(12) Patent Application Publication (10) Pub. No.: US 2012/0064136A1 Baker, JR

US 20120064136A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0064136A1 Baker, JR. et al. (43) Pub. Date: Mar. 15, 2012

(54) ANTI-AGING AND WRINKLE TREATMENT A63L/92 (2006.01) METHODS USING NANOEMULSION A6II 3/327 (2006.01) COMPOSITIONS A613/60 (2006.01) A61O 1704 (2006.01) (75) Inventors: James R. Baker, JR. Ann Arbor, A61O 19/08 (2006.01) MI (US); Susan M. Ciotti, Ann A61O 19/00 (2006.01) Arbor, MI (US) A61O 19/02 (2006.01) A6IP 700 (2006.01) (73) Assignee: Nanobio Corporation A6IP 7/10 (2006.01) A6IP3L/2 (2006.01) (21) Appl. No.: 13/229,080 A6IP 7/02 (2006.01) 1-1. A 6LX 9/07 (2006.01) (22) Filed: Sep. 9, 2011 B82Y5/00 (2011.01) Related U.S. Application Data (52) U.S. Cl...... 424/401; 424/400; 424/59: 424/62: 514/569; 514/714: 514/159;977/788; 977/906; (60) Provisional application No. 61/381.833, filed on Sep. 977/926 10, 2010. (57) ABSTRACT Publication Classification The present invention relates to methods for treating, prevent (51) Int. Cl. ing, minimizing, and/or diminishing signs of aging in the skin A6 IK 8/06 (2006.01) comprising administering to the Subject in need thereof a A6 IK 8/92 (2006.01) nanoemulsion composition.

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ANT-AGING AND WRNKLE TREATMENT niques. However, all of the known treatments have disadvan METHODS USING NANOEMULSION tages and undesirable side effects. COMPOSITIONS 0006 1. Medications and Cosmetics 0007 Commercially available medications used to treat CROSS-REFERENCE TO RELATED wrinkles and signs of skin aging include topical retinoids and APPLICATION non-prescription wrinkle creams. Topical retinoids are 0001. This application claims benefit of U.S. provisional derived from vitamin A, are applied to the skin, and may be Application No. 61/381.833, filed on Sep. 10, 2010, the dis able to reduce fine wrinkles, splotchy pigmentation and skin closure of which is incorporated herein by reference. roughness. Retinoids must be used with a skin-care program that includes Sunscreen and protective clothing because the FIELD OF THE INVENTION medication can make skin burn more easily. Retinoids may also cause redness, dryness, itching, and a burning ortingling 0002 The present disclosure relates to methods for pre sensation. Tretinoin (RenovaR), Retin-AR) and tazarotene venting and/or treating wrinkles and signs of aging skin. The (Avage.R., TazoracR) are examples of topical retinoids. See method comprises topically or Subcutaneously administering Renova (tretinoin cream). U.S. Food and Drug Administra to a subject in need thereof a nanoemulsion composition tion. http://www.fda.gov/ohrms/dockets/ac/02/sides/ having anti-wrinkle and anti-aging properties. 3904S1 01 Bergfeld/sld024.htm (accessed Jun. 22, 2010): Kafi et al., “Improvement of naturally aged skin with vitamin BACKGROUND OF THE INVENTION A (retinol). Archives of Dermatology, 143:606 (2007). A. Background Regarding Wrinkles and Aging Skin 0008. The effectiveness of non-prescription anti-wrinkle creams depends in part on the active ingredient or ingredients. 0003 Wrinkles are a natural part of aging. As a person Retinol, alpha hydroxy acids, kinetin, coenzyme Q10, copper ages, skin gets thinner, drier and less elastic. And it becomes peptides, and antioxidants may result in slight to modest less able to protect itself from damage. As a result, wrinkles, improvements in wrinkles and signs of aging skin. Baumann lines and creases form in the skin. Some wrinkles can become L., “Cosmetics and skin care in dermatology.” In: Wolffetal. deep crevices or furrows and may be especially noticeable Fitzpatrick's Dermatology in General Medicine, 7th ed. (New around the eyes, mouth and neck. McCullough J. L., et al., York, N.Y.: The McGraw-Hill Companies: 2008). However, “Prevention and treatment of skin aging.” Annals of the New nonprescription wrinkle creams contain lower concentrations York Academy of Sciences, 1067:323 (2006). Other signs of of active ingredients (such as alpha hydroxy acids) and other aging skin include, but are not limited to, liver spots or age structurally different actives (such as retinoids) than do pre spots (Solar lentigines), uneven skin tone, Sun-damaged skin, Scription creams. Therefore the claims and efficacy, if any, are and acne or chickenpox Scars. limited and usually short-lived. 0004 Wrinkles are caused by a combination of factors, 0009. Many wrinkle creams and lotions sold in depart Such as age, exposure to ultraviolet (UV) light, Smoking, and ment stores, in drugstores and on the Internet promise to repeated facial expressions. Decreased production of natural reduce wrinkles and prevent or reverse damage caused by the oils makes skin drier and appear more wrinkled. Fat in the Sun. Many of these products are not likely to make a notice deeper layers of skin, which gives the skin a plump appear able difference in the skin. The Food and Drug Administra ance, starts to lessen. This causes loose, saggy skin and more tion (FDA) classifies these creams and lotions as cosmetics, pronounced lines and crevices. Ultraviolet radiation mark which are defined as having no medical value. The FDA edly speeds up the natural aging process and is the primary regulates cosmetic products less strictly than it does drugs cause of early wrinkling Exposure to UV light breaks down products. This means that products do not need to undergo the skin's connective tissue—collagen and elastin fibers, rigorous testing for safety and effectiveness before approval which lie in the deeper layer of skin (dermis). Without the to go on the market. The FDA does not evaluate cosmetic Supportive connective tissue, skin loses its strength and flex products for medical effectiveness, and there is no guarantee ibility. As a result, skin begins to Sagand wrinkle prematurely. that any over-the-counter product will reduce wrinkles. The Smoking can accelerate the normal aging process of skin, claims for cosmetic products are cosmetic 'appearance' contributing to wrinkles. This may be due to changes in the claims and are not medical claims. However, it is difficult for blood Supply to the skin. Finally, facial movements and the consumer to delineate between the two types of claims. expressions, such as Squinting or Smiling, lead to fine lines For example, a drug claim for wrinkles can be “reduces fine and wrinkles. Each time a facial muscle is used, a groove line and wrinkles'. An acceptable cosmetic claim for photo forms beneath the Surface of the skin. And as skin ages, it aging can be: “visibly reduces the appearance offine fines and loses its flexibility and is no longer able to spring back in deep wrinkles caused by photoaging or Sundamage'. Includ place. These grooves then become permanent features on the ing the words “visibly' and “appearance' converts the drug face. See Helfrich et al., “Overview of skin aging and photo claim to a cosmetic claim. This Small change is not com aging. Dermatology Nursing, 20:177 (2008); Freiman et al., pletely understood by the consumer. “Cutaneous effects of smoking.” Journal of Cutaneous Medi 0010. The effectiveness of anti-wrinkle creams depends in cine and Surgery, 8:415 (2004); Just et al., “Effect of smoking part on the active ingredientoringredients. Examples of some on skin elastic fibres: Morphometric and immunohistochemi common ingredients that may result in slight to modest cal analysis. British Journal of Dermatology, 156:85 (2007). improvements in wrinkles include retinol, hydroxyl acids, Coenzyme Q10, copper peptides, Kinetin, and tea extracts. B. Conventional Treatment for Wrinkles and Aging 0011 Retinol is a vitamin A compound and is the first Skin antioxidant to be widely used in nonprescription wrinkle 0005. Current wrinkle and anti-aging treatments for skin creams. Antioxidants are substances that neutralize free radi include medications and Surgical procedures and other tech cals unstable oxygen molecules that break down skin cells US 2012/0064136 A1 Mar. 15, 2012

and cause wrinkles Retinol is less potent than the vitamin A which stimulates the growth of new collagen fibers. As the derivative tretinoin, a topical treatment approved by the Food wound heals, new skin forms that's Smoother and tighter. It and Drug Administration (FDA) for treating wrinkles Tretin can take up to several months to fully heal from ablative laser oin is available only by prescription. Vitamin A derivatives resurfacing. Newer developments in laser technology have are counter-indicated for pregnant women as they increase decreased the healing time. Less intense lasers (nonablative the risk of birth defects. lasers), pulsed light sources and radiofrequency devices don't 0012 Alpha hydroxy acids, beta hydroxy acids and poly injure the epidermis. These treatments heat the dermis and hydroxy acids are all synthetic versions of acids derived from cause new collagen and elastin formation. After several treat Sugar-containing fruits (“hydroxyl acids'). These acids are ments, skin feels firmer and appears refreshed. This means exfoliants—substances that remove the upper layer of old, shorter recovery times, but treatment typically needs to be dead skin and stimulate the growth of Smooth, evenly pig repeated more often and results are Subtle. Laser resurfacing mented new skin. can treat fine to moderate wrinkles, liver spots or age spots 0013. Other examples of cosmetic ingredients that may be (Solar lentigines), uneven skin tone, Sun-damaged skin, and effective in treating wrinkles include Coenzyme Q10, copper acne or chickenpox Scars. Laser resurfacing has limitations. It peptides, kinetin, and tea extracts. Coenzyme Q10 is a nutri can’t remove deep wrinkles or eliminate excessive or sagging ent that helps regulate energy production in cells. Some stud skin (owls). In addition, the effects arent permanent because ies have shown reduction in fine wrinkles around the eyes as a person ages, they continue to acquire expression lines— with no side effects. Other studies show that application lines that result from the natural movement of the face, such before Sun exposure protects against Sundamage. Copper is a as a person Squints or Smiles. Complications of ablative laser trace element found in every cell. In products applied to the resurfacing can include hyperpigmentation or hypopigmen skin, it's combined with Small protein fragments called pep tation (skin tone that turns darker or lighter than normal), tides. herpes virus infection (the virus that causes cold Sores), bac 0014 Copper peptides enhance wound healing. Copper terial infection, acne flares, Small white bumps (milia), scar peptides also stimulate production of collagen and may ring, burns, inflammation of the skin (dermatitis), and pro enhance the action of antioxidants. A plant growth factor, longed redness. For a herpes virus infection, the herpesvirus kinetin may improve wrinkles and uneven pigmentation with is already present but dormant in the skin; laser resurfacing minimal irritation. It's unclear how it works, but it may help can cause the virus to flare up. reduce wrinkles by helping skin retain moisture and by Stimu 0019 For a chemical peel, an acid is applied to the skin, lating the production of collagen. Kinetin may also be a which burns the outer layer of the skin. With medium-depth potent antioxidant. Finally, green, black and oolong tea con peels, the entire epidermis and a small portion of the dermis tain compounds with antioxidant and anti-inflammatory are removed. New skin forms to take its place. The new skin properties. Green tea extracts are most commonly found in is usually smoother and less wrinkled than the old skin. Red wrinkle creams. Side effects of Such cosmetic ingredients ness lasts up to several weeks. With Superficial peels, only a include skin irritation, rashes, and burning or redness. portion of the epidermis is removed. After a series of peels, 00.15 2. Surgical Procedures and Other Techniques less fine wrinkling in the skin and a fading of brown spots may 0016 Surgical procedures and other techniques used to be observed. treat Wrinkles and signs of aging skin include a variety of 0020. Botulinum toxin type A (BotoxR), when injected in skin-resurfacing techniques, injectables, fillers and Surgical Small doses into specific muscles, blocks the chemical signals procedures to Smooth out wrinkles and treat signs of aging that cause muscles to contract. When the muscles can't skin. Each works a little differently and has its own set of tighten, the skin flattens and appears Smoother and less potential results and side effects. Examples include derm wrinkled. BotoxR works well on frown lines between the abrasion, microdermabrasion, laser, chemical peel. Botuli eyebrows and on the bridge of the nose, forehead creases, num toxin type A (Botox), soft tissue fillers, face lift, and crow's-feet at the corners of the eyes, and skin bands on the other Surgical techniques. neck. Results typically last about three to four months. Repeat 0017 Dermabrasion consists of sanding down (planing) injections are needed to maintain results. Not all facial the surface layer of skin with a rapidly rotating brush. The wrinkles benefit from BotoxR injections, however. BotoxR) planing removes the skin Surface and a new layer of skin won't reverse wrinkling caused by Sun damage. Also, it's less grows in its place. Redness, Scabbing and Swelling generally desirable to treat the lines around the mouth because muscles last a couple of weeks. It may take several months for pink in this area are needed for eating and talking Side effects and ness to fade and to see the desired results. Microdermabrasion complications of Botox Rinjections include pain and bruising is similar to dermabrasion, but less Surface skin is removed. at the injection site, redness, headache, flu-like symptoms, It's done using a vacuum Suction over the face while alumi nausea, temporary facial weakness or drooping, and spread of num oxide crystals essentially sandblast the skin. Only a fine the toxin beyond the treatment area, which can cause botu layer of skin is removed. A slight redness to the treated areas lism-like signs and symptoms (trouble Swallowing, muscle may occur. Microdermabrasion usually requires repeated weakness, slurred speech and breathing problems). treatments to maintain the Subtle, temporary results. 0021 Soft tissue fillers, which include fat, collagen and 0.018 Laser resurfacing removes aged or Sun-damaged hyaluronic acid (Restylane(R), Juvederm(R), can be injected skin to allow younger looking skin to grow in its place. Laser into deeper wrinkles on the face. They plump and Smooth out resurfacing is an effective treatment for minor facial flaws. wrinkles and furrows and give the skin more volume. Side For example, it can lessen the appearance offine lines around effects include temporary Swelling, redness and bruising in the eyes, mouth and cheeks. It can also improve a complexion the treated area. The procedure may need to be repeated every having yellowish or grayish skin tones. In ablative (wound few months. ing) laser resurfacing, a laser beam destroys the outer layer of 0022. A face-lift procedure involves removing excess skin skin (epidermis) and heats the underlying skin (dermis), and fat in the lower face and neck and tightening the under US 2012/0064136 A1 Mar. 15, 2012

