, 16g citrulline malate, 8g ascorbic acid, 4g arginine, 4g creatine. 4g beetroot, 4g EEA, 4g caffeine, 40g safflower oil, 18g oleic acid, 6.3g glycerin, 40g Tween 80. The emulsion was applied to a subject at the time points in "‘time used" column in FIG.4. Nitric oxide levels in the subject were measured using Nitric Oxide Indicator Strips (Changchun Merydi Bio-Tech Co., Ltd., Changchun, Jilin, China). Resulting NO levels are shown in “value” columns of FIG.4, with timepoints noted as “time NO test” taken 1-2 hours and 12-14 hours after application of tire emulsion. Darker pink strips indicate higher levels of NO relative to a baseline value shown. The results show elevated levels of NO 12-14 hours after application ofthe emulsion with NO supplements. This shows the emulsion provides for maintained elevated levels of nitric oxide for at least 12 hours.Example 10: Manufacture of a Molecular Application Platform Emulsion with additional compounds for GLP-1 support

[0317] An MAP emulsion with additional compounds for GLP- 1 support was generated by preparing separate aqueous and oil phases. The aqueous phase was made by combining 80 g citric acid (CAS 77-92-9, Millipore Sigma, Burlington, MA) with 80 g water (CAS 7732-18-5, Millipore Sigma, Burlington, MA) and 0.8 g glacial acetic acid (CAS 64-19-7, MilliporeSigma, Burlington, MA). The composition is heated to 38 degrees C and stirred at 500 RPM for 20 min.

[0318] A composition was generated with 8 g citrulline malate (CAS 77-92-9), 8 g beetroot powder (CAS 89957-89-1), 4 g arginine (CAS 74-79-3), 4 g creatine (CAS 57-00-1), 4 g serine (CAS 56-45-1), 8 g glutathione (CAS 70-18-8), 4 g kale (CAS 89958-13-4). 4 g EEA (CAS X002937WET), and 4 g lecithin (SF) (CAS 8002-43-5) at 25 degrees C and stirred for 5 minutes. The composition was added to the aqueous phase with stirring at 1000 RPM and 38 degrees C for 5 minutes. The aqueous composition was further stirred at 1000 RPM and 38 degrees C for 5 minutes.

[0319] The oil phase was made by combining 20 g safflower oil (CAS 8001-23-8, MilliporeSigma, Burlington, MA), 8 g almond oil (CAS 8007-69-0), 16 g avocado oil (CAS 8024-32-6), 8 g glycerin (CAS 56-81-5, MilliporeSigma, Burlington, MA), 9 g oleic acid (CAS 112-80-1, MilliporeSigma, Burlington, MA), and 120 g polysorbate 80 (CAS 9005-65-6) at 25 degrees C. The oil-based composition was stirred for 5 min at 25 degrees C.

[0320] Hie oil phase was drizzled into the aqueous phase at 38 degrees C while stirring at 1000 RPM for 5 minutes, generating an emulsion. The emulsion was further stirred at 38 degrees C for 5 minutes at 1500Attorney Docket No. LAB.003 4.W0.01 RPM.

[0321] After cooling the emulsion to 25 degrees C, the pH was measured to be 2.58.Example 11: Manufacture of a Base Molecular Application Platform

[0322] A base MAP emulsion was generated by preparing separate aqueous and oil phases. The aqueous phase was made by combining 40 g citric acid (CAS 77-92-9, MilliporeSigma, Burlington, MA) with 40 g water (CAS 7732-18-5, MilliporeSigma, Burlington, MA) and 0.4 g glacial acetic acid (CAS 64-19-7. MilliporeSigma, Burlington, MA). The composition is heated to 38 degrees C and stirred at 1000 RPM for 5 min.

[0323] The oil phase was made by combining 10 g safflower oil (CAS 8001-23-8, MilliporeSigma, Burlington, MA), 4.5 g oleic acid (CAS 112-80-1. MilliporeSigma, Burlington, MA), 1.58 g glycerin (CAS 56-81-5, MilliporeSigma, Burlington, MA), and 40 g polysorbate 80 (CAS 9005-65-6) at 25 degrees C. The oil-based composition was stirred for 5 min at 25 degrees C.

[0324] The oil phase was drizzled into the aqueous phase at 38 degrees C while stirring at 1000 RPM for 5 minutes, generating an emulsion. The emulsion was further stirred at 38 degrees C for 5 minutes at 2500 RPM.

[0325] After cooling the emulsion to 21.5 degrees C, the pH was measured to be 1.89.Example 12: Manufacture of a Molecular Application Platform with additional caffeine and kale

[0326] A MAP emulsion with additional compounds including caffeine and kale for GLP-1 was generated by preparing separate aqueous and oil phases. The aqueous phase was made by combining 80 g citric acid (CAS 77-92-9, MilliporeSigma, Burlington, MA) with 80 g water (CAS 7732-18-5, MilliporeSigma, Burlington, MA) and 0.8 g glacial acetic acid (CAS 64-19-7, MilliporeSigma, Burlington, MA). Tire composition is heated to 38 degrees C and stirred at 500 RPM for 20 min.

[0327] A composition was generated with 8 g citrulline malate (CAS 77-92-9), 8 g ascorbic acid (CAS 50-81-7), 8 g beetroot powder (CAS 89957-89-1). 4 g arginine (CAS 74-79-3), 4 g lecithin (SF) (CAS 8002-43-5), 4 g EEA (CAS X002937WET), and 4 g caffeine (CAS 58-08-2) at 25 degrees C and stirred for 5 minutes. The composition was added to the aqueous phase with stirring at 1000 RPM and 38 degrees C for 5 minutes. The aqueous composition was further stirred at 1000 RPM and 38 degrees C for 5 minutes.

[0328] The oil phase was made by combining 20 g safflower oil (CAS 8001-23-8, MilliporeSigma, Burlington, MA), 9 g oleic acid (CAS 112-80-1, MilliporeSigma, Burlington, MA), 3.17 g glycerin (CAS 56-81-5, MilliporeSigma, Burlington, MA), and 80g polysorbate 80 (CAS 9005-65-6) at 25 degrees C. The oil -based composition was stirred for 5 min at 25 degrees C.