lying muscle and connective tissue. The results typically last petrolatum jelly. U.S. Pat. No. 4,777,041 for “Wrinkle treat five to 10 years. Healing times can be lengthy after a face-lift. ment formulation is directed to compositions comprising a Bruising and Swelling are usually evident for several weeks gelable hydrophilic polyurethane polymer base and a precipi after Surgery. tated silica thickener gelling agent. U.S. Pat. No. 7,384,916 for "Methods and compositions for preventing and treating C. Background Regarding Nanoemulsions aging or photodamaged skin is directed to topical compo sitions comprising a peptide manganese complex. U.S. Pat. 0023 Prior teachings related to nanoemulsions are Nos. 7,354,610 and 7,214,395, both for “Pharmaceutical and described in U.S. Pat. No. 6,015,832, which is directed to cosmetic composition against skin aging is directed to com methods of inactivating a Gram-positive bacteria, a bacterial positions comprising phospholipid complexes of extracts of spore, or a Gram-negative bacteria. The methods comprise Vitis vinifera, and phospholipid complexes of standardized contacting the Gram-positive bacteria, bacterial spore, or extract from Centella asiatica. U.S. Pat. No. 7,205,003 for Gram-negative bacteria with a bacteria-inactivating (or bac “Method and topical formulation for treating skin conditions terial-spore inactivating) emulsion. U.S. Pat. No. 6,506,803 is associated with aging is directed to topical compositions directed to methods of killing or neutralizing microbial comprising a cosmeceutically active base, which is either an agents (e.g., bacteria, Virus, spores, fungus, on or in humans inorganic base. Such as an inorganic hydroxide, an inorganic using an emulsion. U.S. Pat. No. 6,559,189 is directed to oxide, or a metal salt of a weak acid, or an organic base. Such methods for decontaminating a sample (human, animal, food, as a nitrogenous base. medical device, etc.) comprising contacting the sample with a 0025. The intact skin of humans is an effective barrier to nanoemulsion. The nanoemulsion, when contacted with bac many natural and synthetic Substances. Many cosmetic and terial, virus, fungi, protozoa, or spores, kills or disables the pharmaceutical agents, which are pharmacologically effec pathogens. The antimicrobial nanoemulsion comprises an oil, tive on oral or systemic administration, may be much less quaternary ammonium compound, one of ethanol/glycerol/ effective or even totally ineffective, when applied topically to PEG, a surfactant, and water. U.S. Pat. No. 6,635,676 is the skin. Therefore, there is an ongoing need in the art for new directed to two different compositions and methods of decon and effective regimens for treating aging-related skin condi taminating samples by treating a sample with either of the tions. The present invention addresses these and other needs compositions. Composition 1 comprises an emulsion that is in the art by providing novel methods and topical formula antimicrobial against bacteria, virus, fungi, protozoa, and/or tions for treating a variety of aging-related skin conditions, spores. The emulsions comprise an oil and a quaternary including wrinkles, age spots, Sun damage (particularly UV ammonium compound. U.S. Pat. No. 7,314,624 is directed to radiation-induced oxidative stress/photodamage), blemishes, methods of inducing an immune response to an immunogen hyperpigmented skin, age spots, increased skin thickness, comprising treating a Subject via a mucosal Surface with a loss of skin elasticity and collagen content, dry skin, lentigi combination of an immunogen and a nanoemulsion. The nes, and melasmas. nanoemulsion comprises oil, ethanol, a Surfactant, a quater 0026. There remains a need for more effective and other nary ammonium compound, and distilled water. US-2005 wise improved methods for treating dermatological condi 0208083-A1 and US-2006-025 1684-A1 are directed to tions related to aging skin, Such as fine lines and wrinkles, and nanoemulsions having droplets with preferred sizes. skin imperfections, such as Scars. The present invention US-2007-0054834-A1 is directed to compositions compris addresses these needs and provides further related advan ing quaternary ammonium halides and methods of using the tages. same to treat infectious conditions. The quaternary ammo nium compound may be provided as part of an emulsion. SUMMARY OF THE INVENTION Finally, US-2007-003.6831-A1 is directed to nanoemulsions comprising an anti-inflammatory agent. 0027. The present invention provides methods for treat 0024 Examples of documents describing compositions ing, preventing, and/or minimizing Wrinkles, signs of aging for treating wrinkles or skin aging include U.S. Pat. No. skin, and/or skin imperfections comprising administering a 6,896,889 for “Immediate effect anti-wrinkle composition, nanoemulsion to a subject. Examples of signs of aging skin based on an aqueous dispersion, of at least one mineral filler.” and/or skin imperfections which can be treated, prevented, directed to a composition comprising colloid particles of a and/or minimized with the methods of the invention include, mineral filler. U.S. Pat. No. 6,808,715 for “Wrinkle Cream,” but are not limited to, (1) fine to moderate wrinkles, (2) liver is directed to an emulsion comprising water, hydrophilic par spots or age spots (lentigines or Solar lentigines), (3) uneven ticles, and hydrophobic particles, wherein the hydrophilic skin tone and/or texture, (4) Sun-damaged skin or photodam and hydrophobic particles form shells encapsulating a gas aged skin (particularly UV radiation-induced oxidative that is suspended in the water. U.S. Pat. No. 6,497.890 for stress), (5) blemishes, (6) hyperpigmented skin, (7) increased Anti-wrinkle preparation and method of reducing wrinkles skin thickness, (8) dry skin, (9) loss of skin elasticity and in facial skin and neck is directed to a method for the collagen content (laxity and firmness), (10) melasmas (a typi prevention or minimization of wrinkles in the face and neck cal pigmentation or hyper-pigmentation of the skin), (11) skin areas of a patient by topically applying finely divided saf clarity and/or radiance, (12) skin Smoothness and/or softness, flower seeds or extract thereof in combination with a phar (13) pore size (larger pore can make an individual appear maceutically acceptable carrier. U.S. Pat. No. 6,344,188 for older), (14) increase hydration, (15) increase skin Smooth “Wrinkle reducing cream, is directed to a cream comprising ness, (16) increase skin tightness, and any combination water, caffeine, and glycerin. U.S. Pat. No. 5,360,824 for thereof. “Human skin cleansing and wrinkle-reducing cream is 0028. The compositions of the invention can also be used directed to a composition comprising water-soluble granules to treat Scars, such as acne and chickenpox Scars. Collectively which can be an inorganic salt, Such as a water-soluble vita the signs of aging skin, skin imperfections and Scars are min and/or water-soluble vitamin-yielding salt, an oil and a referred to as “dermatological conditions.” The nanoemul US 2012/0064136 A1 Mar. 15, 2012 sion comprises droplets having an average diameter of less agents incorporated into the nanoemulsion, thereby enhanc than about 3 microns, and the nanoemulsion droplets com ing the efficacy and reducing the detrimental side effects of prise an aqueous phase, at least one oil, at least one Surfactant, the other agents. and at least one organic Solvent. 0035. In certain embodiments of the invention, the 0029. In one embodiment the nanoemulsion is applied nanoemulsion can have an increased viscosity to aid in per topically, which is a non-invasive administration technique. meation of the nanoemulsion into the dermis and epidermis. In an alternative embodiment, the nanoemulsion can be 0036. In other embodiments of the invention, the applied Subcutaneously. nanoemulsion at the time of topical application is at room temperature or warmer. 0030. In an exemplary embodiment, a method of the 0037. The nanoemulsion comprises droplets having an invention for treating, reducing and/or minimizing the der average particle size of less than about 3 microns, and the matological conditions described above (e.g., wrinkling, nanoemulsion comprises water, at least one oil, at least one signs of aging skin, and/or skin imperfections) in a region of Surfactant, and at least one organic solvent. In one embodi skin comprises applying a nanoemulsion according to the ment of the invention, the Surfactant present in the nanoemul invention to the region of skin. The nanoemulsion can be sion is a cationic Surfactant. In another embodiment of the applied to any skin region of a subject. In one embodiment, invention, the nanoemulsion further comprises a chelating the nanoemulsion is applied to the facial tissue of a subject. In agent. In one embodiment of the invention, nanoemulsions another embodiment, the nanoemulsion is applied to the neck from the present invention, or those derived from the tissue of a Subject. It has been Surprisingly found that the nanoemulsions of the present invention, are diluted. The nanoemulsion compositions of the invention can be used to diluted samples can then be tested to determine if they main Substantially treat, reduce, minimize, and/or diminish the der tain the desired functionality, Such as Surfactant concentra matological conditions described above. tion, stability, and particle size. 0031. In a further embodiment, the nanoemulsion compo 0038 Preferably, the nanoemulsions are in the form of any sition of the invention further comprises one or more active pharmaceutically acceptable dosage form, including but not agents. The presence of Such an active agent is not required, limited to, ointments, creams, emulsions, lotions, gels, liq and Substantial and unexpected anti-aging and/or anti uids, bioadhesive gels, sprays, shampoos, aerosols, pastes, wrinkle properties are observed without the presence of such foams, Sunscreens, capsules, microcapsules, or in the form of an active agent. Thus, the presence of Such an active agent is an article or carrier, such as a bandage, insert, Syringe-like to merely enhance the anti-aging and/or anti-wrinkle proper applicator, pessary, powder, talc or other Solid, shampoo, ties of the compositions of the invention. In one embodiment, cleanser (leave on and wash off product), and agents that an active agent incorporated into a nanoemulsion composi favor penetration within the epidermis, the dermis and keratin tion of the invention is a compound that provide benefits to the layers. Preferably, the nanoemulsions are in a dosage form skin and/or provides desirable properties to a composition Suitable for topical administration. The nanoemulsion is formulated as a cosmetic or medicinal preparation. The active capable of effectively treating and/or preventing signs of agent can be a drug Substance or a non-drug Substance. aging associated with the skin, Such as fine to moderate Examples of non-drug active agents include, but are not lim wrinkles, uneven skintone, and other dermatological signs of ited to, skin lightening agents, tanning agents, skin condition aging skin noted above, without being systemically absorbed ing agents, skin protectants, emollients and humectants. and without significantly irritating the skin. 0032 Examples of exemplary active agents, such as an 0039. The foregoing general description and following active drug Substance or an active cosmetic Substance, that brief description of the drawings and the detailed description can be incorporated into a nanoemulsion composition of the are exemplary and explanatory and are intended to provide invention include, but are not limited to. Botulinum toxin type further explanation of the invention as claimed. Other objects, A (BotoxR), a retinoid (e.g., vitamin A derivatives, retinol, advantages, and novel features will be readily apparent to retinal, tretinoin (retinoic acid, RenovaR), Retin-AR), isotre those skilled in the art from the following detailed description tinoin, alitretinoin, etretinate, acitretin, tazarotene (Avage(R), of the invention. TaZoracR), beXarotene and Adapalene), alpha hydroxy acids, beta hydroxy acids, polyhydroxy acids, hydroxyl acids, kine tin, coenzyme Q10, copper peptides, tea extracts (e.g., green, BRIEF DESCRIPTION OF THE DRAWINGS black and oolong tea extracts), antioxidants (e.g., ascorbic 0040 FIG. 1 illustrates the cross-section view of the acid (vitamin C), glutathione, melatonin, tocopherols, C-to pilosebaceous unit in human cadaver skin and hamster ear copherol, tocotrienols (vitamin E), lipoic acid, uric acid, car after application of nanoemulsion plus fluorescein. otenes, ubiquinone (coenzyme Q), thioredoxin, Polyphenolic 0041 FIG. 2 shows in vitro skin permeation of nanoemul antioxidants (resveratrol, flavonoids), and carotenoids) or any sion formulations into the epidermal layer of pig abdominal mixture thereof. skin at 24 hours after a single topical application of 100 0033. In another embodiment, the composition of the ul/cm. invention comprises an anti-viral agent. Such a composition 0042 FIG. 3 shows in vitro permeation of nanoemulsion is useful, for example, in treating a herpes virus outbreak formulations in pig abdominal skin (epidermis and dermis)at following laser treatment, such as ablative laser resurfacing. 12 and 24 hours after a single topical application of 100 In yet another embodiment, the composition of the invention ul/cm. comprises an anti-acne agent. 0043 FIG. 4 shows the effect the concentration of a 0034. The composition of the invention allows for targeted nanoemulsion has on the particle size and Viscosity of the delivery to the area of skin to be treated. Moreover, the nanoemulsion. With a decrease in concentration of the active, nanoemulsions are able to enhance delivery, and thus effec Viscosity (cP) declines (triangles), whereas the particle size tiveness, of other active drug agents and/or active cosmetic remains constant (bars). US 2012/0064136 A1 Mar. 15, 2012

0044 FIG. 5 shows the results of a permeation study uti reported that the overall appearance of skin was improved, up lizing pigskin epidermis with 5 skin sections (n=5) following to 30% of nanoemulsion users reported that skintone and skin administration of a nanoemulsion (NB-003) twice daily texture was more even, and up to 25% of nanoemulsion users (BID). Higher viscosity (greater than 1000 cps) nanoemul reported that following treatment skin looked and/or felt sions (e.g., 0.8% NB-003) were found to enhance permeation younger. of the nanoemulsion into the epidermis. 0052. In an exemplary embodiment, a method of the 0045 FIG. 6 shows the results of a permeation study uti invention for treating, reducing and/or minimizing dermato lizing pig skin dermis with 5 skin sections (n=5) following logical conditions in a region of skin comprises applying a administration of a nanoemulsion (NB-003) twice daily nanoemulsion according to the invention to the region of skin. (BID). Higher viscosity (greater than 1000 cps) nanoemul In one embodiment the nanoemulsion is applied topically, sions (e.g., 0.8% NB-003) were found to deliver three times which is a non-invasive administration technique. In an alter the amount of the surfactant, cetylpyridinium chloride (CPC) native embodiment, the nanoemulsion can be applied Subcu to the dermis as compared to a lower viscosity nanoemulsion taneously. The nanoemulsion can be applied to any skin (e.g., 0.25% NB-003). region of a Subject. In one embodiment, the nanoemulsion is 0046 FIG. 7 shows the effect of storage temperature of a applied to the facial tissue of a subject. In another embodi nanoemulsion (e.g., NB-003) on the in vitro activity of the ment, the nanoemulsion is applied to the neck tissue of a nanoemulsion against Pacnes in the presence of sebum. Subject. It has been Surprisingly found that the nanoemulsion 0047 FIG. 8 shows the results of the permeation study compositions of the invention can be used to Substantially utilizing pigskin following administration of a nanoemulsion treat, minimize, and/or diminish the dermatological condi formulated with benzoyl peroxide twice daily (BID) as com tions described above. pared to a commercial preparation of 10% benzoyl peroxide. 0053. In a further embodiment, the composition addition 0048 FIG. 9 shows the results of the permeation study ally comprises one or more active agents. The presence of utilizing pig skin following topical administration (100 Such an active agent is not required, and Substantial and ul/cm) of a nanoemulsion with incorporated 0.1% adapalene unexpected anti-aging and/or anti-wrinkle properties are twice daily (BID) as compared to two different commercial observed without the presence of Such an active agent. Thus, preparations of adapalene. the presence of Such active agents is to merely enhance the 0049 FIG. 10 shows the results of the permeation study anti-aging and anti-wrinkle properties of the compositions of utilizing female cadaver abdominal skin following topical the invention. In one embodiment, active agents useful in the administration (100 ul/cm) of a nanoemulsion and incorpo nanoemulsion compositions of the invention are compounds rated 0.1% adapalene once daily (QD) as compared to two that provide benefits to the skin and/or provide desirable different commercial preparations of adapalene. properties to a composition formulated as a cosmetic or medicinal preparation. The active agent useful in the DETAILED DESCRIPTION OF THE PREFERRED nanoemulsion compositions of the invention can be a drug EMBODIMENTS Substance or a non-drug Substance. Examples of non-drug 0050. The present invention provides methods for treat active agents include, but are not limited to, skin lightening ing, preventing, and/or minimizing Wrinkles, signs of aging agents, tanning agents, skin conditioning agents, skin pro skin, and/or skin imperfections comprising administering a tectants, emollients and humectants. nanoemulsion to a subject. Examples of signs of aging skin 0054 Examples of exemplary active agents useful in the and/or skin imperfections which can be treated, prevented, nanoemulsion compositions of the invention, such as an and/or minimized with the methods of the invention include, active drug Substance or an active cosmetic Substance, but are not limited to, (1) fine to moderate wrinkles, (2) liver include, but are not limited to, Botulinum toxin type A spots or age spots (lentigines or Solar lentigines), (3) uneven (BotoxR), a retinoid (e.g., vitaminA derivatives, retinol, reti skin tone and/or texture, (4) Sun-damaged skin or photodam nal, tretinoin (retinoic acid, Renova R, Retin-AR), isotretin aged skin (particularly UV radiation-induced oxidative oin, alitretinoin, etretinate, acitretin, tazarotene (Avage R. stress), (5) blemishes, (6) hyperpigmented skin, (7) increased TaZoracR), beXarotene and Adapalene), alpha hydroxy acids, skin thickness, (8) dry skin, (9) loss of skin elasticity and betahydroxy acids, polyhydroxy acids, hydroxyl acids, kine collagen content, (10) melasmas (atypical pigmentation or tin, coenzyme Q10, copper peptides, tea extracts (e.g., green, hyper-pigmentation of the skin), (11) skin clarity and/or radi black and oolong tea extracts), antioxidants (e.g., ascorbic ance, (12) skin Smoothness and/or softness, (13) pore size acid (vitamin C), glutathione, melatonin, tocopherols, C-to (larger pore can make an individual appear older), (14) copherol, tocotrienols (vitamin E), lipoic acid, uric acid, car increase hydration, (15) increase skin Smoothness, (16) otenes, ubiquinone (coenzyme Q), thioredoxin, Polyphenolic increase skin tightness, and any combination thereof. The antioxidants (resveratrol, flavonoids), and carotenoids) or any compositions of the invention can also be used to treat Scars, mixture thereof. Such as acne and chickenpox Scars. Collectively the signs of 0055. In another embodiment, the composition of the aging skin, skin imperfections and Scars are referred to as invention comprises an anti-viral agent. Such a composition "dermatological conditions.” is useful, for example, in treating a herpes virus outbreak 0051. As described in the examples below, following topi following laser treatment, Such as ablative laser resurfacing. cal application of a nanoemulsion to facial skin, up to 75% of In yet another embodiment, the composition of the invention nanoemulsion users reported that skin was Smoother and comprises an anti-acne agent. softer. Moreover, up to 37.5% of nanoemulsion users reported 0056. The nanoemulsion composition of the invention that following treatment skin demonstrated more clarity and/ allows for targeted delivery to the area of skin to be treated. or radiance, and up to 37.5% of nanoemulsion users reported Moreover, the nanoemulsions are able to enhance delivery, that wrinkles appeared softer and/or less prominent. In addi and thus effectiveness, of other active drug agents and/or tion, following treatment up to 35% of nanoemulsion users active cosmetic agents incorporated into the nanoemulsion, US 2012/0064136 A1 Mar. 15, 2012 thereby enhancing the efficacy and reducing the detrimental available in the pilosebaceous unit, epidermal and dermal side effects of the other agents. tissues without causing disruption to the normal epithelial 0057. In certain embodiments of the invention, the matrix. 0062. In one embodiment of the invention, the nanoemul nanoemulsion can have an increased viscosity to aid in per sion comprises: (a) an aqueous phase; (b) about 1% oil to meation of the nanoemulsion into the dermis and epidermis. about 80% oil; (c) about 0.1% organic solvent to about 50% In other embodiments of the invention, the nanoemulsion at organic solvent; (d) about 0.001% surfactant or detergent to the time of topical application is at room temperature or about 10% surfactant or detergent; (e) about 0.0005% to Wa. about 1.0% of a chelating agent; or (f) any combination 0058. The nanoemulsion comprises droplets having an thereof. In another embodiment of the invention, the average particle size of less than about 3 microns, and the nanoemulsion comprises: (a) about 10% oil to about 80% oil; nanoemulsion comprises water, at least one oil, at least one (b) about 1% organic solvent to about 50% organic solvent; Surfactant, and at least one organic solvent. In one embodi (c) at least one non-ionic Surfactant present in an amount of ment of the invention, the Surfactant present in the nanoemul about 0.1% to about 10%; (d) at least one cationic agent sion is a cationic Surfactant. In another embodiment of the present in an amount of about 0.01% to about 2%; (e) about invention, the nanoemulsion further comprises a chelating 0.0005% to about 1.0% of a chelating agent; or (f) any com agent. In one embodiment of the invention, nanoemulsions bination thereof. from the present invention, or those derived from the 0063. In yet another embodiment of the invention, the nanoemulsions of the present invention, are diluted. The nanoemulsion additionally includes at least one suitable or diluted samples can then be tested to determine if they main desirable active agent (e.g., a drug or cosmetic active agent). tain the desired functionality, Such as Surfactant concentra The active agent can be present in a therapeutically effective tion, stability, and particle size. amount, such as from about 0.001% up to about 99%, about 0.01% up to about 95%, about 0.1% up to about 90%, about 0059. The nanoemulsions can be in the form of any phar 3% up to about 80%, about 5% up to about 60%, about 10% maceutically acceptable dosage form, including but not lim up to about 50%, or any combination thereof (e.g., about 3% ited to, liquids, ointments, creams, oils, emulsions, lotions, up to about 10%). gels, liquids, bioadhesive gels, sprays, shampoos, aerosols, 0064. The quantities of each component present in the pastes, foams, Sunscreens, capsules, microcapsules, or in the nanoemulsion refer to a therapeutic nanoemulsion, and not to form of an article or carrier, such as abandage, insert, Syringe a nanoemulsion to be tested in vitro. This is significant, as like applicator, pessary, powder, talc or other Solid, shampoo, nanoemulsions tested in vitro, such as the nanoemulsions cleanser (leave on and wash off product), day creams, night described in the examples, generally have lower concentra creams, make-up removal creams, foundation creams, make tions of oil, organic solvent, Surfactant or detergent, and (if up removal formulations, protective or skin care body milks, present) chelating agent than that present in a nanoemulsion skin care lotions, gels, or foams (such as cleansing or disin intended for therapeutic use, e.g., topical use. This is because fecting lotions), bath compositions, deodorant compositions, in vitro microbiology studies do not require the nanoemulsion aftershave and pre-shave gels or lotions, and agents that favor droplets to traverse the skin or other barriers. For topical use, penetration within the epidermis, the dermis and keratin lay the concentrations of the components must be higher to result ers. The nanoemulsion is capable of effectively treating, pre in therapeutic levels of nanoemulsion. However, the relative venting, and/or minimizing the dermatological conditions quantities of each component used in a nanoemulsion tested described herein, without being systemically absorbed and in vitro are applicable to a nanoemulsion to be used therapeu without significantly irritating the skin. tically and, therefore, in vitro quantities can be scaled up to 0060. The nanoemulsions comprise droplets having an prepare a therapeutic composition, and in vitro data may well average diameter of less than about 3 microns, and the be predictive of topical application Success. nanoemulsions comprise an aqueous phase, at least one oil, at least one Surfactant or detergent, and at least one organic A. DEFINITIONS solvent. In one embodiment of the invention, the surfactant 0065. The present invention is described herein using sev present in the nanoemulsion is a cationic Surfactant. More eral definitions, as set forth below and throughout the appli than one surfactant or detergent can be present in the cation. nanoemulsions of the invention, and the second Surfactant can 0066. As used herein, “about will be understood by per be the same type (i.e., two cationic Surfactants) or the second sons of ordinary skill in the art and will vary to some extent or third etc. surfactant can be different from the first. For depending upon the context in which it is used. If there are example, the nanoemulsions can comprise a cationic Surfac uses of the term which are not clear to persons of ordinary tant in combination with a non-ionic Surfactant. In another skill in the art given the context in which it is used, “about embodiment of the invention, the nanoemulsion further com will mean up to plus or minus 10% of the particular term. prises a chelating agent. The organic solvent and the aqueous 0067. The term “active agent' is used herein to refer to a phase of the invention can be a non-phosphate based solvent. chemical material or compound that induces a desired ben 0061 The nanoemulsions comprise high energy nanom eficial effect when administered topically or subcutaneously, eter-sized droplets that permeate into the pilosebaceous unit, and includes agents that are therapeutically and/or prophy dermis and/or epidermis. Droplets having a suitable particle lactically effective as pharmaceuticals (pharmacologically size can permeate skin pores and into the pilosebaceous unit, active agents'), as well as agents that are cosmeceutically but can be excluded by tightjunctions between epithelial cells effective ("cosmeceutically active agents'). Also included are and thus do not disrupt tissue matrices or enter blood vessels. derivatives and analogs of those compounds or classes of This minimizes skin irritation and systemic absorption, but compounds specifically mentioned that also induce the yet provides for a composition which is highly topically bio desired effect. By an “effective” amount of an active agent is US 2012/0064136 A1 Mar. 15, 2012

meant a nontoxic but sufficient amount of an active agent to 0076. The term “nanoemulsion,” as used herein, includes provide the desired beneficial effect. More specifically, by a dispersions or droplets, as well as other lipid structures that “therapeutically effective.” “prophylactically effective, or can form as a result of hydrophobic forces that drive apolar "cosmeceutically effective” amount is meant a nontoxic but residues (i.e., long hydrocarbon chains) away from water and sufficient amount of a beneficial agent to provide the desired drive polar head groups toward water, when a water immis therapeutic, prophylactic, or cosmeceutical effect. cible oily phase is mixed with an aqueous phase. These other 0068. The term “aging-related skin condition” relates to lipid structures include, but are not limited to, unilamellar, any skin condition or disorder associated with, caused by, or paucilamellar, and multilamellar lipid vesicles, micelles, and affected by, intrinsic aging and/or extrinsic aging. Aging lamellar phases. The droplets have an average diameterofless related skin conditions that may be treated using the present than about 3 microns. methods and formulations include, but are not limited to, 0077. The terms “pharmaceutically acceptable' or “phar wrinkles, age spots, Sun damage (particularly UV radiation macologically acceptable, as used herein, refer to composi induced oxidative stress), blemishes, hyperpigmented skin, tions that do not substantially produce adverse allergic or age spots, increased skin thickness, loss of skin elasticity and immunological reactions when administered to a host (e.g., collagen content, dry skin, lentigines, melasmas, as well as an animal or a human). Such formulations include any phar SCaS. maceutically acceptable dosage form. As used herein, “phar maceutically acceptable carrier includes any and all sol 0069. The terms “buffer” or “buffering agents” refer to Vents, dispersion media, coatings, wetting agents (e.g., materials which when added to a solution, cause the Solution Sodium lauryl Sulfate), isotonic and absorption delaying to resist changes in pH. agents, disintegrants (e.g., potato starch or sodium starch 0070. “Carriers' or “vehicles' as used herein refer to car glycolate), and the like. rier materials Suitable for incorporation in a topically or Sub (0078. The term “stable' when referring to a “stable cutaneously applied composition. Carriers and vehicles use nanoemulsion' means that the nanoemulsion retains its struc ful herein include any Such materials known in the art, which ture as an emulsion. A desired nanoemulsion structure, for are nontoxic and do not interact with other components of the example, may be characterized by a desired size range, mac formulation in which it is contained in a deleterious manner. roscopic observations of emulsion science (is there one or (0071. The terms “chelator” or “chelating agent” refer to more layers visible, is there visible precipitate), pH, and a any materials having more than one atom with a lone pair of stable concentration of one or more the components. electrons that are available to bond to a metalion. 007.9 The term “subject' as used herein refers to organ 0072 By "cosmeceutically effective' is meant a nontoxic isms to be treated by the compositions of the present inven agent that has medicinal or drug-like properties which, when tion. Such organisms include animals (domesticated animal applied to the surface of skin, beneficially affects the biologi species, wild animals), and humans. cal functioning of that skin. 0080. The term “surfactant” refers to any molecule having 0073. The terms "cosmeceutically active agent” and “cos both a polar head group, which energetically prefers Solvation meceutically active base' are used interchangeably herein to by water, and a hydrophobic tail which is not well solvated by refer to a cosmeceutically effective basic compound or com water. The term "cationic surfactant” refers to a surfactant position of matter which, when topically administered to a with a cationic head group. The term “anionic Surfactant” human patient, is effective to treat one or more aging-related refers to a Surfactant with an anionic head group. skin conditions as defined above. Also included are deriva I0081. As used herein, the term “topically’ refers to appli tives and analogs of those compounds or classes of com cation of the compositions of the present invention to the pounds specifically mentioned that also induce the desired Surface of the skin and tissues. effect, i.e., treatment of an aging-related skin condition. I0082. The terms “treating and “treatment” as used herein 0074 By "cosmeceutically acceptable.” Such as in the refer to reduction in severity and/or elimination of skin recitation of a "cosmeceutically acceptable carrier” or a "cos related conditions resulting from intrinsic and/or extrinsic meceutically acceptable derivative. is meant a compound aging processes of the skin, or other trauma to the skin result that is not biologically or otherwise undesirable, i.e., the ing in, e.g., a scar. The present method of “treating a skin compound may be incorporated into a cosmeceutical formu condition related to aging, as the term is used herein, refers to lation of the invention and topically administered to a patient the prevention of aging-related skin conditions as well as the without causing any undesirable biological effects or inter treatment of aging-related skin conditions in affected indi acting in a deleterious manner with any of the other compo viduals. nents of the cosmeceutical formulation in which it is con tained. The term “pharmaceutically acceptable' is used in an B. VISCOSITY analogous manner, to refer to a compound or composition that I0083. Examples 6 and 7 below demonstrate that increas may be incorporated into a pharmaceutical formulation ing the viscosity of the nanoemulsion can enhance distribu herein (i.e., a cosmeceutical formulation containing one or tion and permeation of the nanoemulsion into the skin, more pharmacologically active agents) without causing thereby producing a nanoemulsion more effective in an anti undesirable biological effects or unwanted interaction with aging and/or anti-wrinkle treatment. other components of the formulation. I0084 FIG. 4 shows the relationship between the particle 0075. The term “dilution refers to dilution of the size (nm), concentration of active (%), and Viscosity of a nanoemulsions of the present invention or those derived from nanoemulsion. The particle size does not change upon dilu the nanoemulsions of the present invention using, for tion of a nanoemulsion; however viscosity significantly example, an aqueous system comprised of PBS or water (Such decreases as a function of the decrease in particle concentra as diHO), or other water soluble components, to the desired tions. Thus, embodiment of the invention encompass using final concentration. dilutions of a nanoemulsion. Table 6 (below) shows the effect US 2012/0064136 A1 Mar. 15, 2012

dilution of a nanoemulsion has on the concentration of the tions described herein, Such as anti-aging and anti-wrinkle active (CPC), viscosity, and particle size. treatments, comprising application of a nanoemulsion I0085 FIGS. 2, 3, 5 and 6 show the results for epidermis according to the invention, wherein the nanoemulsion is at and dermis permeation, respectively. Higher viscosity room temperature (e.g., 20 to 25°C.). In another embodiment nanoemulsions were found to increase the permeation of the of the invention, encompassed are compositions for and nanoemulsion into the epidermis (FIGS. 2, 3 and FIG. 5) and methods of treating dermatological conditions described dermis (FIGS. 3 and 6). herein, such as anti-aging and anti-wrinkle treatments, com I0086 More particularly, as shown in FIGS. 5 and 6, lower prising application of a nanoemulsion according to the inven concentration nanoemulsions, e.g., 0.25% to 0.30%, are tion, wherein the nanoemulsion has been warmed prior to effective in penetrating the skin. Slightly higher or lower application. For example, the nanoemulsion can be warmed concentrations are also effective. However, at a concentration prior to application to a temperature selected from the group of 0.5%, permeation significantly declined. Surprisingly, consisting of about 30° C. or warmer, about 31°C. or warmer, higher concentrations such as 0.8% or more showed a dra about 32°C. or warmer, about 33°C. or warmer, about 34°C. matic increase in permeation due to the increased viscosity of or warmer, about 35° C. or warmer, about 36°C. or warmer, the composition. It is theorized that the increase in Viscosity about 37° C. or warmer, inhibits or limits the evaporation of water from the skin after application of the emulsion, thus preventing the crystalliza D. STABILITY OF THE NANOEMULSIONS OF tion of the active from the nanoemulsion and extending the THE INVENTION time of permeation of the nanoemulsions into the various skin strata. As an alternative to increasing the concentration of the 0089. The nanoemulsions of the invention are stable at nanoemulsion, the Viscosity of the nanoemulsion can be about 40° C. and about 75% relative humidity for a time increased to provide improved therapeutic effectiveness. period of at least up to about 1 month, at least up to about 3 Examples of methods of increasing the Viscosity of a months, at least up to about 6 months, at least up to about 12 nanoemulsion according to the invention including increas months, at least up to about 18 months, at least up to about 2 ing the concentration of the nanoemulsion (e.g., increasing years, at least up to about 2.5 years, or at least up to about 3 CPC concentration or the number of nanoemulsion droplets), years. or adding a thickening agent or gelling agent to the formula 0090. In another embodiment of the invention, the tion (see e.g., FIGS. 2 and 3). nanoemulsions of the invention are stable at about 25°C. and 0087 Thus, in one embodiment of the invention, the about 60% relative humidity for a time period of at least up to nanoemulsion has a viscosity of greater than about 12 centi about 1 month, at least up to about 3 months, at least up to poise (cP), greater than about 15 cl, greater than about 20 cp. about 6 months, at least up to about 12 months, at least up to greater than about 25 cF. greater than about 30 cp greater than about 18 months, at least up to about 2 years, at least up to about 35 cB. greater than about 40 cp greater than about 45 cB. about 2.5 years, or at least up to about 3 years, at least up to greater than about 50 cp, greater than about 55 cl, greater than about 3.5 years, at least up to about 4 years, at least up to about about 60 cp, greater than about 65 cF. greater than about 70 cp. 4.5 years, or at least up to about 5 years. greater than about 75 cl, greater than about 80 cp greater than 0091. Further, the nanoemulsions of the invention are about 85 cB. greater than about 90 cp greater than about 95 cF. stable at about 4°C. for a time period of at least up to about 1 greater than about 100 cp greater than about 150 cB. greater month, at least up to about 3 months, at least up to about 6 than about 200 cp, greater than about 300 cp, greater than months, at least up to about 12 months, at least up to about 18 about 400 cp, greater than about 500 cp, greater than about months, at least up to about 2 years, at least up to about 2.5 600 cB. greater than about 700 cP. greater than about 800 cB. years, at least up to about 3 years, at least up to about 3.5 greater than about 900 cp, greater than about 1000 cp, greater years, at least up to about 4 years, at least up to about 4.5 than about 1500 cp, greater than about 2000 cB. greater than years, at least up to about 5 years, at least up to about 5.5 about 2500 cp, greater than about 3000 cp greater than about years, at least up to about 6 years, at least up to about 6.5 3500 cB. greater than about 4000 cP greater than about 4500 years, or at least up to about 7 years. cP greater than about 5000 cF. greater than about 5500 cB. greater than about 6000 cp greater than about 7000 cp greater ENANOEMULSIONS than about 8000 cp, greater than about 9000 cB. greater than about 10,000 cp, greater than about 15,000 cp greater than 0092. The term “nanoemulsion', as defined herein, refers about 20,000 cp, greater than about 30,000 cp greater than to a dispersion or droplet or any other lipid structure. Typical about 40,000 cp, greater than about 50,000 cp greater than lipid structures contemplated in the invention include, but are about 60,000 cB. greater than about 70,000 cB. greater than not limited to, unilamellar, paucilamellar and multilamellar about 80,000 cB. greater than about 90,000 cB. greater than lipid vesicles, micelles and lamellar phases. about 100,000 cB. greater than about 150,000 cB. greater than 0093. The nanoemulsion of the present invention com about 200,000 cB. greater than about 250,000 cB, or up to prises droplets having an average diameter size of less than about 259,300 cP. about 3 microns, less than about 2500 nm, less than about 2000 nm, less than about 1500 nm, less than about 1000 nm, C. TEMPERATURE less than about 950 nm, less than about 900 nm, less than about 850 nm, less thanabout 800 nm, less than about 750 nm, 0088. One tactic that can increase the effectiveness of a less than about 700 nm, less than about 650 nm, less than nanoemulsion according to the invention in anti-aging and about 600 nm, less thanabout 550 nm, less than about 500 nm, anti-wrinkle treatments is ensuring that the nanoemulsion is less than about 450 nm, less than about 400 nm, less than at room temperature or warmer prior to application. Thus, in about 350 nm, less thanabout 300 nm, less than about 250 nm, another embodiment of the invention, encompassed are com less than about 225 nm, less than about 220 nm, less than positions for and methods of treating dermatological condi about 210 nm, less thanabout 205 nm, less than about 200 nm, US 2012/0064136 A1 Mar. 15, 2012