[0329] The oil phase was drizzled into the aqueous phase at 38 degrees C while stirring at 1000 RPM forAtorney Docket No. LAB.003 4.W0.01 5 minutes, generating an emulsion. Tire emulsion was further stirred at 38 degrees C for 5 minutes at 2000 RPM.Example 13: Manufacture of a Molecular Application Platform with Additional Compounds for GLP-1 Support and Muscle Mass Retention

[0330] A MAP emulsion with additional compounds for GLP-1 support and muscle mass retention was generated by preparing separate aqueous and oil phases. The aqueous phase was made by combining 400 g citric acid (CAS 77-92-9, MilliporeSigma, Burlington, MA) with 400 g water (CAS 7732-18-5, MilliporeSigma, Burlington, MA). The composition is heated to 38 degrees C and stirred at 500 RPM for 20 min.

[0331] A composition was generated with 40 g citrulline (CAS 372-75-8), 40 g ascorbic acid (CAS 50-81-7), 20 g beetroot powder (CAS 89957-89-1), 12 g creatine (CAS 57-00-1), 12 g glutathione (CAS 70-18-8), 12 g arginine (CAS 74-79-3), 12 g EEA (CAS X002937WET), 12 g leucine (CAS 61-90-5), 4 g calcium beta-hydroxy-beta-methylbutyrate (HMB) (CAS 135236-72-5), 12 g caffeine (CAS 58-08-20) and 5 g xantlian gum (CAS 11138-66-2) at 25 degrees C and stirred for 5 minutes. The composition was added to the aqueous phase with stirring at 1000 RPM and 38 degrees C for 5 minutes. The aqueous composition was further stirred at 1000 RPM and 38 degrees C for 5 minutes.

[0332] The oil phase was made by combining 100 g safflower oil (CAS 8001-23-8, MilliporeSigma, Burlington, MA), 45 g oleic acid (CAS 112-80-1, MilliporeSigma, Burlington, MA), 10 g glycerin (CAS 56-81-5. MilliporeSigma, Burlington, MA), and 400g polysorbate 80 (CAS 9005-65-6) at 25 degrees C. The oil-based composition was stirred for 5 min at 25 degrees C.

[0333] The oil phase was drizzled into the aqueous phase at 38 degrees C while stirring at 1000 RPM for 5 minutes, generating an emulsion. Tire emulsion was further stirred for 29 minutes at 2500 RPM.Example 14: Clinical Trial to Evaluate Pharmacokinetics and Nitric Oxide Generation of a Corplex™ Donepezil 10 mg MAP Emulsion

[0334] A randomized, open-label, 3 -way crossover study with up to 66 healthy, adult male and female subjects are enrolled. All subjects receive LA001, Corplex Donepezil in a MAP emulsion as described in Example 7, applied to the abdomen.

[0335] During treatment period, all subjects receive a once-weekly 10 mg LA00L target dose 10 mg donepezil / day, applied for 7 days (1 week) on the abdomen.

[0336] Blood samples for donepezil PK are collected pre-dose until the end of each treatment period.

[0337] Nitric oxide levels as detected by salivary nitric oxide are collected pre-dose until the end of each treatment period and up to one week after cessation of treatment.Attorney Docket No. LAB.0Q3_4.WO.01

[0338] The PK sample and sal i van nitric oxide collection time points are as follows:

[0339] Week 1: Pre- LA001 application prior to 0 hour and post- LA001 application at 2, 6, 12, 24, 36, 48, 60, 72, 84. 96. 108, 120. 132, 144. and 156 hours.

[0340] Week 2: 168 hours, and at up to 528 hours.

[0341] Skin irritation will be monitored throughout LA001 treatments. Safety will be monitored throughout the study by adverse event reporting, repeated clinical and laboratory evaluations.

[0342] Inclusion Criteria:

[0343] Healthy, adult, male or female

[0344] Body mass index > 18.0 and < 32.0 kg / m2 at screening

[0345] Medically healthy with no clinically significant medical history , physical examination, laboratory’ profiles, vital signs or electrocardiograms (ECGs), as deemed by the Investigator.

[0346] Have a Fitzpatrick skin type of I, II or III or have skin colorimeter scores equivalent to the allowed Fitzpatrick skin type.

[0347] Table 13. Primary’ Outcome Measures

[0348] Table 14. Secondary Outcome MeasuresAttorney Docket No. LAB.003 4.W0.01Example 15: A Molecular Application Platform (MAP) Emulsion

[0349] A Molecular Application Platform (MAP) emulsion was prepared using the following components: citric acid, ascorbic acid, citrulline malate, safflower oil, oleic acid, Tween 80, and water. The amounts of each component in preparing the emulsion were 4.8g citric acid, 3.8g ascorbic acid. 5.8g citrulline malate, 26.1g safflower oil, 2.6g oleic acid, 13.0g Tween 80, and 191g water. Following the preparation, the emulsion was administered topically to a subject at start time points each day. Nitric oxide levels in the subject were measured using Nitric Oxide Indicator Strips after 12-14 hours after tire start time points each day. Tire topical administration of the emulsion resulted in elevated nitric oxide levels in the subject. The results indicate topical administration of the emulsion results in elevated nitric oxide levels that are maintained 12-14 hours after administration.Example 16: Effect of different weight percentages of a non-ionic emulsifier (polysorbate 80) on the emulsion

[0350] A series of dermatological emulsions were prepared to evaluate the effect of a non-ionic emulsifier- polysorbate 80 on the physical stability of the emulsions.

[0351] Each emulsion was prepared by the same procedure as disclosed herein. Water was heated to a temperature of around 85°C. After heating the water was placed in a beaker with constant stirring, and the aqueous phase components - citric acid, citrulline malate (2:1), and ascorbic acid were added slowly ensuring constant mixing. After the complete mixing the aqueous phase mixture was allowed to cool to around 66°C. In a separate vessel, the contents of oil phase - safflower oil, oleic acid, and polysorbate 80 were mixed at room temperature (25°C). The contents of the oil phase were mixed at around 800 rpm for 2-15 minutes at a temperature of about 50°C. After both the aqueous phase and the oil phase were prepared, the entire volume of the oil phase was added to the water phase while maintaining vigorous stirring throughout. The stirring continued at 800 RPM for 10-15 minutes at 50°C to allow the emulsionAttorney Docket No. LAB.003 4.W0.01 to stabilize and mature.