less than about 190 nm, less than about 175 nm, less than leaf oil, eucalyptus leaf oil, lemon grass leaf oil, melaleuca about 150 nm, or any combination thereof. In one embodi leaf oil, oregano leaf oil, patchouli leaf oil, peppermint leaf ment, the droplets have an average diameter size greater than oil, pine needle oil, rosemary leaf oil, spearmint leaf oil, tea about 125 nm and at least 400 nm. In another embodiment, the tree leaf oil, thyme leaf oil, wintergreen leaf oil, flower oil, droplets have an average diameter of 180 nm. chamomile oil, clary sage oil, clove oil, geranium flower oil, 0094) 1. Aqueous Phase hyssop flower oil, jasmine flower oil, lavender flower oil, 0095. The aqueous phase can comprise any type of aque manuka flower oil, Marhoram flower oil, orange flower oil, ous phase including, but not limited to, water (e.g., H2O, rose flower oil, ylang-ylang flower oil, Bark oil, cassia Bark distilled water, tap water) and Solutions (e.g., phosphate oil, cinnamon bark oil, Sassafras Bark oil, Wood oil, camphor buffered saline (PBS) solution). In certain embodiments, the wood oil, cedar wood oil, rosewood oil, Sandalwood oil), aqueous phase comprises water at a pH of about 4 to 10, rhizome (ginger) wood oil, resin oil, frankincense oil, myrrh preferably about 6 to 8. The water can be deionized (herein oil, peel oil, bergamot peel oil, grapefruit peel oil, lemon peel after “DiHO). In some embodiments the aqueous phase oil, lime peel oil, orange peel oil, tangerine peel oil, root oil, comprises phosphate-buffered saline (PBS). The aqueous Valerian oil, Oleic acid, Linoleic acid, Oleyl alcohol, Isos phase may further be sterile and pyrogen free. tearyl alcohol, semi-synthetic derivatives thereof, and any 0096 2. Organic Solvents combinations thereof. 0097 Organic solvents in the nanoemulsions of the inven 0102 The oil may further comprise a silicone component, tion include, but are not limited to, C-C alcohol, diol, triol, Such as a volatile silicone component, which can be the sole dialkyl phosphate, tri-alkyl phosphate, such as tri-n-butyl oil in the silicone component or can be combined with other phosphate, semi-synthetic derivatives thereof, and combina silicone and non-silicone, Volatile and non-volatile oils. Suit tions thereof. In one aspect of the invention, the organic able silicone components include, but are not limited to, Solvent is an alcohol chosen from a nonpolar solvent, a polar methylphenylpolysiloxane, simethicone, dimethicone, phe Solvent, a protic solvent, or an aprotic solvent. nyltrimethicone (or an organomodified version thereof), 0098 Suitable organic solvents for the nanoemulsion alkylated derivatives of polymeric silicones, cetyl dimethi include, but are not limited to, ethanol, methanol, isopropyl cone, lauryl trimethicone, hydroxylated derivatives of poly alcohol, glycerol, medium chain triglycerides, diethyl ether, meric silicones, such as dimethiconol, Volatile silicone oils, ethyl acetate, acetone, dimethyl sulfoxide (DMSO), acetic cyclic and linear silicones, cyclomethicone, derivatives of acid, n-butanol, butylene glycol, perfumers alcohols, isopro cyclomethicone, hexamethylcyclotrisiloxane, octamethylcy panol, n-propanol, formic acid, propylene glycols, glycerol, clotetrasiloxane, decamethylcyclopentasiloxane, volatile lin Sorbitol, industrial methylated spirit, triacetin, hexane, ben ear dimethylpolysiloxanes, isohexadecane, isoeicosane, Zene, toluene, diethyl ether, chloroform, 1,4-dixoane, tet isotetracosane, polyisobutene, isooctane, isododecane, semi rahydrofuran, dichloromethane, acetone, acetonitrile, dim synthetic derivatives thereof, and combinations thereof. ethylformamide, dimethyl sulfoxide, formic acid, semi 0103) The volatile oil can be the organic solvent, or the synthetic derivatives thereof, and any combination thereof. Volatile oil can be present in addition to an organic solvent. 0099 3. Oil Phase Suitable volatile oils include, but are not limited to, a terpene, 0100. The oil in the nanoemulsion of the invention can be monoterpene, sesquiterpene, carminative, aZulene, menthol, any cosmetically or pharmaceutically acceptable oil. The oil camphor, thujone, thymol, nerol, linalool, limonene, can be volatile or non-volatile, and may be chosen from geraniol, perillyl alcohol, nerolidol, farnesol, ylangene, bis animal oil, vegetable oil, natural oil, synthetic oil, hydrocar abolol, farmesene, ascaridole, chenopodium oil, citronellal, bon oils, silicone oils, semi-synthetic derivatives thereof, and citral, citronellol, chamaZulene, yarrow, guaiaZulene, chamo combinations thereof. mile, semi-synthetic derivatives, or combinations thereof. In 0101 Suitable oils include, but are not limited to, mineral one aspect of the invention, the volatile oil in the silicone oil, squalene oil, flavor oils, silicon oil, essential oils, water component is different than the oil in the oil phase. insoluble vitamins, Isopropyl stearate. Butyl stearate, Octyl 0104 4. Surfactants/Detergent palmitate, Cetyl palmitate, Tridecyl behenate, Diisopropyl 0105. The surfactant or detergent in the nanoemulsion of adipate, Dioctyl sebacate, Menthyl anthranhilate, Cetyl the invention can be a pharmaceutically acceptable ionic Sur octanoate, Octyl salicylate, Isopropyl myristate, neopentyl factant, a pharmaceutically acceptable nonionic Surfactant, a glycol dicarpate cetols, Ceraphyls(R), Decyl oleate, diisopro pharmaceutically acceptable cationic Surfactant, a pharma pyl adipate, C2-alkyl lactates, Cetyl lactate, Lauryl lactate, ceutically acceptable anionic Surfactant, or a pharmaceuti IsoStearyl neopentanoate, Myristyl lactate, Isocetyl Stearoyl cally acceptable Zwitterionic Surfactant. stearate, Octyldodecyl stearoyl stearate, Hydrocarbon oils, 0106 Exemplary useful surfactants are described in Isoparaffin, Fluid paraffins, Isododecane, Petrolatum, Argan Applied Surfactants: Principles and Applications. Tharwat F. oil, Canola oil, Chile oil, Coconut oil, corn oil, Cottonseed oil, Tadros, Copyright 82005 WILEY-VCHVerlag GmbH & Co. Flaxseed oil, Grape seed oil, Mustard oil, Olive oil, Palm oil, KGaA, Weinheim ISBN: 3-527-30629-3), which is specifi Palm kernel oil, Peanut oil, Pine seed oil, Poppy seed oil, cally incorporated by reference. Pumpkin seed oil, Rice bran oil, Safflower oil, Tea oil, Truffle 0107 Further, the surfactant can be a pharmaceutically oil,Vegetable oil, Apricot (kernel) oil, Jojoba oil (simmondsia acceptable ionic polymeric Surfactant, a pharmaceutically chinensis seed oil), Grapeseed oil, Macadamia oil. Wheat acceptable nonionic polymeric Surfactant, a pharmaceuti germ oil, Almond oil, Rapeseed oil, Gourd oil, Soybean oil, cally acceptable cationic polymeric Surfactant, a pharmaceu Sesame oil, Hazelnut oil, Maize oil, Sunflower oil, Hemp oil, tically acceptable anionic polymeric Surfactant, or a pharma Bois oil, Kuki nut oil, Avocado oil, Walnut oil, Fish oil, berry ceutically acceptable Zwitterionic polymeric Surfactant. oil, allspice oil, juniper oil, seed oil, almond seed oil, anise Examples of polymeric Surfactants include, but are not lim seed oil, celery seed oil, cumin seed oil, nutmeg seed oil, leaf ited to, a graft copolymer of a poly(methyl methacrylate) oil, basil leafoil, bay leafoil, cinnamon leafoil, common sage backbone with multiple (at least one) polyethylene oxide US 2012/0064136 A1 Mar. 15, 2012

(PEO) side chain, polyhydroxystearic acid, an alkoxylated from about 6 to about 22 carbonatoms and y is between about alkyl phenol formaldehyde condensate, a polyalkylene glycol 4 and about 100, and preferably, between about 10 and about modified polyester with fatty acid hydrophobes, a polyester, 100. Preferably, the alkoxylated alcohol is the species semi-synthetic derivatives thereof, or combinations thereof. wherein Rs is a lauryl group andy has an average value of 23. 0108 Surface active agents or surfactants, are amphip 0.112. In a different embodiment, the surfactant is an athic molecules that consist of a non-polar hydrophobic por alkoxylated alcohol which is an ethoxylated derivative of tion, usually a straight or branched hydrocarbon or fluorocar lanolin alcohol. Preferably, the ethoxylated derivative of bon chain containing 8-18 carbon atoms, attached to a polar lanolin alcohol is laneth-10, which is the polyethylene glycol or ionic hydrophilic portion. The hydrophilic portion can be ether of lanolin alcohol with an average ethoxylation value of nonionic, ionic or Zwitterionic. The hydrocarbon chain inter 10. acts weakly with the water molecules in an aqueous environ 0113 Nonionic surfactants include, but are not limited to, ment, whereas the polar orionic head group interacts strongly an ethoxylated Surfactant, an alcohol ethoxylated, an alkyl with water molecules via dipole or ion-dipole interactions. phenol ethoxylated, a fatty acid ethoxylated, a monoalkaola Based on the nature of the hydrophilic group, Surfactants are mide ethoxylated, a Sorbitan ester ethoxylated, a fatty amino classified into anionic, cationic, Zwitterionic, nonionic and ethoxylated, an ethylene oxide-propylene oxide copolymer, polymeric Surfactants. Bis(polyethylene glycol bisimidazoyl carbonyl), nonox 0109 Suitable surfactants include, but are not limited to, ynol-9, Bis(polyethylene glycol bisimidazoyl carbonyl), ethoxylated nonylphenol comprising 9 to 10 units of ethyl BrijR35, BrijR 56, BrijR 72, Brij.R. 76, Brij(R92V, BrijR 97, eneglycol, ethoxylated undecanol comprising 8 units of eth Brij(R) 58P. Cremophor(R) EL, Decaethylene glycol mon yleneglycol, polyoxyethylene (20) Sorbitan monolaurate, ododecyl ether, N-Decanoyl-N-methylglucamine, n-Decyl polyoxyethylene (20) Sorbitan monopalmitate, polyoxyeth alpha-D-glucopyranoside, Decyl beta-D-maltopyranoside, ylene (20) sorbitan monostearate, polyoxyethylene (20) sor n-Dodecanoyl-N-methylglucamide, n-Dodecyl alpha-D- bitan monooleate, Sorbitan monolaurate, Sorbitan mono maltoside, n-Dodecyl beta-D-maltoside, n-Dodecyl beta-D- palmitate, Sorbitan monostearate, Sorbitan monooleate, maltoside, Heptaethylene glycol monodecyl ether, Heptaeth ethoxylated hydrogenated ricin oils, Sodium laurylsulfate, a ylene glycol monododecyl ether, Heptaethylene glycol diblock copolymer of ethyleneoxyde and propyleneoxyde, monotetradecyl ether, n-Hexadecyl beta-D-maltoside, Hexa Ethylene Oxide-Propylene Oxide Block Copolymers, and ethylene glycol monododecyl ether, Hexaethylene glycol tetra-functional block copolymers based on ethylene oxide monohexadecyl ether, Hexaethylene glycol monooctadecyl and propylene oxide, Glyceryl monoesters, Glyceryl caprate, ether, Hexaethylene glycol monotetradecyl ether, Igepal Glyceryl caprylate, Glyceryl cocate, Glyceryl erucate, Glyc CA-630, Igepal CA-630, Methyl-6-O-(N-heptylcarbam eryl hydroxysterate, Glyceryl isostearate, Glyceryl lanolate, oyl)-alpha-D-glucopyranoside, Nonaethylene glycol mon Glyceryl laurate, Glyceryllinolate, Glyceryl myristate, Glyc ododecyl ether, N N-Nonanoyl-N-methylglucamine, Octa eryl oleate, Glyceryl PABA, Glyceryl palmitate, Glyceryl ethylene glycol monodecyl ether, Octaethylene glycol ricinoleate, Glyceryl Stearate, Glyceryl thighlycolate, Glyc monododecyl ether, Octaethylene glycol monohexadecyl eryl dilaurate, Glyceryl dioleate, Glyceryl dimyristate, Glyc ether, Octaethylene glycol monooctadecyl ether, Octaethyl eryl disterate, Glyceryl sesuioleate, Glyceryl Stearate lactate, ene glycol monotetradecyl ether, Octyl-beta-D-glucopyrano Polyoxyethylene cetyl/stearyl ether, Polyoxyethylene cho side, Pentaethylene glycol monodecyl ether, Pentaethylene lesterol ether, Polyoxyethylene laurate or dilaurate, Polyoxy glycol monododecyl ether, Pentaethylene glycol monohexa ethylene Stearate or distearate, polyoxyethylene fatty ethers, decyl ether, Pentaethylene glycol monohexyl ether, Pentaeth Polyoxyethylene lauryl ether, Polyoxyethylene stearyl ether, ylene glycol monooctadecyl ether, Pentaethylene glycol polyoxyethylene myristyl ether, a steroid, Cholesterol, Beta monooctyl ether, Polyethylene glycol diglycidyl ether, Poly sitosterol, Bisabolol, fatty acid esters of alcohols, isopropyl ethylene glycol ether W-1, Polyoxyethylene 10 tridecyl ether, myristate, Aliphati-isopropyl n-butyrate, Isopropyl n-hex Polyoxyethylene 100 stearate, Polyoxyethylene 20 isohexa anoate, Isopropyl n-decanoate, Isoproppyl palmitate, Octyl decyl ether, Polyoxyethylene 20 oleyl ether, Polyoxyethylene dodecyl myristate, alkoxylated alcohols, alkoxylated acids, 40 stearate, Polyoxyethylene 50 stearate, Polyoxyethylene 8 alkoxylated amides, alkoxylated Sugar derivatives, alkoxy stearate, Polyoxyethylene bis(imidazolyl carbonyl), Poly lated derivatives of natural oils and waxes, polyoxyethylene oxyethylene 25 propylene glycol Stearate, Saponin from polyoxypropylene block copolymers, nonoxynol-14, PEG-8 Quillaja bark, SpanR 20, Span R 40, SpanR 60, SpanR 65, laurate, PEG-6 Cocoamide, PEG-20 methylglucose ses SpanR 80, SpanR 85, Tergitol, Type 15-S-12, Tergitol, Type quistearate, PEG40 lanolin, PEG-40 castor oil, PEG-40 15-S-30, Tergitol, Type 15-S-5, Tergitol, Type 15-S-7, Tergi hydrogenated castor oil, polyoxyethylene fatty ethers, glyc tol, Type 15-S-9, Tergitol, Type NP-10, Tergitol, Type NP-4, eryl diesters, polyoxyethylene Stearyl ether, polyoxyethylene Tergitol, Type NP-40, Tergitol, Type NP-7, Tergitol, Type myristyl ether, and polyoxyethylene lauryl ether, glyceryl NP-9, Tergitol, Tergitol, Type TMN-10, Tergitol, Type TMN dilaurate, glyceryl dimyState, glyceryl distearate, semi-syn 6, Tetradecyl-beta-D-maltoside, Tetraethylene glycol mono thetic derivatives thereof, or mixtures thereof. decyl ether, Tetraethylene glycol monododecyl ether, Tetra 0110. Additional suitable surfactants include, but are not ethylene glycol monotetradecyl ether, Triethylene glycol limited to, non-ionic lipids, such as glyceryl laurate, glyceryl monodecyl ether, Triethylene glycol monododecyl ether, Tri myristate, glyceryl dilaurate, glyceryl dimyristate, semi-syn ethylene glycol monohexadecyl ether, Triethylene glycol thetic derivatives thereof, and mixtures thereof. monooctyl ether, Triethylene glycol monotetradecyl ether, 0111. In additional embodiments, the surfactant is a poly Triton CF-21, Triton CF-32, Triton DF-12, Triton DF-16, oxyethylene fatty ether having a polyoxyethylene head group Triton GR-5M, Triton QS-15, Triton QS-44, Triton X-100, ranging from about 2 to about 100 groups, or an alkoxylated Triton X-102, Triton X-15, Triton X-151, Triton X-200, Tri alcohol having the structure Rs (OCH2CH2), OH, ton X-207, Triton(R) X-114, Triton RX-165, Triton RX-305, wherein Rs is a branched or unbranched alkyl group having Triton(R) X-405, Triton(R) X-45, Triton(R) X-705-70, US 2012/0064136 A1 Mar. 15, 2012

TWEENR) 20, TWEENR 21, TWEENR 40, TWEENR 60, Alkyl dimethylbenzyl ammonium chloride (47% C12, 18% TWEENR 61, TWEENR) 65, TWEENR 80, TWEENR 81, C14), Alkyl dimethylbenzyl ammonium chloride (55% C16, TWEENR 85, Tyloxapol, n-Undecyl beta-D-glucopyrano 20% C14), Alkyl dimethylbenzyl ammonium chloride (58% side, semi-synthetic derivatives thereof, or combinations C14, 28% C16), Alkyl dimethylbenzyl ammonium chloride thereof. (60% C14, 25% C12), Alkyl dimethyl benzyl ammonium 0114. In addition, the nonionic surfactant can be a polox chloride (61% C11, 23% C14), Alkyl dimethylbenzyl ammo amer. Poloxamers are polymers made of a block of polyoxy nium chloride (61% C12, 23% C14), Alkyl dimethylbenzyl ethylene, followed by a block of polyoxypropylene, followed ammonium chloride (65% C12, 25% C14), Alkyl dimethyl by a block of polyoxyethylene. The average number of units benzyl ammonium chloride (67% C12, 24% C14), Alkyl of polyoxyethylene and polyoxypropylene varies based on dimethylbenzyl ammonium chloride (67% C12, 25% C14), the number associated with the polymer. For example, the Alkyl dimethyl benzyl ammonium chloride (90% C14, 5% smallest polymer, Poloxamer 101, consists of a block with an C12), Alkyl dimethylbenzyl ammonium chloride (93% C14, average of 2 units of polyoxyethylene, a block with an aver 4% C12), Alkyl dimethylbenzyl ammonium chloride (95% age of 16 units of polyoxypropylene, followed by a block with C16, 5% C18), Alkyl didecyl dimethyl ammonium chloride, an average of 2 units of polyoxyethylene. Poloxamers range Alkyl dimethylbenzyl ammonium chloride (C12-16), Alkyl from colorless liquids and pastes to white solids. In cosmetics dimethylbenzyl ammonium chloride (C12-18), dialkyl dim and personal care products, Poloxamers are used in the for ethylbenzyl ammonium chloride, Alkyl dimethyl dimethy mulation of skin cleansers, bath products, shampoos, hair conditioners, mouthwashes, eye makeup remover and other benzyl ammonium chloride, Alkyl dimethyl ethyl ammonium skin and hair products. Examples of Poloxamers include, but bromide (90% C14, 5% C16, 5% C12), Alkyl dimethyl ethyl are not limited to, Poloxamer 101, Poloxamer 105, Polox ammonium bromide (mixed alkyland alkenyl groups as in the amer 108, Poloxamer 122, Poloxamer 123, Poloxamer 124, fatty acids of soybean oil), Alkyl dimethyl ethylbenzyl Poloxamer 181, Poloxamer 182, Poloxamer 183, Poloxamer ammonium chloride, Alkyl dimethyl ethylbenzyl ammonium 184, Poloxamer 185, Poloxamer 188, Poloxamer 212, Polox chloride (60% C14), Alkyl dimethyl isopropylbenzyl ammo amer 215, Poloxamer 217, Poloxamer 231, Poloxamer 234, nium chloride (50% C12, 30% C14, 17% C16, 3% C18), Poloxamer 235, Poloxamer 237, Poloxamer 238, Poloxamer Alkyl trimethyl ammonium chloride (58% C18, 40% C16, 282, Poloxamer 284, Poloxamer 288, Poloxamer 331, Polox 1% C14, 1% C12), Alkyl trimethyl ammonium chloride (90% amer 333, Poloxamer 334, Poloxamer 335, Poloxamer 338, C18, 10% C16), Alkyldimethyl(ethylbenzyl) ammonium Poloxamer 401, Poloxamer 402, Poloxamer 403, Poloxamer chloride (C12-18), Di-(C8-10)-alkyl dimethyl ammonium 407, Poloxamer 105 Benzoate, and Poloxamer 182 Diben chlorides, Dialkyl dimethyl ammonium chloride, Dialkyl ZOate. methylbenzyl ammonium chloride, Didecyl dimethylammo 0115 Suitable cationic surfactants include, but are not nium chloride, Diisodecyl dimethyl ammonium chloride, limited to, a quaternary ammonium compound, an alkyl tri Dioctyl dimethyl ammonium chloride, Dodecyl bis(2-hy methyl ammonium chloride compound, a dialkyl dimethyl droxyethyl) octyl hydrogen ammonium chloride, Dodecyl ammonium chloride compound, a cationic halogen-contain dimethyl benzyl ammonium chloride, Dodecylcarbamoyl ing compound. Such as cetylpyridinium chloride, Benzalko methyl dimethyl benzyl ammonium chloride, Heptadecyl nium chloride, Benzalkonium chloride, Benzyldimethyl hydroxyethylimidazolinium chloride, Hexahydro-1,3,5-tris hexadecylammonium chloride, (2-hydroxyethyl)-s-triazine, Myristalkonium chloride (and) Benzyldimethyltetradecylammonium chloride, Benzyldode Quat RNIUM 14, N,N-Dimethyl-2-hydroxypropylammo cyldimethylammonium bromide, Benzyltrimethylammo nium chloride polymer, n-Tetradecyl dimethylbenzyl ammo nium tetrachloroiodate, Dimethyldioctadecylammonium nium chloride monohydrate, Octyl decyl dimethyl ammo bromide, Dodecylethyldimethylammonium bromide, Dode nium chloride, Octyl dodecyl dimethyl ammonium chloride, cyltrimethylammonium bromide, Dodecyltrimethylammo Octyphenoxyethoxyethyl dimethylbenzyl ammonium chlo nium bromide, Ethylhexadecyldimethylammonium bromide, ride, Oxydiethylenebis(alkyl dimethyl ammonium chloride), Girard's reagent T. Hexadecyltrimethylammonium bromide, Trimethoxysily propyl dimethyl octadecyl ammonium chlo Hexadecyltrimethylammonium bromide, N,N',N'-Polyoxy ride, Trimethoxysilyl quats, Trimethyl dodecylbenzyl ammo ethylene(10)-N-tallow-1,3-diaminopropane, Thonzonium nium chloride, semi-synthetic derivatives thereof, and com bromide, Trimethyl(tetradecyl)ammonium bromide, 1,3,5- binations thereof. Triazine-1,3,5(2H4H.6H)-triethanol, 1-Decanaminium, 0116 Exemplary cationic halogen-containing compounds N-decyl-N,N-dimethyl-, chloride, Didecyl dimethyl ammo include, but are not limited to, cetylpyridinium halides, cetyl nium chloride, 2-(2-(p-(Diisobutyl)cresosxy)ethoxy)ethyl trimethylammonium halides, cetyldimethylethylammonium dimethyl benzyl ammonium chloride, 2-(2-(p-(Diisobutyl) halides, cetyldimethylbenzylammonium halides, cetyltribu phenoxy)ethoxy)ethyl dimethylbenzyl ammonium chloride, tylphosphonium halides, dodecyltrimethylammonium Alkyl 1 or 3 benzyl-1-(2-hydroxethyl)-2-imidazolinium halides, or tetradecyltrimethylammonium halides. In some chloride, Alkyl bis(2-hydroxyethyl)benzyl ammonium chlo particular embodiments, Suitable cationic halogen containing ride, Alkyl demethylbenzyl ammonium chloride, Alkyl dim compounds comprise, but are not limited to, cetylpyridinium ethyl 3,4-dichlorobenzyl ammonium chloride (100% C12), chloride (CPC), cetyltrimethylammonium chloride, cetyl Alkyl dimethyl 3,4-dichlorobenzyl ammonium chloride benzyldimethylammonium chloride, cetylpyridinium bro (50% C14, 40% C12, 10% C16), Alkyl dimethyl 3,4-dichlo mide (CPB), cetyltrimethylammonium bromide (CTAB), robenzyl ammonium chloride (55% C14, 23% C12, 20% cetylidimethylethylammonium bromide, cetyltributylphos C16), Alkyl dimethylbenzyl ammonium chloride, Alkyl dim phonium bromide, dodecyltrimethylammonium bromide, ethyl benzyl ammonium chloride (100% C14), Alkyl dim and tetradecyltrimethylammonium bromide. In particularly ethyl benzyl ammonium chloride (100% C16), Alkyl dim preferred embodiments, the cationic halogen containing ethyl benzyl ammonium chloride (41% C14, 28% C12), compound is CPC, although the compositions of the present US 2012/0064136 A1 Mar. 15, 2012

invention are not limited to formulation with a particular nanoemulsion is greater than about 0.002%, greater than cationic containing compound. about 0.003%, greater than about 0.004%, greater than about 0117 Suitable anionic surfactants include, but are not lim 0.005%, greater than about 0.006%, greater than about ited to, a carboxylate, a Sulphate, a Sulphonate, a phosphate, 0.007%, greater than about 0.008%, greater than about chenodeoxycholic acid, chenodeoxycholic acid sodium salt, 0.009%, greater than about 0.010%, or greater than about cholic acid, ox or sheep bile, Dehydrocholic acid, Deoxy 0.001%. In one embodiment, the concentration of the cationic cholic acid, Deoxycholic acid, Deoxycholic acid methyl agent in the nanoemulsion is less than about 5.0% and greater ester, Digitonin, Digitoxigenin, N,N-Dimethyldodecylamine than about 0.001%. N-oxide, Docusate sodium salt, Glycochenodeoxycholic acid 0.120. In another embodiment of the invention, the Sodium salt, Glycocholic acid hydrate, synthetic, Glyco nanoemulsion comprises at least one cationic Surfactant and cholic acid sodium salt hydrate, synthetic, Glycodeoxycholic at least one non-cationic Surfactant. The non-cationic Surfac acid monohydrate, Glycodeoxycholic acid sodium salt, Gly tant is a nonionic Surfactant, Such as a polysorbate (Tween), colithocholic acid 3-sulfate disodium salt, Glycolithocholic such as polysorbate 80 or polysorbate 20. acid ethyl ester, N-Lauroylsarcosine sodium salt, N-Lauroyl 0.121. In one embodiment, the non-ionic surfactant is sarcosine Solution, N-Lauroylsarcosine solution, Lithium present in a concentration of about 0.05% to about 7.0%, or dodecyl sulfate, Lithium dodecyl sulfate, Lithium dodecyl the non-ionic Surfactant is present in a concentration of about Sulfate, Lugol Solution, Niaproof 4. Type 4.1-Octanesulfonic 0.3% to about 4%. In yet another embodiment of the inven acid sodium salt, Sodium 1-butanesulfonate, Sodium 1-de tion, the nanoemulsion comprises a cationic Surfactant canesulfonate, Sodium 1-decanesulfonate, Sodium 1-dode present in a concentration of about 0.01% to about 2%, in canesulfonate, Sodium 1-heptanesulfonate anhydrous, combination with a nonionic Surfactant. Sodium 1-heptanesulfonate anhydrous, Sodium 1-nonane 0.122 5. Active Agents Sulfonate, Sodium 1-propanesulfonate monohydrate, Sodium I0123. In a further embodiment, the composition addition 2-bromoethanesulfonate, Sodium cholate hydrate, Sodium ally comprises one or more active agents. The presence of choleate, Sodium deoxycholate, Sodium deoxycholate Such an active agent is not required, and Substantial and monohydrate, Sodium dodecyl sulfate, Sodium hexane unexpected anti-aging and/or anti-wrinkle properties are Sulfonate anhydrous, Sodium octyl sulfate, Sodium pentane observed without the presence of Such an active agent. Thus, Sulfonate anhydrous, Sodium taurocholate, Taurochenode the presence of Such active agents is to merely enhance the oxycholic acid sodium salt, Taurodeoxycholic acid sodium anti-aging and anti-wrinkle properties of the compositions of salt monohydrate, Taurohyodeoxycholic acid sodium salt the invention. In another embodiment, the composition fur hydrate, Taurolithocholic acid 3-sulfate disodium salt, Taur ther comprises at least one active agent for rendering the oursodeoxycholic acid sodium salt, Trizma(R) dodecyl sulfate, composition Suitable as a cosmetic preparation. TWEENR 80, Ursodeoxycholic acid, semi-synthetic deriva 0.124. In one embodiment, active agents useful in the tives thereof, and combinations thereof. nanoemulsion compositions of the invention are compounds 0118 Suitable Zwitterionic surfactants include, but are not that provide benefits to the skin and/or provide desirable limited to, an N-alkyl betaine, laurylamindo propyl dimethyl properties to a composition formulated as a cosmetic or betaine, an alkyl dimethyl glycinate, an N-alkyl amino pro medicinal preparation. The active agent useful in the pionate, CHAPS, minimum 98% (TLC), CHAPS, minimum nanoemulsion compositions of the invention can be a drug 98% (TLC), CHAPS, for electrophoresis, minimum 98% Substance or a non-drug Substance. Examples of non-drug (TLC), CHAPSO, minimum 98%, CHAPSO, CHAPSO, for active agents include, but are not limited to, skin lightening electrophoresis, 3-(Decyldimethylammonio)propane agents, tanning agents, skin conditioning agents, skin pro Sulfonate inner salt, 3-Dodecyldimethylammonio)propane tectants, emollients and humectants, and Sunscreen actives. Sulfonate inner salt, 3-(Dodecyldimethylammonio)propane 0.125 Examples of exemplary active agents useful in the sulfonate inner salt, 3-(N,N-Dimethylmyristylammonio) nanoemulsion compositions of the invention, such as an propanesulfonate, 3-(N,N-Dimethyloctadecylammonio) active drug Substance or an active cosmetic Substance, propanesulfonate, 3-(N,N-Dimethyloctylammonio) include, but are not limited to, Botulinum toxin type A propanesulfonate inner salt, 3-(N.N- (BotoxR), a retinoid (e.g., vitaminA derivatives, retinol, reti Dimethylpalmitylammonio)propanesulfonate, semi nal, tretinoin (retinoic acid, Renova R, Retin-AR), isotretin synthetic derivatives thereof, and combinations thereof. oin, alitretinoin, etretinate, acitretin, tazarotene (Avage R. 0119. In some embodiments, the nanoemulsion comprises TaZoracR), beXarotene and Adapalene), alpha hydroxy acids, a cationic Surfactant, which can be cetylpyridinium chloride. betahydroxy acids, polyhydroxy acids, hydroxyl acids, kine In other embodiments of the invention, the nanoemulsion tin, coenzyme Q10, copper peptides, tea extracts (e.g., green, comprises a cationic Surfactant, and the concentration of the black and oolong tea extracts), antioxidants (e.g., ascorbic cationic Surfactant is less than about 5.0% and greater than acid (vitamin C), glutathione, melatonin, tocopherols, C-to about 0.001%. In yet another embodiment of the invention, copherol, tocotrienols (vitamin E), lipoic acid, uric acid, car the nanoemulsion comprises a cationic Surfactant, and the otenes, ubiquinone (coenzyme Q), thioredoxin, Polyphenolic concentration of the cationic Surfactant is selected from the antioxidants (resveratrol, flavonoids), and carotenoids), col group consisting of less than about 5%, less than about 4.5%, loidal oatmeal (AveenoR), Soybean extract, or any mixture less than about 4.0%, less than about 3.5%, less than about thereof. 3.0%, less than about 2.5%, less than about 2.0%, less than I0126. In another embodiment, the composition of the about 1.5%, less than about 1.0%, less than about 0.90%, less invention comprises an anti-viral agent. Such a composition than about 0.80%, less than about 0.70%, less than about is useful, for example, in treating a herpes virus outbreak 0.60%, less than about 0.50%, less than about 0.40%, less following laser treatment, Such as ablative laser resurfacing. than about 0.30%, less than about 0.20%, or less than about I0127. In yet another embodiment, the composition of the 0.10%. Further, the concentration of the cationic agent in the invention comprises an anti-acne agent. Exemplary topical US 2012/0064136 A1 Mar. 15, 2012

anti-acne agents include, but are not limited to, benzoyl per DNA, cytochrome C, darutoside, dextran sulfate, dimethi oxide, salicylic acid, acitretin, alcloxa, aldioxa, allantoin, cone copolyols, dimethylsilanol hyaluronate, DNA, elastin, dibenzothiophene, etarotent, etretinate, motretinide, nordihy elastin amino acids, epidermal growth factor, ergocalciferol, droguaiaretic acid, podofilox, podophyllum resin, resorci ergosterol, ethylhexyl PCA, fibronectin, folic acid, gelatin, nalm resorcinol monoacetate, Sumarotene, tetroquinone, ada gliadin, beta-glucan, glucose, glycine, glycogen, glycolipids, palene, tretinoin, erythromycin, clindamycin, azelaic acid, glycoproteins, glycosaminoglycans, glycosphingolipids, hydrocortisone, Sodium hyaluronate, Sulfur, urea, meclocy horseradish peroxidase, hydrogenated proteins, hydrolyzed cline, dapsone, retinoids and retinoid derivatives. Other anti acne ingredients include Ascorbyl Tetraisopalmitate, Dipo proteins, jojoba oil, keratin, keratin amino acids, and kinetin. tassium Glycyrrhizinate, Ascorbyl Tetraisopalmitate, 0.132. Other examples of skin conditioning agents include, Niacinamide, alpha bisabolol can also be included in the but are not limited to, lactoferrin, lanosterol, lauryl PCA, nanoemulsion of this invention. All of these skin care ingre lecithin, linoleic acid, linolenic acid, lipase, lysine, lysozyme, dients have properties that help to reduce and control acne, malt extract, maltodextrin, melanin, methionine, mineral and acne related problems such as sebum production. salts, niacin, niacinamide, oat amino acids, oryzanbl, palmi 0128. Additional anti-acne agents include acne herbal toyl hydrolyzed proteins, pancreatin, papain, PEG, pepsin, medicines, such as Tea Tree Oil red clover, lavender, leaves of phospholipids, phytosterols, placental enzymes, placental strawberry, chaste tree berry extract, burdock root, dandelion lipids, pyridoxal 5-phosphate, quercetin, resorcinol acetate, leaves, milk thistle, papaya enzymes, burdock and dandelion, riboflavin, RNA, saccharomyces lysate extract, silk amino eucalyptus, thyme, witch hazel, sage oil, camphor, cineole, acids, sphingolipids, Stearamidopropyl betaine, Stearyl roSmarinic acid and tannins in the sage oil. palmitate, tocopherol, tocopheryl acetate, tocopheryl 0129 Representative sunscreen drugs are active ingredi linoleate, ubiquinone, vitis vinifera (grape) seed oil, wheat ents that absorb, reflect, or scatter radiation in the UV range at amino acids, Xanthan gum, and Zinc gluconate. Skin condi wavelengths from 290 to 400 nanometers. Specific examples tioning agents, other than those listed above, may also be include benzophenone-3 (oxybenzone), benzophenone-4 used, as is readily appreciated by those skilled in the art. (Sulisobenzone), benzophenone-8(dioxybenzone), butyl I0133. In other embodiments, the compositions may methoxydibenzoylmethane (AVobenzone), DEA-methoxy include a skin protectant, defined herein as a compound that cinnamate (diethanolamine methoxycinnamate), ethyl dihy protects injured or exposed skin or mucous membrane Sur droxypropyl PABA (ethyl 4-bis(hydroxypropyl)aminoben faces from harmful or irritating external compounds. Repre zoate), ethylhexyl dimethyl PABA (Padimate O), ethylhexyl sentative examples thereof include algae extract, allantoin, methoxycinnamate (octyl methoxycinnamate), ethylhexyl aluminum hydroxide, aluminum Sulfate, betaine, camellia salicylate (octyl salicylate), homosalate, menthyl anthranilate Sinensis leaf extract, cerebrosides, dimethicone, glucurono (Meradimate), octocrylene, PABA (aminobenzoic acid), phe lactone, glycerin, kaolin, lanolin, malt extract, mineral oil, nylbenzimidazole sulfonic acid (Ensulizole), TEA-salicylate petrolatum, potassium gluconate, and talc. Those skilled in (trolamine Salicylate), titanium dioxide, and Zinc oxide. One the art will readily appreciate that skin protectants, other than skilled in the art will appreciate that other Sunscreen agents those listed above, may be included in the compositions used may be used in the compositions and preparations of the for the methods of the present invention. present invention. 0.134. An emollient, as the term is used herein, is a cos 0130 Representative skin lightening agents include, but metic ingredient that can help the skin maintain a soft, are not limited to, ascorbic acid and derivatives thereof, kojic Smooth, and pliable appearance. Emollients are able to pro acid and derivatives thereof, hydroquinone and derivatives vide these benefits, largely owing to their ability to remain on thereof. azelaic acid, various plant extracts such as those from the skin Surface or in the stratum corneum to act as a lubricant licorice, grape seed and bear berry, and mixtures of any one or and reduce flaking. Some examples of emollients, Suitable for more of the foregoing. Those skilled in the art will appreciate embodiments of this invention, are acetylarginine, acetylated that other skin lightening agents may be included in the com lanolin, algae extract, apricot kernel oil PEG-6 esters, avo positions used for some of the methods of the present inven cado oil PEG-11 esters, bis-PEG-4 dimethicone, butoxyethyl tion. Stearate, CsCl acid glycol ester, CC alkyl lactate, capry 0131. As noted above, the compositions may further com lyl glycol, cetyl esters, cetyl laurate, coconut oil PEG-10 prise skin conditioning agents. Such agents comprise Sub esters, di-CC alkyl tartrate, diethyl sebacate, dihydrocho stances that enhance the appearance of dry or damaged skin, lesteryl butyrate, dimethiconol, dimyristyl tartrate, diste as well as materials that adhere to the skin to reduce flaking, areth-5 lauroyl glutamate, ethyl avocadate, ethylhexyl restore Suppleness, and generally improve the appearance of myristate, glyceryl isostearates, glyceryl oleate, hexyldecyl skin. Representative examples of skin conditioning agents Stearate, hexyl isostearate, hydrogenated palm glycerides, include acetyl cysteine, N-acetyl dihydrosphingosine, acry hydrogenated Soy glycerides, hydrogenated tallow glycer lates/behenyl acrylate? dimethicone acrylate copolymer, ides, hydroxypropyl bisiso Stearamide MEA, isostearyl neo adenosine, adenosine cyclic phosphate, adensosine phos pentanoate, isostearyl palmitate, isotridecyl isononanoate, phate, adenosine triphosphate, alanine, albumen, algae laureth-2acetate, lauryl polyglyceryl-6cetearyl glycol ether, extract, allantoin and derivatives, aloe barbadensis extracts, methylgluceth-20 benzoate, mineral oil, myreth-3 palmitate, aluminum PCA, amyloglucosidase, arbutin, arginine, aZu octylidecanol, octyldodecanol, odontella aurita oil, 2-olea lene, bromelain, buttermilk powder, butylene glycol, caf mido-1.3 octadecanediol, palm glycerides, PEG avocado feine, calcium gluconate, capsaicin, carbocysteine, carnos glycerides, PEG castor oil, PEG-22/dodecyl glycol copoly ine, beta-carotene, casein, catalase, cephalins, ceramides, mer, PEG shorea butter glycerides, phytol, raffinose, stearyl chamomilla recutita (matricaria) flower extract, cholecalcif citrate, Sunflower seed oil glycerides, and tocopheryl gluco erol, cholesteryl esters, coco-betaine, coenzyme A, corn side. Those skilled in the art will readily appreciate that emol starch modified, crystallins, cycloethoxymethicone, cysteine lients, other than those listed above, may also be used. US 2012/0064136 A1 Mar. 15, 2012