[0352] Polysorbate 80 was incorporated at varying w% levels. Hie emulsion LAB2P104.4 comprises 20g of polysorbate 80, and 10 g of citric acid, i.e., in a 2: 1 w / w ratio. The emulsions LAB2P104.3, LAB2P104.2, and LAB2P104.1 comprise 15g, 10g, and 5g, of polysorbate 80 respectively, whereas the amount of citric acid remained 10 g in all the emulsions. Therefore, the w / w ratio of polysorbate 80 to citric acid in the formulations LAB2P104.4, LAB2P104.3, LAB2P104.2, and LAB2P104.1 were 2:1, 1.5:1, 1:1. and 0.5:1, respectively.

[0353] Following table shows the components of the emulsions that were prepared according to the present example.

[0354] Table 15

[0355] Each emulsion was stored on ice, and the stability was assessed by visual inspection. Tire results are shown on the table below.

[0356] Table 16

[0357] This data indicates that the non-ionic emulsifier, such as polysorbate 80 plays a role in maintaining the structural integrity of the emulsion. Tire emulsion that had 2: 1 polysorbate 80 and citric acid did not display any breakage, whereas in the emulsions having lower ratios of polysorbate 80: citric acid, such as 1.5:1, 1:1, and 0.5:1 breakage up to different levels of the emulsions was observed within 4 hours when stored on ice. The emulsion with tire ratio of polysorbate 80: citric acid of 0.5: 1 exhibited 100% breakage within 4 hours when stored on ice.Attorney Docket No. LAB.003 4.W0.01Example 17: Effect of the inclusion of different weight percentages of a crosslinker on the emulsion

[0358] A series of dermatological emulsions in the form of hydrogels were prepared to evaluate the effect of a crosslinker- hydroxypropyl methylcellulose (HPMC) on the physical stability of the emulsions in the form of hydrogels.

[0359] Each emulsion was prepared by the same procedure as disclosed herein. Water was heated to a temperature of around 85°C. After heating, the water was placed in a beaker with constant stirring, and the contents of aqueous phase - citric acid, citrulline malate (2:1), ascorbic acid, and HPMC (if required, as per the emulsion that was prepared) were added slowly ensuring constant mixing. After the complete mixing the combination of water, citric acid, and HPMC was allowed to cool to around 66°C. In a separate vessel, the contents of oil phase - safflower oil, oleic acid, and polysorbate 80 were mixed at room temperature (25°C). The contents of the oil phase were mixed at around 800 rpm for 2-15 minutes at a temperature of about 50°C. After both the aqueous phase and the oil phase were prepared, the entire volume of tire oil phase was added to the water phase while maintaining vigorous stirring throughout. The stirring continued at 800 RPM for 10-15 minutes at 50°C to allow the emulsion to stabilize and mature.

[0360] Tire cross-linker - HPMC was incorporated at varying w% levels. The emulsion LAB2P096.1, LAB2P096.2, LAB2P096.3, and LAB2P096.4 comprises 1g, 2g, 4g, and 0g of HPMC, respectively, whereas the amount of citric acid remained 10 g in all the emulsions. Therefore, the w / w ratio of crosslinker (HPMC) to citric acid in tire formulations LAB2P096.1, LAB2P096.2, LAB2P096.3 were 0.1:1, 0.2:1, and 0.4:1, respectively.

[0361] Following table shows the components of the emulsions that were prepared according to the present example.

[0362] Table 17

[0363] Each emulsion was stored at room temperature, and the stability was assessed by visualAttorney Docket No. LAB.0Q3_4.WO.01 inspection. The results are shown on the table below.

[0364] Table 18

[0365] This data indicates a correlation betw een the concentration of HPMC and the rate of hydrogel breakage. At 0% HPMC, the hydrogels exhibited stability with no observed breakage. However, when HPMC was added, the hydrogel integrity decreased, leading to higher rates of breakage. And in the emulsion where HPMC was added at a 40% weight vs citric acid (0.4: 1 w / w ratio), complete (100%) breakage within the 4-hour period was observed.Example 18: Preparation of a transdermal composition: LAB2P1

[0366] Preparation of Combination A

[0367] All materials for Combination A were assembled at room temperature (25°C). In a 2000 ml dry mixing beaker, the following powdered ingredients were carefully weighed and combined in the order listed: citric acid 300 g (1.56 mol), citrulline 2: 1 malate 165 g (0.53 mol), ascorbic acid 132 g (0.75 mol), EEA 60 g (0.43 mol), magnesium citrate 15 g (0.01 mol), calcium-HMB 7.5 g (0.03 mol), potassium citrate 7.5 g (0.02 mol), ferrous gluconate 0.9 g, creatine 30 g, leucine 30 g (0.23 mol), and xanthan gum 30 g. Once all components had been added to the vessel, the dry blend was mixed at a low speed of 10 RPM for 5 minutes to ensure uniform distribution of all ingredients. This combination was then set aside for later use.

[0368] Water Preparation and Initial Mixing

[0369] While Combination A was resting, the water phase was prepared by heating 1800 g of water to 85°C in an external heating container. When the temperature had been reached, the heated water was added to a 5000 ml beaker equipped with an overhead stirrer. Once the water had been added, stirring began at 800 RPM for 1 minute to establish a stable vortex and ensure uniform temperature throughout the liquid.

[0370] Incorporation of Combination A

[0371] Hie prepared Combination A was gradually added to the heated water with stirring over the course of 1 minute. The powder was added slowly and steadily to prevent clumping and to ensure proper hydration of all components, particularly the xanthan gum and other hydrophilic ingredients. After the complete addition of Combination A, stirring continued at 800 RPM for 5 minutes while the mixtureAttorney Docket No. LAB.003 4.W0.01 cooled from 85°C down to 60°C. During this time, the mixture was observed for complete dissolution, unifonn consistency, and an increase in viscosity (approximately 10-14 kPa).

[0372] Preparation of Combination B

[0373] While the main mixture was stirring and cooling, Combination B was prepared in a separate 20000 ml beaker. At room temperature (25°C), the following components of oil phase were combined: polysorbate 80 (PS80) 1050 g (1.74 mol), safflower oil 375 g (1.34 mol), oleic acid 199.8 g (0.71 mol), tea tree oil 9 g (0.04 mol), and jojoba oil 9 g (0.01 mol). Once all the oil phase components had been combined, the oil phase was heated to 50°C while mixing at 800 RPM for 2 minutes to ensure complete homogenization and uniform temperature distribution throughout the oil blend.

[0374] Integration of Oil Phase

[0375] After both the aqueous phase (containing Combination A) and the oil phase (Combination B) had been adequately prepared, the entire volume of Combination B was slowly added to the main mixture over 1 minute, maintaining vigorous stirring throughout to form a stable emulsion. Once Combination B had been completely incorporated, mixing continued at 800 RPM for 10 minutes at 50°C to allow tire emulsion to stabilize and mature.