0135 Humectants are cosmetic ingredients that help dine, imidazolidinyl urea, phenol, potassium Sorbate, benzoic maintain moisture levels in skin. Some examples of Suitable acid, bronopol, chlorocresol, paraben esters, phenoxyetha humectants are: acetylarginine, algae extract, aloe barbaden nol, Sorbic acid, alpha-tocophernol, ascorbic acid, ascorbyl sis leaf extract, betaine, 2,3-butanediol, chitosan lauroyl gly palmitate, butylated hydroxyanisole, butylated hydroxytolu cinate, diglycereth-7 malate, diglycerin, diglycol guanidine ene, Sodium ascorbate, Sodium metabisulphite, citric acid, Succinate, erythritol, fructose, glucose, glycerin, honey, edetic acid, semi-synthetic derivatives thereof, and combina hydrolyzed wheat protein/PEG-20 acetate copolymer, tions thereof. hydroxypropyltrimonium hyaluronate, inositol, lactitol, 0140. The nanoemulsion may further comprise at least one maltitol, maltose, mannitol, mannose, methoxy PEG, myris pH adjuster. Suitable pH adjusters in the nanoemulsion of the tamidobutyl guanidine acetate, polyglyceryl Sorbitol, potas invention include, but are not limited to, diethyanolamine, sium PCA, propylene glycol, Sodium PCA, Sorbitol. Sucrose, lactic acid, monoethanolamine, triethylanolamine, sodium and urea. Other humectants may be used for yet additional hydroxide, Sodium phosphate, semi-synthetic derivatives embodiments of this invention, as will be appreciated by thereof, and combinations thereof. those skilled in the art. 0.141. In addition, the nanoemulsion can comprise a 0.136 Examples of antiviral agents include, but are not chelating agent. In one embodiment of the invention, the limited to, nucleoside analogs (e.g., acyclovir (ZoviraX(R). chelating agent is present in an amount of about 0.0005% to famciclovir (Famvir R), and valaciclovir (ValtrexR)), aman about 1.0%. Examples of chelating agents include, but are not tadine (Symmetrel(R), oseltamivir (TamifluR), rimantidine limited to, ethylenediamine, ethylenediaminetetraacetic acid (Flumadine(R), and Zanamivir (RelenzaR), Cidofovir (Vis (EDTA), and dimercaprol, and a preferred chelating agent is tide(R), foscarnet (Foscavir(R), ganciclovir (Cytovene?R), rib ethylenediaminetetraacetic acid. avirin (Virazole(R), penciclovir (Denavir R), buciclovir, acy 0142. The nanoemulsion can comprise a buffering agent, clic guanosine derivatives, (E)-5-(2-bromovinyl)-2'- Such as a pharmaceutically acceptable buffering agent. deoxyuridine and structurally related analogues thereofi.e., Examples of buffering agents include, but are not limited to, the cytosine derivative (E)-5-(2-bromovinyl)-2'-deoxycyti 2-Amino-2-methyl-1,3-propanediol, 2.99.5% (NT), dine and the 4'-thio derivative (E)-5-(2-bromovinyl)-2'- 2-Amino-2-methyl-1-propanol, 299.0% (GC), L-(+)-Tar deoxy-4-thiouridine, Nucleoside/Nucleotide Analogues taric acid, 299.5% (T), ACES, 299.5% (T), ADA, 299.0% (e.g., Abacavir (Ziagen, ABC), Didanosine (Videx, dd), (T), Acetic acid, 299.5% (GC/T), Acetic acid, for lumines Emtricitabine (Emtriva, FTC), Lamivudine (Epivir, 3TC), cence, 299.5% (GC/T), Ammonium acetate solution, for Stavudine (Zerit, d4T), Tenofovir (Viread, TDF), Zalcitabine molecular biology, ~5 M in H2O, Ammonium acetate, for (Hivid, ddC), and Zidovudine (Retrovir, AZT, ZDV)): Non luminescence, 299.0% (calc. on dry substance, T), Ammo nucleoside Reverse Transcriptase Inhibitors (e.g., Delavird nium bicarbonate, 299.5% (T), Ammonium citrate dibasic, ine (Rescriptor, DLV), Efavirenz (Sustiva, Stocrin, EFV), 299.0% (T), Ammonium formate solution, 10 M in H.O. Etravirine (Intelence, TMC 125), Nevirapine (Viramune, Ammonium formate, 299.0% (calc. based on dry substance, NVP)); Protease Inhibitors (Amprenavir (Agenerase, APV), NT), Ammonium oxalate monohydrate, 299.5% (RT), Atazanavir (Reyataz, ATV), Darunavir (Prezista, DRV. TMC Ammonium phosphate dibasic solution, 2.5 M in H2O, 114), Fosamprenavir (Lexiva, Telzir, FPV), Indinavir (Crixi Ammonium phosphate dibasic, 299.0% (T), Ammonium van, IDV), Lopinavir/Ritonavir (Kaletra), Nelfinavir (Vira phosphate monobasic solution, 2.5 M in H2O, Ammonium cept, NFV), Ritonavir (Norvir, RTV), Saquinavir (Invirase, phosphate monobasic, 299.5% (T), Ammonium sodium SQV), and Tipranavir (Aptivus, TPV)); Fusion Inhibitors phosphate dibasic tetrahydrate, 299.5% (NT), Ammonium (e.g., Enfluvirtide (Fuzeon, ENF, T-20)); Chemokine Core sulfate solution, for molecular biology, 3.2 MinH2O, Ammo ceptor Antagonists (e.g., Maraviroc (Selzentry, Celsentri, nium tartrate dibasic solution, 2 MinH2O (colorless solution MVC)); and Integrase Inhibitors (e.g., Raltegravir (Isentress, at 20° C.), Ammonium tartrate dibasic, 299.5% (T), BES RAL)). Preferred antiviral agents for incorporation into a buffered saline, for molecular biology, 2x concentrate, BES. nanoemulsion include, but are not limited to, acyclovir (Zovi 299.5% (T), BES, for molecular biology, 299.5% (T), rax(R), penciclovir (Demavor(R), famciclovir (Famvir R), and BICINE buffer Solution, for molecular biology, 1 M in HO, valaciclovir (Valtrex(R). Other exemplary active agents which BICINE, 299.5% (T), BIS-TRIS, 299.0% (NT), Bicarbon can be incorporated into a nanoemulsion for treating a herpes ate buffer solution, 20.1 M NaCO, 20.2 M NaHCO viral outbreak include, but are not limited to, docosanol Boric acid, 299.5% (T), Boric acid, for molecular biology, (Abreva(R) 299.5% (T), CAPS, 299.0% (TLC), CHES, 299.5% (T), 0.137 6. Additional Ingredients Calcium acetate hydrate, 299.0% (calc. on dried material, 0.138. Additional compounds suitable for use in the KT), Calcium carbonate, precipitated, 299.0% (KT), Cal nanoemulsions of the invention include but are not limited to cium citrate tribasic tetrahydrate, 298.0% (calc. on dry sub one or more solvents, such as an organic phosphate-based stance, KT), Citrate Concentrated Solution, for molecular Solvent, bulking agents, coloring agents, pharmaceutically biology, 1 M in H2O, Citric acid, anhydrous, 299.5% (T), acceptable excipients, a preservative, pH adjuster, buffer, Citric acid, for luminescence, anhydrous, 299.5% (T), chelating agent, etc. The additional compounds can be Diethanolamine, 299.5% (GC), EPPS, 299.0% (T), Ethyl admixed into a previously emulsified nanoemulsion, or the enediaminetetraacetic acid disodium salt dihydrate, for additional compounds can be added to the original mixture to molecular biology, 299.0% (T). Formic acid solution, 1.0 M be emulsified. In certain of these embodiments, one or more in HO, Gly-Gly-Gly, 299.0% (NT), Gly-Gly, 299.5% additional compounds are admixed into an existing (NT), Glycine, 299.0% (NT), Glycine, for luminescence, nanoemulsion composition immediately prior to its use. 299.0% (NT), Glycine, for molecular biology, 299.0% 0139 Suitable preservatives in the nanoemulsions of the (NT), HEPES buffered saline, for molecular biology, 2x con invention include, but are not limited to, cetylpyridinium centrate, HEPES, 299.5% (T), HEPES, for molecular biol chloride, benzalkonium chloride, benzyl alcohol, chlorhexi ogy, 299.5% (T), Imidazole buffer Solution, 1 M in H2O, US 2012/0064136 A1 Mar. 15, 2012

Imidazole, 299.5% (GC), Imidazole, for luminescence, drate, 299.0% (T), Sodium phosphate dibasic solution, 0.5M 299.5% (GC), Imidazole, for molecular biology, 299.5% in HO, Sodium phosphate dibasic, anhydrous, 299.5% (T), (GC), Lipoprotein Refolding Buffer, Lithium acetate dihy Sodium phosphate dibasic, for molecular biology, 299.5% drate, 299.0% (NT), Lithium citrate tribasic tetrahydrate, (T), Sodium phosphate monobasic dihydrate, 299.0% (T), 299.5% (NT), MES hydrate, 299.5% (T), MES monohy Sodium phosphate monobasic dihydrate, for molecular biol drate, for luminescence, 299.5% (T), MES solution, for ogy, 299.0% (T), Sodium phosphate monobasic monohy molecular biology, 0.5 M in HO, MOPS, 299.5% (T), drate, for molecular biology, 299.5% (T), Sodium phosphate monobasic solution, 5 M in HO, Sodium pyrophosphate MOPS, for luminescence, 299.5% (T), MOPS, for molecular dibasic, 299.0% (T), Sodium pyrophosphate tetrabasic biology, 299.5% (T), Magnesium acetate solution, for decahydrate, 299.5% (T), Sodium tartrate dibasic dihydrate, molecular biology, ~1 Min H2O, Magnesium acetate tetrahy 299.0% (NT), Sodium tartrate dibasic solution, 1.5 M in drate, 299.0% (KT), Magnesium citrate tribasic nonahy H2O (colorless solution at 20° C.), Sodium tetraborate drate, 298.0% (calc. based on dry substance, KT), Magne decahydrate, 299.5% (T), TAPS, 299.5% (T), TES, 299. sium formate solution, 0.5M in HO, Magnesium phosphate 5% (calc. based on dry substance, T), TM buffer solution, for dibasic trihydrate, 298.0% (KT). Neutralization solution for molecular biology, pH 7.4, TNT buffer solution, for molecu the in-situ hybridization for in-situ hybridization, for molecu lar biology, pH 8.0, TRIS Glycine buffer solution, 10x con lar biology, Oxalic acid dihydrate, 299.5% (RT), PIPES, centrate, TRIS acetate—EDTA buffer solution, for molecular 299.5% (T), PIPES, for molecular biology, 299.5% (T), biology, TRIS buffered saline, 10x concentrate, TRIS glycine Phosphate buffered saline, solution (autoclaved), Phosphate SDS buffer solution, for electrophoresis, 10x concentrate, buffered saline, washing buffer for peroxidase conjugates in TRIS phosphate-EDTA buffer solution, for molecular biol Western Blotting, 10x concentrate, piperazine, anhydrous, ogy, concentrate, 10x concentrate, Tricine, 299.5% (NT), 299.0% (T), Potassium D-tartrate monobasic, 299.0% (T), Triethanolamine, 299.5% (GC), Triethylamine, 299.5% Potassium acetate Solution, for molecular biology, Potassium (GC), Triethylammonium acetate buffer, volatile buffer, ~1.0 acetate solution, for molecular biology, 5 M in H2O, Potas M in H2O, Triethylammonium phosphate solution, volatile sium acetate solution, for molecular biology, ~1 M in H2O, buffer, ~1.0M in H.O.Trimethylammonium acetate solution, Potassium acetate, 299.0% (NT), Potassium acetate, for volatile buffer, ~1.0 M in H2O, Trimethylammonium phos luminescence, 299.0% (NT), Potassium acetate, for molecu phate solution, volatile buffer, ~1 M in H2O, Tris-EDTA lar biology, 299.0% (NT), Potassium bicarbonate, 299.5% buffer solution, for molecular biology, concentrate, 100x (T), Potassium carbonate, anhydrous, 299.0% (T), Potas concentrate, Tris-EDTA buffer solution, for molecular biol sium chloride, 299.5% (AT), Potassium citrate monobasic, ogy, pH 7.4, Tris-EDTA buffer solution, for molecular biol 299.0% (dried material, NT), Potassium citrate tribasic solu ogy, pH 8.0, Trizma Racetate, 299.0% (NT), Trizma(R) base, tion, 1 M in H2O, Potassium formate solution, 14 M in H2O, 299.8% (T), Trizma(R) base, 299.8% (T), Trizma(R) base, for Potassium formate, 299.5% (NT), Potassium oxalate mono luminescence, 299.8% (T), Trizma R base, for molecular hydrate, 299.0% (RT), Potassium phosphate dibasic, anhy biology, 299.8% (T), Trizma(R) carbonate, 298.5% (T), drous, 299.0% (T), Potassium phosphate dibasic, for lumi Trizma(R) hydrochloride buffer solution, for molecular biol nescence, anhydrous, 299.0% (T), Potassium phosphate ogy, pH 7.2, Trizma(R) hydrochloride buffer solution, for dibasic, for molecular biology, anhydrous, 299.0% (T), molecular biology, pH 7.4, Trizma(R) hydrochloride buffer Potassium phosphate monobasic, anhydrous, 299.5% (T), solution, for molecular biology, pH 7.6, Trizma Rhydrochlo Potassium phosphate monobasic, for molecular biology, ride buffer solution, for molecular biology, pH 8.0, Trizma(R) anhydrous, 299.5% (T), Potassium phosphate tribasic mono hydrochloride, 299.0% (AT), Trizma(R) hydrochloride, for hydrate, 2.95% (T), Potassium phthalate monobasic, 2.99. luminescence, 299.0% (AT), Trizma(R) hydrochloride, for 5%. (T), Potassium sodium tartrate solution, 1.5 M in H.O. Potassium sodium tartrate tetrahydrate, 299.5% (NT), Potas molecular biology, 299.0% (AT), and Trizma R) maleate, sium tetraborate tetrahydrate, 299.0% (T), Potassium tet 299.5% (NT). raoxalate dihydrate, 299.5% (RT), Propionic acid solution, 0143. The nanoemulsion can comprise one or more emul 1.0M in HO, STE buffer solution, for molecular biology, pH Sifying agents to aid in the formation of emulsions. Emulsi 7.8, STET buffer solution, for molecular biology, pH 8.0, fying agents include compounds that aggregate at the oil/ Sodium 5,5-diethylbarbiturate, 299.5% (NT), Sodium water interface to form a kind of continuous membrane that acetate solution, for molecular biology, ~3 Min HO, Sodium prevents direct contact between two adjacent droplets. Cer acetate trihydrate, 299.5% (NT), Sodium acetate, anhy tain embodiments of the present invention feature nanoemul drous, 299.0% (NT), Sodium acetate, for luminescence, sions that may readily be diluted with water to a desired anhydrous, 299.0% (NT), Sodium acetate, for molecular concentration without impairing their anti-fungal orantiyeast biology, anhydrous, 299.0% (NT), Sodium bicarbonate, properties. 299.5% (T), Sodium bitartrate monohydrate, 299.0% (T), 0144. In addition to the foregoing active agents, the com Sodium carbonate decahydrate, 299.5% (T), Sodium car positions employed in the methods of the present invention bonate, anhydrous, 299.5% (calc. on dry substance, T), may also comprise inert and physiologically acceptable car Sodium citrate monobasic, anhydrous, 299.5% (T), Sodium riers or diluents. Suitable carriers or diluents include, but are citrate tribasic dihydrate, 299.0% (NT), Sodium citrate triba not limited to water, physiological saline, bacteriostatic saline sic dihydrate, for luminescence, 299.0% (NT), Sodium cit (e.g., Saline containing 0.9 mg/ml benzyl alcohol), petrola rate tribasic dihydrate, for molecular biology, 299.5% (NT), tum based creams (e.g., USP hydrophilic ointments and simi Sodium formate solution, 8 M in HO, Sodium oxalate, 299. lar creams), various types of pharmaceutically acceptable 5% (RT), Sodium phosphate dibasic dihydrate, 299.0% (T), gels, and short chain alcohols and glycols (e.g., ethyl alcohol Sodium phosphate dibasic dihydrate, for luminescence, 299. and propylene glycol). 0% (T), Sodium phosphate dibasic dihydrate, for molecular 0145. In other further embodiments, the compositions biology, 299.0% (T), Sodium phosphate dibasic dodecahy employed may comprise additional ingredients such as fatty US 2012/0064136 A1 Mar. 15, 2012