[0376] Final Component Addition

[0377] After the emulsion had been thoroughly mixed, the temperature was reduced to 25°C and 45 g (0.29 mol) of menthol was carefully added to the mixture. Menthol was added at room temperature to prevent excessive volatilization. Once menthol had been added, the final formulation was mixed at the previous stirring rate for 5 minutes, maintaining a temperature of 35°C to ensure even distribution of the menthol throughout the product.

[0378] The final product had a total batch weight of approximately 4265.7 g. Once the final mixing step had been completed, the preparation was ready for transfer to appropriate containers or for further processing as required by the specific application.

[0379] Table 19Attorney Docket No. LAB.0Q3_4.WO.01Example 19: Preparation of a transdermal composition: LAB2P2

[0380] The Preparation of Combination A

[0381] In a 2000 ml dry mixing beaker, 300g of citric acid was added. Further, Primary active ingredients were added: 1. Citrulline 2: 1 Malate - 165 g; 2. Ascorbic Acid - 132 g; 3. EEA (Essential Amino Acids) - 60 g; 4. Collagen - 60 g; 5. Creatine - 60 g; 6. Biotin - 60 g; 7. Theanine - 60 g; 8.Glycine - 90 g; 9. GABA - 60 g; and 10. Taurine - 60 g. Further, secondary active ingredients were added to the above mixture: 11. Arnica Extract - 45 g (2 g material + 43 g water); 12. Saw Palmetto - 45 g; 13. Vitamin E - 45 g; 14. B12 Complex - 22.5 g; 15. D-Ribose - 22.5 g; 16. Beta Carotene - 10.5 g; 17. Folic Acid - 10.5 g; 18. Hyaluronic Acid - 5.25 g; and 19. Vitamin D - 5.25 g. In the next step, tire following mineral ingredients were added: 20. Manganese Gluconate - 3 g; 21. Zinc Gluconate - 3 g; 22. Copper Gluconate - 0.6 g; 23. Chromium GTF - 0.06 g; 24. Magnesium Citrate - 15 g (2 g material + 13 g water); 25. Calcium HMB - 7.5 g; 26. Potassium Citrate - 7.5 g; and 27. Ferrous Gluconate - 0.9 g. In tire next step, additional active ingredients were added: 28. Creatine (additional) - 30 g; 29. Leucine - 30 g: and 30. Xanthan Gum (thickener) - 30 g. Once all components had been added to tire vessel, the dry blend was mixed at room temperature at a low speed of 10 RPM for 5 minutes to ensure uniform distribution of all ingredients. This combination was then set aside for later use.

[0382] Water Preparation and Initial Mixing

[0383] While Combination A was resting, the water phase was prepared by heating 1800 g of water to 85°C in an external heating container. When the temperature had been reached, the heated water was added to a 5000 ml beaker equipped with an overhead stirrer. Once the water had been added, stirring began at 800 RPM for 1 minute to establish a stable vortex and ensure uniform temperature throughout the liquid.

[0384] Incorporation of Combination A

[0385] The prepared Combination A was gradually added to the heated water with stirring over the course of 1 minute. The powder was added slowly and steadily to prevent clumping and to ensure proper hydration of all components, particularly the xanthan gum and other hydrophilic ingredients. After theAttorney Docket No. LAB.003 4.W0.01 complete addition of Combination A, stirring continued at 800 RPM for 5 minutes while the mixture cooled from 85°C down to 60°C. During this time, the mixture was observed for complete dissolution, and uniform consistency.

[0386] Preparation of Combination B

[0387] While the main mixture was stirring and cooling, Combination B was prepared in a separate 20000 ml beaker. At room temperature (25°C), tire following components of oil phase were combined: polysorbate 80 (PS80) 1050 g (1.74 mol), safflower oil 375 g (1.34 mol), oleic acid 199.8 g (0.71 mol), tea tree oil 9 g (0.04 mol), and jojoba oil 9 g (0.01 mol). Once all the oil phase components had been combined, tire oil phase was heated to 50°C while mixing at 800 RPM for 2 minutes to ensure complete homogenization and uniform temperature distribution throughout the oil blend.

[0388] Integration of Oil Phase

[0389] After both the aqueous phase (containing Combination A) and the oil phase (Combination B) had been adequately prepared, the entire volume of Combination B was slowly added to the main mixture over 1 minute, maintaining vigorous stirring throughout to form a stable emulsion. Once Combination B had been completely incorporated, mixing continued at 800 RPM for 10 minutes at 50°C to allow the emulsion to stabilize and mature.

[0390] Final Component Addition

[0391] After the emulsion had been thoroughly mixed, the temperature was reduced to 25°C and 45 g (0.29 mol) of menthol was carefully added to the mixture. Menthol was added at room temperature to prevent excessive volatilization. Once menthol had been added, the final formulation was mixed at the previous stirring rate for 5 minutes, maintaining a temperature of 35°C to ensure even distribution of the menthol throughout the product.

[0392] The final product had a total batch weight of approximately 4933.86 g. Once the final mixing step had been completed, the preparation was ready for transfer to appropriate containers or for further processing as required by the specific application.

[0393] Table 20Atorney Docket No. LAB.003 4.W0.01

[0394] The disclosed embodiments, examples and experiments are not intended to limit the scope of the disclosure or to represent that the experiments below are all or tire only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. It should be understood that variations in the methods as described may be made without changing the fundamental aspects that the experiments are meant to illustrate. Thus, it should be understood that although tire present invention has been specifically disclosed by preferred aspects and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims. Example 20: Administration of GLP-1 metabolic companion emulsion for 90 days

[0395] A test emulsion according to the present disclosure was prepared and applied to a subject, alongside administration of a GLP- 1 agonist for 90 days, demonstrating less muscle mass loss comparedAttorney Docket No. LAB.003 4.W0.01 to historical GLP-1 agonist data during a 12-week period.

[0396] Preparation of the test emulsion: Preparation of aqueous phase.