alcohols, fatty acids, organic or inorganic bases, preserving 0150 Topical administration includes administration to agents (such as phenoxyethanol and mixtures of various para the skin, including surface of the hair follicle and piloseba bens), wax esters, Steroid alcohols, triglyceride esters, phos ceous unit. pholipids such as lecithin and cephalin, polyhydric alcohol 0151 Pharmaceutically acceptable dosage forms for topi esters, fatty alcohol ethers, hydrophilic lanolin derivatives, hydrophilic beeswax derivatives, cocoa butter waxes, silicon cal administration include, but are not limited to, ointments, oils, pH balancers, cellulose derivatives, hydrocarbon oils creams, liquids, emulsions, lotions, gels, bioadhesive gels, Such as palm oil, coconut oil, and mineral oil, and mixtures aerosols, pastes, foams, Sunscreens, or in the form of an thereof. article or carrier, Such as abandage, insert, Syringe-like appli 0146 Additional ingredients may be included in the above cator, pessary, powder, talc or other Solid, cleanser (leave on compositions to vary the texture, viscosity, color and/or and wash off product), and agents that favor penetration appearance thereof, as is appreciated by one of ordinary skill within the pilosebaceous gland. in the art. Accordingly, in a further embodiment, the compo 0152 The pharmaceutical compositions may be formu sitions, in addition to at least one peptide manganese com lated for immediate release, Sustained release, controlled plex, comprise an emulsifying agent, a Surfactant, a thicken release, delayed release, or any combinations thereof into the ing agent, an excipient or a mixture thereof. epidermis or dermis, with no systemic absorption. In some 0147 More specifically, emulsifiers and surfactants may embodiments, the formulations may comprise a penetration be included in those compositions used for the present inven enhancing agent for enhancing penetration of the nanoemul tion that are formulated as emulsions. Either water-in-oil or sion through the stratum corneum and into the epidermis or oil-in-water emulsions may be formulated. Examples of Suit dermis. Suitable penetration-enhancing agents include, but able Surfactants and emulsifying agents include nonionic are not limited to, alcohols such as ethanol, triglycerides and ethoxylated and nonethoxylated Surfactants, abietic acid, aloe compositions. The amount of the penetration-enhancing almond oil PEG, beeswax, butylglucoside caprate, C.C. acid glycol ester, CoCs alkyl phosphate, caprylic/capric trig agent may comprise from about 0.5% to about 40% by weight lyceride PEG-4 esters, ceteareth-7, cetyl alcohol, cetyl phos of the formulation. phate, corn oil PEG esters, DEA-cetyl phosphate, dextrin 0153. In some embodiments, the formulation for delivery laurate, dilaureth-7 citrate, dimyristyl phosphate, glycereth via a “patch” comprising a therapeutically effective amount 17 cocoate, glyceryl erucate, glyceryl laurate, hydrogenated of the nanoemulsion is envisioned. As used herein a “patch' castor oil PEG esters, isosteareth-11 carboxylic acid, lecithin, comprises at least a topical formulation and a covering layer, lysolecithin, nonoxynol-9, octyldodeceth-20, palm glycer such that the patch can be placed over the area to be treated. ide, PEG diisostearate, PEG stearamine, poloxamines, polyg Preferably, the patch is designed to maximize delivery lyceryls, potassium linoleate, PPG’s, raffinose myristate, through the stratum corneum and into the epidermis or der Sodium caproyl lactylate, sodium caprylate, Sodium cocoate, mis, while minimizing absorption into the circulatory system, Sodium isostearate, sodium tocopheryl phosphate, Steareths, and little to no skin irritation, reducing lag time, promoting TEA-C2C pareth-3 Sulfate, tri-CCs pareth-6 phosphate, uniform absorption, and reducing mechanical rub-off and and trideceths. Other surfactants and emulsifiers may be used, dehydration. as will be appreciated by those skilled in the art. 0154 Adhesives for use with the drug-in-adhesive type 0148 Examples of thickening (i.e., viscosity increasing) patches are well known in the art. Suitable adhesive include, agents include, but are not limited to, those agents commonly but are not limited to, polyisobutylenes, silicones, and acryl used in skin care preparations, such as acrylamides copoly ics. These adhesives can function under a wide range of mer, agarose, amylopectin, bentonite, calcium alginate, cal conditions, such as, high and low humidity, bathing, Sweating cium carboxymethyl cellulose, carbomer, carboxymethyl etc. Preferably the adhesive is a composition based on natural chitin, cellulose gum, dextrin, gelatin, hydrogenated tallow, or synthetic rubber, a polyacrylate Such as, polybutylacrylate, hydroxytheylcellulose, hydroxypropylcellulose, hydroxpro polymethylacrylate, poly-2-ethylhexyl acrylate; polyviny pyl Starch, magnesium alginate, methylcellulose, microcrys lacetate; polydimethylsiloxane; or and hydrogels (e.g., high talline cellulose, pectin, various PEG's, polyacrylic acid, molecular weight polyvinylpyrrolidone and oligomeric poly polymethacrylic acid, polyvinyl alcohol, various PPG's. ethylene oxide). The most preferred adhesive is a pressure Sodium acrylates copolymer, sodium carrageenan, Xanthan sensitive acrylic adhesive, for example DurotakR adhesives gum, and yeast beta-glucan. Thickening agents other than (e.g., DurotakR 2052, National Starch and Chemicals). The those listed above may also be used in related embodiments of adhesive may contain a thickener, such as a silica thickener the present invention. (e.g., Aerosil, Degussa, Ridgefield Park, N.J.) or a crosslinker Such as aluminumacetylacetonate. F. PHARMACEUTICAL COMPOSITIONS 0.155 Suitable release liners include but are not limited to 014.9 The nanoemulsions of the invention may be formu occlusive, opaque, or clear polyester films with a thin coating lated into pharmaceutical compositions that comprise the of pressure sensitive release liner (e.g., silicone-fluorsilicone, nanoemulsion in a therapeutically effective amount and Suit and perfluorcarbon based polymers. able, pharmaceutically-acceptable excipients for topical 0156 Backing films may be occlusive or permeable and administration to a human Subject in need thereof. Such are derived from synthetic polymers like polyolefin oils poly excipients are well known in the art. By the phrase “therapeu ester, polyethylene, polyvinylidine chloride, and polyure tically effective amount' it is meant any amount of the thane or from natural materials like cotton, wool, etc. Occlu nanoemulsion that is effective in preventing and/or treating sive backing films, such as synthetic polyesters, result in acne. One possible way to treat acne is by killing or inhibiting hydration of the outer layers of the stratum corneum while the growth of Pacnes, causing Pacnes to lose pathogenicity, non-occlusive backings allow the area to breath (i.e., promote or any combination thereof. water vapor transmission from the skin surface). More pref US 2012/0064136 A1 Mar. 15, 2012 erably the backing film is an occlusive polyolefin foil (Alevo, Dreieich, Germany). The polyolefin foil is preferably about TABLE 1 0.6 to about 1 mm thick. Exemplary Therapeutically Effective Nanoemulsions 0157. The shape of the patch can be flat or three-dimen sional, round, oval, square, and have concave or convex outer Form. Soy- Etha shapes, or the patch or bandage can also be segmented by the (CPC bean Tween no CPC 96 EDTA HO user into corresponding shapes with or without additional % w/v) oil 96 20% % (mg/mL) % (mM) % auxiliary means. Formulation 31.4 2.96 3.37 0.53 (5) 0.037 (1) 61.70 #1: 0.50% 0158. The nanoemulsions of the invention can be applied Formulation 15.7 148 1.68 0.27 (2.5) 0.0185 (0.5) 80.85 and/or delivered utilizing electrophoretic delivery/electro #2; 0.25% Formulation 62.79 5.92 6.73 1.068 (10) 0.075 (2) 23.42 phoresis. Such transdermal methods, which comprise apply #3: 1.0% ing an electrical current, are well known in the art. Formulation 18.84 1.78 2.02 0.320 (3) 0.0224 (0.6) 77.03 0159. The pharmaceutical compositions for administra #4; 0.3% tion may be applied in a single administration or in multiple Formulation 6.28 0.59 0.67 0.107 (1) 0.0075 (0.2) 92.34 administrations. The pharmaceutical compositions are topi #5; 0.1% cally or Subcutaneously applied for at least once a week, at least twice a week, at least once a day, at least twice a day, multiple times daily, multiple times weekly, biweekly, at least H. METHODS OF MANUFACTURE once a month, or any combination thereof. The pharmaceu (0162 The nanoemulsions of the invention can be formed tical compositions are topically applied for a period of time of using classic emulsion forming techniques. See e.g., U.S. about one month, about two months, about three months, 2004/0043041. See also the method of manufacturing about four months, about five months, about six months, nanoemulsions described in U.S. Pat. Nos. 6,559,189, 6,506, about seven months, about eight months, about nine months, 803, 6,635,676, 6,015,832, and U.S. Patent Publication Nos. about ten months, about eleven months, about one year, about 2004.0043041, 20050208083, 2006025 1684, and 1.5 years, about 2 years, about 2.5 years, about 3 years, about 2007003.6831, and WO 05/030172, all of which are specifi cally incorporated by reference. In an exemplary method, the 3.5 years, about 4 years, about 4.5 years, and about 5 years. oil is mixed with the aqueous phase under relatively high Between applications, the application area may be washed to shear forces (e.g., using high hydraulic and mechanical remove any residual nanoemulsion. forces) to obtain a nanoemulsion comprising oil droplets 0160 Preferably, the pharmaceutical compositions are having an average diameterofless than about 1000 nm. Some applied to the skin area in an amount of from about 0.001 embodiments of the invention employ a nanoemulsion having mL/cm to about 5.0 mL/cm. An exemplary application an oil phase comprising an alcohol Such as ethanol. The oil amount and area is about 0.2 mL/cm, although any amount and aqueous phases can be blended using any apparatus from 0.001 mL/cm up to about 5.0 mL/cm can be applied. capable of producing shear forces sufficient to form an emul Following topical administration, the nanoemulsion may be Sion, such as French Presses or high shear mixers (e.g., FDA occluded or semi-occluded. Occlusion or semi-occlusion approved high shear mixers are available, for example, from may be performed by overlaying abandage, polyoleofin film, Admix, Inc., Manchester, N.H.). Methods of producing such impermeable barrier, or semi-impermeable barrier to the topi emulsions are described in U.S. Pat. Nos. 5,103,497 and cal preparation. Preferably, after application, the treated area 4,895,452, herein incorporated by reference in their entire is covered with a dressing. Typically, for a method of the ties. present invention, aside from the content of the composition 0163. In an exemplary embodiment, the nanoemulsions used, a small amount of the composition (from about 1 ml to used in the methods of the invention comprise droplets of an about 5 ml) is applied to exposed areas of skin from a suitable oily discontinuous phase dispersed in an aqueous continuous container or applicator, and, if necessary, the composition is phase, such as water. The nanoemulsions of the invention are then spread over and/or rubbed into the skin using the hand, stable, and do not decompose even after long storage periods. finger, or other Suitable device. Each composition disclosed Certain nanoemulsions of the invention are non-toxic and herein is typically packaged in a container that is appropriate safe when swallowed, inhaled, or contacted to the skin of a in view of the composition's viscosity and intended use by the Subject. consumer. For example, a lotion or fluid cream may be pack 0164. The compositions of the invention can be produced aged in a bottle, roll-ball applicator, capsule, propellant in large quantities and are stable for many months at a broad driven aerosol device, or a container fitted with a manually range of temperatures. The nanoemulsion can have textures/ operated pump. A cream may simply be stored in a non consistencies ranging from that of a semi-solid cream to that deformable bottle, or in a squeeze container, Such as a tube or of a thin lotion and can be applied topically by hand and a lidded jar. sprayed onto a surface. As stated above, at least a portion of the emulsion may be in the form of lipid structures including, G. EXEMPLARY NANOEMULSIONS but not limited to, unilamellar, multilamellar, and paucliamel lar lipid vesicles, micelles, and lamellar phases. 0161 Several exemplary nanoemulsions are described 0.165. The present invention contemplates that many below, although the methods of the invention are not limited variations of the described nanoemulsions will be useful in to the use of such nanoemulsions. The components and quan the methods of the present invention. To determine if a can tity of each can be varied as described herein in the prepara didate nanoemulsion is suitable for use with the present tion of other nanoemulsions. Unless otherwise noted, all con invention, three criteria are analyzed. Using the methods and centrations are expressed in terms of% w/w. standards described herein, candidate emulsions can be easily US 2012/0064136 A1 Mar. 15, 2012

tested to determine if they are suitable. First, the desired (0170 Exemplary nanoemulsions (“NB-00X) shown in ingredients are prepared using the methods described herein, Table 1 comprised, in an aqueous medium, soybean oil, to determine if a nanoemulsion can beformed. If a nanoemul Tween 20R) as a nonionic Surfactant, ethanol, cetylpyridinium sion cannot be formed, the candidate is rejected. Second, the chloride (CPC) as a cationic surfactant, EDTA, and water, and candidate nanoemulsion should form a stable emulsion. A optionally, a thickening agent for the gel formulation.

TABLE 2

Compositions of the Nanoemulsions (NB-00X) and Nanoemulsion Gels (NB-Gel). The percentages are wtiwt, unless otherwise noted. Soybean oil Tween Ethanol CPC EDTA Klucel Water Formulation % 20% % % (w/v) % % %

O.1% NB-OOX 6.279 O.S92 0.679 0.107 O.OO74 O 92.34 O.3% NB-OOX 18.837 1.776 2.037 0.32O O.O22 O 77.01 0.1% NB-Gel 6.279 O.S92 20.679 0.107 O.OO74 196 92.34 0.3% NB-Gel 18.837 1.776 22.037 0.32O O.O22 196 77.01 nanoemulsion is stable if it remains in an emulsion form for a (0171 The nanoemulsions were then formulated at 10 dif sufficient period to allow its intended use. For example, for ferent concentrations, as two-fold serial dilutions from nanoemulsions that are to be stored, shipped, etc., it may be 0.0064% NB-00X (equivalent to 64 pug CPC/ml) to desired that the nanoemulsion remain in emulsion form for 0.000012.5% NB-00X (equivalent to 0.125ug CPC/ml). Each months to years. Typical nanoemulsions that are relatively dilution contained varying concentrations of soybean oil, unstable, will lose their form within a day. Third, the candi Tween 20R), ethanol, CPC, and EDTA. Combination products were also prepared; stock emulsions containing NB-00X gel date nanoemulsion should have efficacy for its intended use. (3 mg CPC/ml)+2% salicyclic acid or NB-00X gel--0.5% 0166 The nanoemulsion of the invention can be provided benzoyl peroxide (BPO) were serially diluted two-fold. in many different types of containers and delivery systems. (0172 A. Source of Drugs For example, in some embodiments of the invention, the (0173 NB-00X (liquid formulation), lot X1151 and nanoemulsions are provided in a cream or other solid or NB-00X gel, were prepared at concentrations of 6000 ug/ml semi-solid form. The nanoemulsions of the invention may be and 3000 ug/ml respectively. These lots were prepared at incorporated into hydrogel formulations. NanoBio Corporation from NB-PO-004-FP manufactured at 0167. The nanoemulsions can be delivered (e.g., to a sub Contract Pharmaceutical Laboratories (CPL), Buffalo, N.Y., ject or customers) in any suitable container. Suitable contain USA. Placebo lots (placebo for NB-00X gel, contains thick ers can be used that provide one or more single use or multi ening agent and additional solvent) were prepared from use dosages of the nanoemulsion for the desired application. manufactured at NanoBio Corporation. Since nanoemulsions In some embodiments of the invention, the nanoemulsions are are not a single Small molecule, their relative activity can be provided in a suspension or liquid form. Such nanoemulsions expressed in terms of the concentration of cationic Surfactant can be delivered in any suitable container including spray present. Thus, the activity of NB-00X formulations is bottles (e.g., pressurized spray bottles). expressed in microgram CPC per ml. NB-00X gel (lot X1158) contained a thickening agent in addition to the com I. EXAMPLES ponents of NB-00X. Combination products were made as stock emulsions containing NB-00X gel (3 mg CPC/ml)+2% 0168 The invention is further described by reference to salicyclic acid or NB-00X gel--0.5% benzoyl peroxide the following examples, which are provided for illustration (BPO). only. The invention is not limited to the examples, but rather 0.174 Salicylic acid was purchased from J. T. Baker as includes all variations that are evident from the teachings VWR International catalog number 0300-01. BPO in the provided herein. All publicly available documents referenced form of Invisible Acne cream containing 10% BPO was pur herein, including but not limited to U.S. patents, are specifi chased from Meijer Distribution Inc. (Grand Rapids, Mich.). cally incorporated by reference. 0.175 Since NB-00X is a nanoemulsion and is preferen tially taken up by the transfollicular route (Ciotti et al., Example 1 “Novel nanoemulsion NB-001 permeates skin by the follicu lar route.” Abstr. 45" Intersci. Conf. Antimicrob. Agents Preparation of Nanoemulsions Chemother., abstr. A-1898 (2008)), incorporation of a drug, 0169 Exemplary emulsions are produced by mixing a Such as an anti-acne drug, into the nanodroplets could be used water-immiscible oil phase into an aqueous phase with a to effectively deliver these additional agents to the desired proprietary manufacturing method. The two phases (aqueous site. phase and oil phase) are combined together and processed to yield an emulsion. The emulsion is further processed to Example 2 achieve the desired particle size. For the gel formulation, a Skin Permeation Studies thickening agent, such as Klucel can be added to the 0176 The purpose of this example was to evaluate the in nanoemulsion. For example, Klucel is dissolved in water or vitro absorption into the epidermis and dermis of nanoemul any aqueous solvent and added to the nanoemulsion to sions according to the invention. Pig skin was used as an achieve the desired concentration. animal model. US 2012/0064136 A1 Mar. 15, 2012 19

0177 A. In Vitro Skin Model and Swabbed independently to remove all residual formula 0.178 The in vitro skin model has proven to be a valuable tion from the skin Surface. Receptor Solution was also tool for the study of percutaneous absorption of topically sampled at 24 hours from the receptor of each cell and filtered applied compounds. The model uses excised skin mounted in into vials. specially designed diffusion chambers that allow the skin to 0187 Skin samples were collected as described above: be maintained at a temperature and humidity that match typi weights of the epidermal and dermal samples were obtained. cal in vivo conditions. Franz, T.J., “Percutaneous absorption: The epidermal and dermal tissues were extracted with abso on the relevance of invitro data.J. Invest. Dermatol., 64:190 lute ethanol, Sonicated, and filtered and assayed using HPLC. 195 (1975). A finite dose of formulation is applied to the 0188 F. Epidermal and Dermal Calculations epidermis, and outer Surface of the skin and compound 0189 The amount of CPC that permeated into the epider absorption is measured by monitoring its rate of appearance mis, dermis and the receptor compartment was determined by in the receptor solution bathing the dermal surface of the skin. HPLC. A standard concentration of CPC was generated and Data defining total absorption, rate of absorption, as well as used to determine the concentration of CPC in the dosing skin content can be accurately determined in this model. The area. The levels of CPC in each skin area are represented as method has historic precedent for accurately predicting in the amount per wet tissue weight (ug/grams)--the standard vivo percutaneous absorption kinetics. Franz TJ, “The finite deviation. dose technique as a valid in vitro model for the study of 0190. The results of CPC permeation studies are shown in percutaneous absorption in man. In: Skin. Drug Application FIGS. 2 and 3. There was an increase in the delivery of the and Evaluation of Environmental Hazards, Current Problems CPC marker to the epidermis and dermis with the 0.3% in Dermatology, vol. 7, Simon et al. (Eds) (Basel, Switzer NB-00X as compared to the 0.1% NB-001X formulation, as land, S. Karger, 1978, pp 58-68.) expected. The gels for the 0.1% NB-00X and 0.3% NB-00X (0179 B. Nanoemulsions Used in the Study did not hinder delivery. The amount of CPC found in the