[0397] A test emulsion including, among other ingredients, beetroot powder, citrulline malate, arginine, and creatine, as nitric oxide agents, palm oil as a source of oleic acid, maracuja oil as a source of linoleic acid, and polysorbate 80 as an emulsifier was prepared as follow: Tire aqueous phase was generated by preparing and combining three separate combinations: Tire first combination was made by combining 603g citric acid (CAS 77-92-9), 603g water, and 6.03g acetic acid (CAS 641-97-1), and mixing at 500 RPM for 20 minutes at 38°C. The second combination was made in a separate container by combining 75.4g citrulline malate (CAS 70796-17-7), 15.1g arginine (74-79-3), 30.2g lecithin (CAS 8002-43-5), 30.2g EEA (CAS X002937WET), and 30.2g riboflavin (CAS 83-88-5) and mixing for 5 minutes at 25°C. The first and second combinations were combined to form an in-process aqueous while mixing at 1000 RPM for 5 minutes at 38°C. The in-process aqueous phase was mixed at 1000 RPM for an additional 5 minutes at 38°C. The third combination was made by combining 103g beetroot powder (CAS 89957-89-1), 71.8g glucosamine, 61.5g caffeine (CAS 58-08-2), 61.5g creatine (CAS 57-00-1), 61.5g leucine (CAS 61-90-5), 51.3g menthol (CAS 89-78-1), 51.3g vitamin E oil (CAS 10191-41-0), 35.9g chondroitin (CAS 7 / 9 / 9082). 35.9g xanthan gum (CAS 11138-66-2), and 20.5g HMB (CAS 135236-72-5), and mixing for 5 minutes at 25°C. The third combination and the in-process aqueous phase were combined and mixed at 2500 RPM for 29 minutes at 38°C to form tire final aqueous phase formulation.

[0398] Preparation of the exemplary emulsion: Preparation of the oil phase.

[0399] Tire oil phase was made in a separate container by combining 453g polysorbate 80 (CAS 9005-65-6), 136g palm oil (CAS 8002-75-3), and 67.9g maracuja oil (CAS 68956-68-3), and mixing for 5 minutes at 38°C.

[0400] Generation of the test emulsion.

[0401] Hie oil phase was added to the final aqueous phase formulation while mixing at 1500 RPM for 5 minutes at 38°C to form the final formulation, which was then mixed at 1500 RPM for 30 minutes at 38°C to generate the test emulsion.

[0402] The subject applied 15g to 45g of the test emulsion once daily to their full body, feet to scalp for 90 days. During that 90 day period the subject also administered Zepbound® (tirzepatide), a dual GLP-1 / GIP agonist, once weekly via injection following a protocol of 2.5mg administered during days 1-30, 5mg administered during days 31-60, and 7.5mg administered during days 61-90.

[0403] Results

[0404] The table below displays the endpoints that were measured in tire subject, the baseline results during week 1, the results at week 12, and the difference between week 1 and week 12. Physiological and biochemical endpoints were measured using standardized clinical and laboratory procedures. BodyAttorney Docket No. LAB.0Q3_4.WO.01 composition parameters, including fat mass, fat-free (FF) body mass, muscle mass, and skeletal muscle mass, were determined via bioelectrical impedance analysis (BIA) using an electric resistance body composition analyzer. Anthropometric measurements such as height, weight, and body mass index (BMI) were recorded using standard clinical instruments. Blood-based metabolic and cardiovascular endpoints, including total cholesterol (Total C), triglycerides (TriG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and hemoglobin A1C (H-A1C), were quantified through venous blood draws analyzed by an accredited clinical laboratory (e.g., Quest Diagnostics) following fasting collection protocols. Cardiovascular function endpoints such as resting heart rate (Rest HR), systolic and diastolic blood pressure (BP Sys, BP Dia), and pulse oximetry (Pulse Ox Low) were assessed using validated automated monitors. Nitric oxide (NO) levels were evaluated using commercially available NO test strips and saliva samples according to manufacturer instructions.

[0405] Table 21: Week 1 Baseline and Week 12 ResultsAttorney Docket No. LAB.003_4.WG.01

[0406] From week 1 to week 12, the subject experienced a 39% reduction in fat mass, while only experiencing an 11% reduction in fat-free mass. This is favorable compared to the only 33.9% reduction in fat mass and the 10.9% reduction in lean mass experienced by subjects taking a dual GLP-l / GIP agonist after 72-weeks. (Hamza et al.. Expert Opinion on Pharmacotherapy, 26(1), 31-49 (2024). Also, the ratio of total fat mass to total fat-free mass decreased in the subject by 30% over the 12 week period, which is greater compared to the decrease of only 25% in subjects taking a dual GLP-l / GIP agonist even after 72-weeks. (Hamza et aL, 2024). Tire subject also experienced a 12% relative increase in fat-free body-mass percentage over the 12 week period. These results are consistent with systemic delivery of the agent(s) in the emulsion and the positive effect when used to treat a subject who is taking a dual GLP-l / GIP agonist. The subject also displayed a 13% reduction in total cholesterol, a 30% reduction in triglycerides, and a 15% reduction in LDL. Furthermore, the subject experienced a 27% reduction in both systolic and diastolic blood pressure (BP Sys, BP Dia), and an 8% increase in blood oxygen (Pulse Ox Low). Finally, as further evidence of the systemic delivery and effectiveness of emulsions provided herein that include nitric oxide -promoting agent(s), a 900% increase in nitric oxide levels were observed in this subject between week 1 and week 12.

[0407] It is also noteworthy that the subject experienced no nausea or upset stomach, no GI issues, no cravings, no diarrhea, no body aches or fatigue, no hair change or loss, no Ozempic face, no headaches, no allergic or skin reactions, and no dehydration, which are common side effect of GLP-1 agonist use.

[0408] Example 21. Long-term blood pressure-lowering effects of systemic NO-increasing emulsionsThis example demonstrates the long term decreases in blood pressure, increases in NO, and increase in SpO2 that result after daily administration of a systemic NO-increasing emulsion provided herein.

[0409] Materials and Methods

[0410] A series of systemic NO-increasing emulsions were prepared over a period of around 4 years. Components of these NO-promoting emulsions included NO-increasing agents (either beetroot, arginine, and / or citrulline as nitric oxide-promoting agents), linoleic acid, or a source thereof, oleic acid, or a source thereof, citric acid, and polysorbate 80 as the emulsifier. Tire emulsions had pH between 3.2 and 4.5 during approximately years 1 and 2, and pH between 4.5 and 5.5 for approximately the last 2 years.

[0411] More specifically, in addition to the above characteristics and components, the systemic nitric oxide-increasing emulsions that were administered for the last year of the trial met these characteristics:citric acid, optionally with a source of acetic acid (weak organic acid(s)), combined in total in an amount from 0.2% to 45.0% w / w of the emulsion;the total systemic-nitric oxide-increasing agents were present in a weight ratio from 0.1 : 1.0 to 3.0: 1.0 relative to the weak organic acid(s) in total;water, present in a weight ratio from 0.5: 1 to 45: 1 relative to the weak organic acid(s) in total;Attorney Docket No. LAB.003 4.W0.01 the linoleic acid and / or oleic acid, or a source thereof, were present in a weight ratio from 02:1.0 to 4.0: 1.0 relative to the weak organic acid(s) in total; andpolysorbate 80 in total present in a weight ratio from 1.0: 1.0 to 5.0: 1.0 relative to the weak organic acid(s) in total.Furthermore, the total fatty acids, and / or CIO or longer non-fatty acid hydrocarbons if present in the emulsion, comprised less than or equal to a total of 15.0% w / w of saturated fatty acids and / or saturated CIO or longer non-fatty acid hydrocarbons,

[0412] LAB1 TDP (see Table LAB1 TDP) is a representative NO-increasing emulsion that was one of the systemic nitric acid-increasing emulsions prepared and administered by the human subject during the 2nd 2 years of the study. It is noteworthy that LAB1 TDP includes the direct NO precursors citrulline malate and arginine. Furthermore LAB1 TDP includes beetroot as a plant nitrate source as well as the NO-supporting agent, creatine. Also note that the gram weights are provided for relative comparison purposes only and not the batch size actually prepared.

[0413] The LAB1 TDP emulsion was made as follows: Tire aqueous phase liquid components were combined and mixed at 38C for 20 minutes at 500 RPM. The dry components of the LAB1 TDP formulation were combined and mixed for 5 minutes at 25C. Then the mixed dry components were added to the 38C mixed aqueous components while mixing at 1,000 RPM and incubated at 38C for an additional 5 minutes while mixing at 1,000 RPM to form the complete aqueous phase.

[0414] The organic phase components were combined together and mixed at 25 C for 5 minutes to fonn the mixed organic phase liquid. Then the mixed organic phase liquid was added to the complete aqueous phase liquid at 38C while mixing at 1,500 RPM to form the complete LAB1 TDP formulation. Then the complete LAB1 TDP formulation was mixed at 38C for 30 minutes at 1,500 RPM to form the LAB1 TDP emulsion.

[0415] Hie subject topically administered 0.5 to 1.5 ounces of the systemic NO-increasing emulsions as discussed above daily for a period of around 4 years.

[0416] Results

[0417] Upon daily topical administration of 0.25 to 1.5 ounces of the systemic NO-increasing emulsions, the subject experienced a long-tenn drop in blood pressure from around 130 / 70 to around 100 / 65 mmHg that remained at / near the lower levels for the final 4 years of the trial. Furthermore, the subject's SpO2 increased from around 90% to around 95% when readings were taking a year after the initial administration, and then remained at the higher level for the remaining 3 years of the trial.Furthennore, heart rate dropped from about 85 bpm to about 70 bpm. Finally, elevated levels of NO were observed for the final year of the trial, which was the entire period they were measured for this trial.

[0418] Thus, daily administration of emulsions herein, w ere demonstrated to be systemic NO-increasingAttorney Docket No. LAB.0Q3_4.WO.01emulsions, and such increased systemic NO levels were sustained for the entire year it was measured. Furthermore, the emulsions caused a multi-year decrease in blood pressure and heart rate, and a multiyear increase in SpO2.

[0419] Table LAB1P TDP: Components of LAB1P TDP emulsion*Note that PS80 contains 4.00g of water. Thus, water content is 28.1% (26.3%+1.8%)

[0420] Hie disclosed embodiments, examples and experiments are not intended to limit the scope of the disclosure or to represent that the experiments above are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for.

[0421] The foregoing description and accompanying drawings set forth a number of representative embodiments at the present time. Various modifications, additions, and alternative designs will, of course, become apparent to those skilled in the art in light of the foregoing teachings without departing from the scope hereof, which is indicated by the following claims rather than by the foregoing description. AllAttorney Docket No. LAB.003 4.W0.01 changes and variations that fall within the meaning and range of equivalency of the claims are to be embraced within their scope.

Claims

Attorney Docket No. LAB.003 4.W0.01What is claimed is:

1. A transde rmal composition in the form of an emulsion, comprising:at least one weak organic acid comprising citric acid present in total in an amount from 0.2% to 45.0% w / w of the emulsion;at least one agent, wherein the at least one agent in total is present in a weight ratio from 0.1 : 1.0 to 3.0:1.0 relative to tire at least one weak organic acid in total;water, present in a weight ratio from 0.5: 1 to 45: 1 relative to the at least one weak organic acid in total;at least one fatty acid source comprising at least one cis unsaturated fatty acid selected from oleic acid and linoleic acid, wherein the at least one fatty acid source in total is present in a weight ratio from 0.2: 1.0 to 4.0: 1.0 relative to the at least one weak organic acid in total; andat least one non-ionic emulsifier comprising one or more cis unsaturated fatty acids, wherein the at least one non-ionic emulsifier in total is present in a weight ratio from 1.0:1.0 to 5.0:1.0 relative to the at least one weak organic acid in total,wherein the transdermal composition has a pH in the range of 2.0 to 5.5,wherein total fatty acids, and / or Cio or longer non-fatty acid hydrocarbons if present in the emulsion, comprise less than or equal to a total of 15.0% w / w of saturated fatty acids and / or saturated Cio or longer non-fatty acid hydrocarbons,wherein the non-ionic emulsifier comprises polysorbate 80,wherein the agent comprises arginine, citrulline, citrulline malate, beetroot, or any combination thereof, andwherein the transdermal composition is capable of delivering the at least one agent to the blood stream of a subject when applied to the skin of the subject and increasing systemic nitric oxide level in the subject.

2. A multi-component transdermal system, comprising:(a) an aqueous phase comprising:at least one weak organic acid in total present in an amount from 1.0% to 75.0% w / w of the aqueous phase;at least one agent, wherein the at least one agent in total present in the aqueous phase is present in a weight ratio from 0.1 : 1.0 to 3.0: 1.0 relative to the at least one weak organic acid in total present in the aqueous phase; andwater, present in the aqueous phase in a weight ratio from 0.5: 1.0 to 45:1.0 relative to the at least one weak organic acid in total present in the aqueous phase,wherein the aqueous phase has a pH in tire range of 2.0 to 5.5;Attorney Docket No. LAB.003 4.W0.01(b) an oil phase comprising:at least one fatty acid source comprising at least one cis unsaturated fatty acid selected from oleic acid and linoleic acid, wherein the at least one fatty acid source in total present in the oil phase is present in a weight ratio from 0.2: 1.0 to 30: 1.0 relative to the at least one weak organic acid in total present in the aqueous phase; andat least one non-ionic emulsifier comprising one or more cis unsaturated fatty acids, wherein the at least one non-ionic emulsifier in total present in the oil phase is present in a weight ratio from 0.5 : 1.0 to 25 : 1.0 relative to tire at least one weak organic acid in total present in the aqueous phase, wherein the non-ionic emulsifier comprises or is derived from one or more oleic acid residues and / or one or more linoleic acid residues,wherein the combination of the aqueous phase and the oil phase equals 100% w / w of the emulsion, andwherein the transdermal system is capable of forming a transdermal emulsion having total fatty acids and / or Cw or longer hydrocarbons that comprise less than or equal to atotal of 15.0% w / w of saturated fatty acids and / or saturated Cio or longer non-fatty acid hydrocarbons.wherein the at least one agent comprises arginine, citrulline, citrulline malate, beetroot, or any combination thereof, andwherein the transdermal emulsion is capable of delivering tire at least one agent to the blood stream of a subject when applied to the skin of the subject and increasing systemic nitric oxide level in the subject.

3. The multi-component transdermal system of claim 2, wherein the at least one weak organic acid comprises citric acid.

4. Tire multi-component transdermal system of claim 3, wherein the at least one non-ionic emulsifier comprises polysorbate 80.

5. A method for delivering the at least one agent to the bloodstream of a subject, comprising administering the transdennal composition of claim 1 to the skin of the subject, wherein the systemic nitric oxide level is increased in the subject at 12 hours after such administration.

6. Tire method of claim 5, wherein the at least one weak organic acid comprises citric acid and wherein the at least one non-ionic emulsifier comprises polysorbate 80.

7. The method of claim 6, wherein the subject is being treated with a GLP-1 agonist.

8. An emulsion for topical administration, comprising:Attorney Docket No. LAB.003 4.W0.01a) an aqueous phase comprising:citric acid, or a salt thereof, in an amount that is about 15% to about 35% w / w of the emulsion;water in an amount that is about 15% to about 35% w / w of the emulsion; and glacial acetic acid, or a salt or ion thereof, in an amount that is about 0% to about 2% w / w of the emulsion; andan agent that is about 15% to about 25% w / w of the emulsion, wherein the agent comprises ascorbic acid or it’s derivative and arginine, citrulline, citrulline malate, beetroot, or any combination thereof; andb) an oil phase comprising:an oil in amount that is about 3% to about 15% w / w of the emulsion, wherein the oil comprises less than 15% saturated fatty acids, and wherein the oil comprises linoleic acid, an unsaturated fatty acid in an amount that is about 1% to about 20% w / w of the emulsion, wherein the unsaturated fatty acid comprises oleic acid;glycerin in an amount that is about 0.0% to about 7% w / w of the emulsion; and polysorbate 80 that is about 5% to about 50% w / w of the emulsion, wherein the emulsion has a pH of 2.0 to 5.5 and comprises from about 55% to about 75% w / w of the aqueous phase and about 25% to about 45% w / w of the oil phase, andwherein topical administration of the emulsion to the skin of a subject provides for a relative increase in a systemic nitric oxide level in the subject as compared to a systemic nitric oxide level measured prior to administration of the emulsion.

9. The emulsion of claim 8, wherein the oil comprising linoleic acid is safflower oil.

10. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of any one of claims 1 to 9, wherein the at least one agent further comprises ascorbic acid or its derivative.

11. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of any one of claims 1 to 9, wherein the at least one agent comprises arginine, citrulline, citrulline malate, or a combination thereof.

12. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of any one of claims 1 to 9, wherein the at least one agent further comprises a nitric oxide pathwayAttorney Docket No. LAB.003 4.W0.01 nitrogenous agent, a nitric oxide supporting agent, or a nitric oxide adjunct, or a combination thereof.

13. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of any one of claims 1 to 9, wherein tire at least one agent further comprises creatine, glutamine, norvaline, ornithine, histidine, beta-alanine, agmatine, betaine, L-theanine, glutathione, or any nitrate, or any combination thereof.

14. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of any one of claims 1 to 9, wherein the oil comprises fish oil, safflower oil, high-oleic oil, grapeseed oil, rapeseed oil, flaxseed oil, hemp oil, walnut oil, poppyseed oil, com oil, soybean oil, cottonseed oil, peanut oil, hemp oil, wheatgerm oil, rice bran oil. pistachio oil, canola oil, egg yolk, linseed oil, sunflower oil, avocado oil. sesame oil. olive oil, canola oil, or any combination thereof.

15. Tire transdermal composition, the multi -component transdermal system, the emulsion, or the method of any one of claims 1 to 9, wherein the oil comprises safflower oil.

16. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of any one of claims 1 to 9, wherein the at least one weak organic acid is present in total in an amount from 0.1% to 10.0% of the emulsion.

17. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of any one of claims 1 to 9, wherein the at least one weak organic acid is present in total in an amount from 25.0% to 45.0% of tire emulsion.

18. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of any one of claims 1 to 9, wherein the emulsion further comprises between 1% and 25%, or between 5% and 15%, or between 10% and 15% caffeine.

19. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of any one of claims 1 to 9, wherein the total fatty acids and / or Cm or longer non-fatty acid hydrocarbons in the emulsion in total comprise a total of less than or equal to 10.0% w / w of saturated fatty acids and / or saturated non-fatty acid hydrocarbons.

20. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of any one of claims 1 to 9, wherein the total fatty acids and / or Cio or longer non-fatty acid hydrocarbons in the emulsion in total comprise a total of less than or equal to 5.0% w / w of saturated fatty acids and / or saturated non-fatty acid hydrocarbons.Attorney Docket No. LAB.003 4.W0.01 21. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of any one of claims 1 to 9, wherein the transdermal composition or the transdermal emulsion is capable of delivering the agent to the blood stream of a subject when applied to the skin of the subject in within 15 minutes.

22. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of any one of claims 1 to 9, wherein the at least one fatty acid source comprises safflower oil and oleic acid.

23. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of any one of claims 1 to 9, wherein the oil phase and the aqueous phase are capable of forming a transdermal emulsion comprising 50% to 90% w / w of the aqueous phase, and 10% to 50% w / w of tire oil phase.

24. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of any one of claims 1 to 9, wherein the emulsion comprises no Cio or longer saturated hydrocarbons that are not fatty acids.

25. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of any one of claims 1 to 9, wherein the non-ionic emulsifier is selected from the group consisting of an ethoxylated derivative, a sugar-based derivative, a glycerol ester, a polyglycerol ester, a propylene glycol ester, and a polyethylene glycol (PEG) ester.

26. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of claim 25, wherein the ethoxylated derivative is selected from the group consisting of ethoxylated fatty acid esters, ethoxylated sorbitan esters, ethoxylated glycerides, and ethoxylated fatty acid amides.

27. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of any one of claims 1 to 9, wherein the weight ratio of the non-ionic emulsifier is at least 1.0: 1.0 relative to the weak organic acid.

28. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of any one of claims 1 to 9, wherein the emulsion does not comprise a crosslinker.

29. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of claim 28, wherein the crosslinker comprises hydroxypropyl methylcellulose (HPMC).

30. The transdermal composition, the multi-component transdermal system, the emulsion, or the methodAttorney Docket No. LAB.003 4.W0.01 of any one of claims 1 to 9, wherein the at least one non-ionic emulsifier is a hydrophilic non-ionic emulsifier having a hydrophilic-lipophilic balance (HLB) in the range of 10-20.

31. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of claim 30, wherein the at least one agent comprises at least one hydrophilic agent having a logP less than 0.

32. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of any one of claims 1 to 9, wherein the emulsion comprises a crosslinker having less than or equal to a w / w ratio of 0.3: 1 with respect to the at least one weak organic acid in total.

33. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of any one of claims 1 to 9, wherein the emulsion comprises a crosslinker having a w / w ratio in the range of 0.01: 1 to 0.3:1 with respect to the at least one weak organic acid in total.

34. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of any one of claims 1 to 9, wherein the at least one non-ionic emulsifier in total is present in a weight ratio from 1.0: 1.0 to 4.0: 1.0 relative to the at least one weak organic acid in total.

35. The transdennal composition, the multi-component transdermal system, the emulsion, or the method of any one of claims 1 to 9, wherein the at least one non-ionic emulsifier in total is present in a weight ratio from 2.0: 1.0 to 4.0: 1.0 relative to the at least one weak organic acid in total.

36. A method according to any one of claim 5 to 7, wherein at least one of the one or more agents enter the bloodstream of the subject within 2 hours after such administration.

37. A method according to any one of claim 5 to 7, wherein the administering is performed once or twice per day for at least 30 days.

38. A method according to claim 37, wherein each of the administering is performed in an amount between 0.2 oz and 3.0 oz of the transdermal composition or emulsion.

39. A method according to claim 37, wherein each of the administering is performed in an amount between 0.5 oz and 1.5 oz of the transdermal composition or emulsion.

40. A method according to claim 37, wherein each of the administering comprises contacting at least one area of the skin of the subject one or more times.

41. A method according to any one of claims 5 to 7, wherein at least one agent of the at least one agent,Attorney Docket No. LAB.003 4.W0.01 penetrates the skin within 5 minutes after the administering.

42. A method according to any one of claims 5 to 7, wherein at least one agent of the at least one agent, penetrates the skin within 10 minutes after the administering.

43. A method according to any one of claims 5 to 7. wherein at least one agent of the at least one agent, enters the bloodstream within 15 minutes after tire administering.

44. A method according to any one of claim 5 to 7, wherein the blood pressure of the subject decreases within 30 minutes after the administering.

45. A method according to any one of claims 5 to 7, wherein the subject was treated with a GLP-1 agonist within one week before the administering.

46. A method according to any one of claims 5 to 7. wherein the subject suffers from, or suffered from low blood oxygen, weight loss, cachexia, muscle atrophy, muscle mass loss, muscle fatigue, high blood pressure, or any combination thereof, within 1 month before the administering.

47. A method according to any one of claims 5 to 7. wherein the subject suffers from, or suffered from high blood pressure before the administering, and the systolic blood pressure of the subject is reduced by at least 10 mmHg after the administering compared to before the administering.

48. The method of claim 47. wherein the systolic blood pressure of the subject is reduced by between 10 and 50 mmHg at 8 hours after the most recent administering compared to at the time of the first administering, and wherein the administering comprises daily dosing for at least 7 days.

49. A method according to any one of claims 5 to 7, wherein the blood oxygen of the subject increases by 2-8% after the administering compared to before the administering.

50. A method according to any one of claims 5 to 7, wherein the blood oxygen of the subject increases by 2-8% after the most recent administering compared to at the time of the first administering, and wherein the administering comprises daily dosing for at least 7 days.

51. A method of preventing or reducing muscle mass loss that is correlated to treatmentwith a GLP-1 agonist, comprising topical administration of a transdermal composition of any one of claims 1 to 4, or 8 to 9.

52. A method according to any one of claims 5 to 7, wherein the agent comprises citrulline, citrulline malate, or a combination thereof to provide a total citrulline, and wherein the amount of total citrullineAttorney Docket No. LAB.003 4.W0.01 applied to the skin of the subject is between 0.1 g and 2.0 g.

53. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of any one of claims 1 to 9, wherein the agent comprises citrulline, citrulline malate, or a combination thereof to provide a total citrulline, and wherein the total percentage of total citrulline in the emulsion is between 0.75% and 10.0%.

54. A method according to any one of claims 5 to 7, wherein the agent comprises citrulline malate 1 : 1 or 2: 1, or a combination thereof, and wherein the total amount of citrulline malate applied to the skin of the subject is between 0.1 g and 2.0 g.

55. The transdermal composition, the multi-component transdermal system, the emulsion, or the method of any one of claims 1 to 9, wherein the agent comprises citrulline malate 1 : 1 or citrulline malate 2: 1, or a combination thereof, and wherein the total percentage of citrulline malate in tire emulsion is between 0.75% and 10.0%.

56. A method according to any one of claims 5 to 7, wherein the agent comprises arginine, and wherein the amount of arginine applied to the skin of the subject is between 0.1 g and 1.0 g.

57. The transdennal composition, the multi-component transdennal system, the emulsion, or the method of any one of claims 1 to 9, wherein the agent comprises arginine, and wherein the total percentage of arginine in the emulsion is between 0.25% and 2.0%.

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