TABLE 3 Soybean oil Tween Ethanol CPC 96 EDTA Klucel Water Formulation % 20% % (w/v) % % % O.1% NB-001 6.279 O.S92 0.679 0.107 O.OO74 O 92.34 O.3% NB-OO1 18.837 1,776 2.037 O.32O O.O22 O 77.01 0.1% NB-Gel 6.279 O.S92 20.679 0.107 O.OO74 190 92.34 0.3% NB-Gel 18.837 1.776 22.037 0.32O O.O22 190 77.01

0180 C. Pig Skin receptor compartment at 24 hours was below the level of 0181 Full thickness, abdominal skin (~1000 um thick detection (5ug/ml) for all the formulations. ness) from 5.4 month old male Hanford Swine (S/N 5353) was 0191 At the twelve hour time point, the gel formulation used in permeation studies and obtained from Sinclair delivered two-fold higher levels of CPC into the epidermis, Research Center, Inc., Auxvasse, Mo. The subcutaneous fat indicating a fast rate of delivery. The dermal levels were was removed using a scalpel and the skin was stored in alu similar (See FIG. 3). minum foil pouches at ~70° C. until use. At time of use, the skin was thawed by placing the sealed pouch in 30°C. water Example 3 for approximately five minutes. Thawed skin was removed from the pouch and cut into circular discs (30 mm diameter) Skin Permeation Studies With Nanoemulsion+Sec to fit between the donor and receiversides of the permeation ond Active Ingredient chambers. 0.192 The purpose of this example was to evaluate the in 0182 D. Franz Diffusion Cell Methodology: Conditions, vitro absorption of a second active ingredient from the Parameters, Procedure nanoemulsion into the epidermis and dermis according to the 0183 Percutaneous absorption was measured using the in invention. Two different active ingredients were evaluated vitro cadaver skin finite dose technique. Thirty mm of swine following incorporation into the nanoemulsion: benzoyl per skin was placed onto the Surface of each cell. Each receptor oxide or adapalene. compartment was filled with distilled water, pH 7 and the 0193 The nanoemulsion test formulations contained donor compartment was left open to ambient laboratory con 0.3% (w/w) NB-001 with 0.1% (w/w) Adapalene or 0.3% ditions. The receptor compartment spout was covered with a (w/w) NB-00X with either 0.5% (w/w) BPO or 2.5% (w/w) screw cap to minimize evaporation of the receptor Solution. BPO. Control formulations tested were commercially avail All cells were mounted in a diffusion apparatus in which the able products; Persa-Gel-10 (10% benzoyl peroxide; Johnson receptor solution was maintained at 37°C. The receptor com & Johnson), 0.1% Differin Lotion (0.1% Adapelene; Gal partment was maintained at 34.5°C. in a water bath and was derma) and 0.3% Differin Gel (0.3% Adapalene gel: Gal stirred with a magnetic stirrer. derma). 0184 The skin was equilibrated before applying 113 uL of 0194 A. In Vitro Skin Model each test article onto the skin Surface. 0.195 The in vitro skin model has proven to be a valuable 0185. E. Sampling (Receptor Sampling, Epidermis, Der tool for the study of percutaneous absorption of topically mis, Surface Swabs) applied compounds. The model uses excised skin mounted in 0186 Twenty-four hours after application of the first dose, specially designed diffusion chambers that allow the skin to the Surface of the dosing area was rinsed with ethanol Solution be maintained at a temperature and humidity that match typi US 2012/0064136 A1 Mar. 15, 2012 20 cal in vivo conditions. Franz, T.J., “Percutaneous absorption: skin was thawed by placing the sealed pouch in 30°C. water on the relevance of invitro data.J. Invest. Dermatol., 64:190 for approximately five minutes. Thawed skin was removed 195 (1975). A finite dose of formulation is applied to the from the pouch and cut into circular discs (30 mm diameter) epidermis and outer Surface of the skin and compound to fit between the donor and receiversides of the permeation absorption is measured by monitoring its rate of appearance chambers. (0199 D. Human Cadaver Skin in the receptor solution bathing the dermal surface of the skin. 0200 Cryopreserved, dermatomed human cadaver Data defining total absorption, rate of absorption, as well as abdominal skin from a Caucasian female donor was used in skin content can be accurately determined in this model. The permeation studies and obtained from Life Legacy tissue method has historic precedent for accurately predicting in organ donor bank. Cadaver skin was stored in aluminum foil vivo percutaneous absorption kinetics. Franz TJ, “The finite pouches at -70° C. until use. At time of use, the skin was dose technique as a valid in vitro model for the study of thawed by placing the sealed pouch in 37° C. water for percutaneous absorption in man. In: Skin. Drug Application approximately five minutes. Thawed skin was removed from and Evaluation of Environmental Hazards, Current Problems the pouch and cut into circular discs (30 mm diameter) to fit in Dermatology, vol. 7, Simon et al. (Eds) (Basel, Switzer between the donor and receiversides of the permeation cham land, S. Karger, 1978, pp 58-68.) bers. (0196. B. Nanoemulsions Used in the Study 0201 E. Franz Diffusion Cell Methodology: Conditions, Parameters, Procedure 0202 Percutaneous absorption was measured using the in TABLE 4 vitro cadaver skin finite dose technique. Thirty mm of Swine Quantitative Composition of 0.3% NB-00X with Benzoyl Peroxide skin was placed onto the Surface of each cell. Each receptor compartment was filled with distilled water, with a solubiliz 0.3% NB-00X with 0.3% NB-00X with ing solvent (such as 10% ethanol) and or an anti-oxidant 0.5% Benzoyl 2.5% Benzoyl (0.1% BHT) and the donor compartment was left open to Components Peroxide (% w/w) Peroxide (% w/w) ambient laboratory conditions. The receptor compartment Cetylpyridinium Chloride O.3204 O.3204 spout was covered with a screw cap to minimize evaporation Monohydrate, USP of the receptor solution. All cells were mounted in a diffusion Purified Water, USP qs qs Soybean Oil, USP 18.84 18.84 apparatus in which the receptor Solution was maintained at Dehydrated Alcohol, USP 2.019 2.019 37°C. The receptor compartment was maintained at 34.5°C. (anhydrous ethanol) in a water bath and was stirred with a magnetic stirrer. The Polysorbate 20, NF 1.776 1.776 skin was equilibrated before applying 113 uI of each test Edetate Disodium Dihydrate, O.O222 O.O222 (EDTA) USP article onto the skin surface. The testarticle was applied twice persa-gel (R)-10 5 25 at eight hour intervals for the Swine skin studies and once a (contains 10% benzoyl day for the human cadaver skin study. peroxide) 0203 F. Sampling (Receptor Sampling, Epidermis, Der Sterile Water for Irrigation 45 25 mis, Surface Swabs) USP 0204 Twenty-four hours after application of the first dose, Total (%) 1OO 1OO the Surface of the dosing area was rinsed with ethanol Solution and Swabbed independently to remove all residual formula contains 10% benzoyl peroxide and other excipients (carbomer, disodium EDTA, hydrox ypropyl-methylcellulose, laureth 4, sodium hydroxide, water) tion from the skin Surface. Receptor Solution was also sampled at 24 hours from the receptor of each cell and filtered into vials. TABLE 5 0205 Skin samples were collected as described above: and weights of the epidermal and dermal samples were Quantitative Composition of 0.3% NB-001 with 1% Adapalene obtained. The epidermal and dermal tissues were extracted O.3% NB-003 with 196 with absolute ethanol, Sonicated, and filtered and the second Components Adapalene (% w/w) active ingredient assayed using HPLC. Cetylpyridinium Chloride O.3204 0206 G. Epidermal and Dermal Calculations Monohydrate, USP 0207. The amount of the second active ingredient that Purified Water, USP 76.9224 permeated into the epidermis, dermis and the receptor com Soybean Oil, USP 18.84 Dehydrated Alcohol, USP 2.019 partment was determined by HPLC. A standard concentration (anhydrous ethanol) of the active was generated and used to determine the con Polysorbate 20, NF 1.776 centration of active in the dosing area. The levels of active in Edetate Disodium Dihydrate, O.O222 each skin area are represented as the amount per wet tissue (EDTA) USP weight (ug/grams)+the standard deviation. Adapalene O.1 0208. The results of benzoyl peroxide and adapalene per Total (%) 100 meation studies are shown in FIGS. 8, 9 and 10, respectively. There was an increase in the delivery of the second active incorporated in the nanoemulsion to the epidermis and dermis (0197) C. PigSkin as compared to a commercial preparation. 0198 Full thickness, abdominal skin (~1000 um thick Example 4 ness) from 5.4 month old male Hanford Swine (S/N 5353) was used in permeation studies and obtained from Sinclair Viscosity Research Center, Inc., Auxvasse, Mo. The subcutaneous fat 0209. The purpose of this example was to evaluate the was removed using a scalpel and the skin was stored in alu effect of concentration of a nanoemulsion has on the Viscosity minum foil pouches at -70° C. until use. At time of use, the of the nanoemulsion. US 2012/0064136 A1 Mar. 15, 2012

0210 FIG. 4 shows the relationship between the particle nanoemulsions (e.g. 0.8% NB-003) were found to deliver size (nm), concentration of active (%), and viscosity of a three times the amount of the Surfactant, cetylpyridinium nanoemulsion. The particle size does not change upon dilu chloride (CPC) to the dermis as compared to a lower viscosity tion of a nanoemulsion; however viscosity significantly nanoemulsion (e.g., 0.25% NB-003). decreases as a function of the decrease in particle concentra 0214 Thus, increasing the Viscosity of a nanoemulsion tions. Table 6 shows the effect dilution of a nanoemulsion has can increase the permeation of the nanoemulsion into the on the concentration of the active (CPC), viscosity, and par dermis and epidermis, thereby producing a composition more ticle size. effective in killing bacteria or other organisms.

TABLE 6 Example 6 0215. The purpose of this example was to evaluate the NB-001 Process Optimization - Dilution efficacy of a nanoemulsion in treating the signs of aging Percentage of present on facial skin. Concentrated Theoretical CPC Particle Size 0216. Two different nanoemulsions were prepared as in NB-001 Potency (% wt v) Viscosity (cP) (nm) Example 1: 0.1% NB-003 and 0.3% NB-003. 100% 1.O 259,300 181 80% O.8 3200 179 TABLE 7 60% O.6 11.5 181 SO% O.S 11.5 18O Soybean CPC 40% 0.4 7.5 178 oil Tween Ethanol % EDTA Water 30% O.3 6.5 179 Formulation % 20% % (w/v) % % 20% O.2 4.5 181 10% O.1 2.5 18O O.1% NB-003 6.279 O.S92 O.679 0.107 O.OO74 92.34 O.3% NB-003 18837 1.776 2.037 0.32O O.O22 77.01

Example 5 0217. Two groups of human subjects topically applied either 0.1% NB-003 or 0.3% NB-003 to facial skin twice a Viscosity and Permeation day for a period of 29 days. 8 subjects were in Group 1 and 0211. The purpose of this example was to evaluate the topically applied the 0.1% NB-003 formulation daily to facial effect viscosity of a nanoemulsion has on the permeation of skin, and 20 subjects were in Group 2 and topically applied the active into the dermis and epidermis. the 0.3% NB-003 formulation daily to facial skin. At the end 0212 A permeation study was conducted using the proto of the 29 day test period, the subjects were polled regarding col described in Example 4 with five skin sections (n=5). Four various aspects of the effectiveness of the nanoemulsion in different concentrations of nanoemulsion (see Table 6) were treating and/or minimizing signs of aging present on the skin. tested: 0.25%, 0.30%, 0.50% and 0.80%. FIGS. 6 and 7 show The following aspects of the nanoemulsion were evaluated: the results for epidermis and dermis permeation, respectively. (1) effectiveness of the nanoemulsion in improving the Specifically, FIG. 6 shows the results of the permeation study Smoothness and/or softness of skin (i.e., making the skin feel utilizing pig skin epidermis with 5 skin sections (n=5) fol smoother and softer following treatment); (2) effectiveness of lowing administration of a nanoemulsion (NB-003) twice the nanoemulsion in improving the overall appearance of daily (BID). Higher viscosity (greater than 1000 cps) skin; (3) effectiveness of the nanoemulsion in evening out nanoemulsions (e.g. 0.8% NB-003) were found to have skintone and texture; (4) effectiveness of the nanoemulsion in greater permeation of the nanoemulsion into the epidermis. improving the clarity and/or radiance of skin; (5) effective 0213 Similarly, FIG. 7 shows the results of a permeation ness of the nanoemulsion in making the skin look younger; study utilizing pig skin epidermis with 5 skin sections (n=5) and (6) effectiveness of the nanoemulsion in making wrinkles following administration of a nanoemulsion (NB-003) twice appear softer and/or less prominent. The results of the polling daily (BID). Higher viscosity (greater than 1000 cps) questions are shown below in the table below. US 2012/0064136 A1 Mar. 15, 2012 22 Table 8

Ai Subjects NB-003-002 would consider using this product as a... S. S My wrinkles appear softer or less. S My skin looks/fees younger Š My skin has more clarity/radiance SS his treatment evens out my skin tone... S Š This treatment improves the overall. SS Myskin feets smoother and softer S Š

O S 15 O 25 Š Disagree : Neutral Agree

% ------' US 2012/0064136 A1 Mar. 15, 2012

0218. The results were significant. In particular, 75% of about 55 cB. greater than about 60 cp greater than about 65 cB. 0.1% NB-003 users reported that skin was smoother and greater than about 70 cp greater than about 75 cl, greater than softer following treatment. Similarly, 37.5% of 0.1% NB-003 about 80 cp, greater than about 85 cF. greater than about 90 cp. users reported that following treatment skin demonstrated greater than about 95 cp, greater than about 100 cp, greater more clarity and/or radiance, and that wrinkles appeared than about 150 cp, greater than about 200 cp, greater than softer and/or less prominent. Moreover, 25% of 0.1% NB-003 about 300 cp greater than about 400 cp, greater than about users reported that following treatment the overall appear 500 cB. greater than about 600 cP. greater than about 700 cB. ance of skin was improved, skin tone and skin texture was greater than about 800 cp greater than about 900 cB. greater more even, and skin looked and/or felt younger. than about 1000 cp greater than about 1500 cB. greater than 0219. Significant and unexpected results were also about 2000 cp, greater than about 2500 cp greater than about observed with the 0.3% NB-003 group, where following 3000 cB. greater than about 3500 cP greater than about 4000 treatment 40% reported that skin was smoother and softer, cP greater than about 4500 cp, greater than about 5000 cp. 35% reported that the overall appearance of skin was greater than about 5500 cp, greater than about 6000 cp greater improved and that skin demonstrated more clarity and/or than about 7000 cp greater than about 8000 cB. greater than radiance, 30% reported that skin tone and skin texture was about 9000 cp, greater than about 10,000 cp, greater than more even, and 20% reported that skin looked and/or felt about 15,000 cp greater than about 20,000 cp greater than younger and that wrinkles appeared softer and/or less promi about 30,000 cp greater than about 40,000 cp greater than nent. about 50,000 cB. greater than about 60,000 cB. greater than 0220 Collectively, following treatment with either 0.1% about 70,000 cB. greater than about 80,000 cB. greater than NB-003 and 0.3% NB-003, 50% of subjects reported that skin about 90,000 cB. greater than about 100,000 cB. greater than felt smoother and softer, 35.7% reported that skin had more about 150,000 cB. greater than about 200,000 cB. greater than clarity and/or radiance, 32.1% reported that the overall about 250,000 cB, or up to about 259,300 cF. appearance of skin was improved, 28.6% reported that skin 4. The method of claim 1, wherein: tone and texture was more even, 25% reported that wrinkles (a) the nanoemulsion is at room temperature at the time of appeared softer and/or less prominent, and 21.4% reported administration; or that skin looked and or felt younger. (b) prior to application the nanoemulsion is warmed to a 0221. These results demonstrate the effectiveness of the temperature selected from the group consisting of about nanoemulsions of the invention in anti-aging treatments for 30° C. or warmer, about 31° C. or warmer, about 32° C. skin. or warmer, about 33° C. or warmer, about 34° C. or 0222. It will be apparent to those skilled in the art that warmer, about 35° C. or warmer, about 36° C. or various modifications and variations can be made in the meth warmer, and about 37° C. ods and compositions of the present invention without depart 5. The method of claim 1, wherein: ing from the spirit or scope of the invention. Thus, it is (a) the nanoemulsion droplets have an average diameter intended that the present invention cover the modifications selected from the group consisting of less than about 950 and variations of this invention provided they come within the nm, less than about 900 nm, less than about 850 nm, less Scope of the appended claims and their equivalents. than about 800 nm, less than about 750 nm, less than What is claimed is: about 700 nm, less than about 650 nm, less than about 1. A method of treating, preventing, minimizing, and/or 600 nm, less than about 550 nm, less than about 500 nm, diminishing a dermatological condition comprising adminis less than about 450 nm, less than about 400 nm, less than tering a nanoemulsion to a subject, wherein: about 350 nm, less than about 300 nm, less than about (a) the nanoemulsion comprises droplets having an average 250 nm, less than about 225 nm, less than about 220 nm, diameter of less than about 3 microns; and less than about 210 nm, less than about 205 nm, less than (b) the nanoemulsion droplets comprise an oil phase with about 200 nm, less than about 190 nm, less than about at least one oil, an aqueous phase comprising at least one 175 nm, less than about 150 nm, less than about 100 nm, Surfactant, at least one organic solvent, and water. greater than about 50 nm, greater than about 70 nm, 2. The method of claim 1, wherein the dermatological greater than about 125 nm, and any combination thereof; condition is selected from the group consisting of (1) fine to (b) the nanoemulsion droplets have an average diameter moderate wrinkles, (2) liver spots or age spots (lentigines or greater than about 125 nm andless than about 450 nmi; or Solar lentigines), (3) uneven skin tone and/or texture, (4) (c) any combination thereof. Sun-damaged skin or photodamaged skin (particularly UV 6. The method of claim 1, wherein: radiation-induced oxidative stress), (5) blemishes, (6) hyper (a) the nanoemulsion is applied topically or subcutane pigmented skin, (7) increased skin thickness, (8) dry skin, (9) ously; loss of skin elasticity and collagen content, (10) melasmas (b) the nanoemulsion is applied topically to any Superficial (atypical pigmentation or hyper-pigmentation of the skin), skin structure; (11) skin clarity and/or radiance, (12) skin Smoothness and/or (c) the nanoemulsion is applied to the facial or neck tissue; softness, (13) scars, (14) pore size, (14) hydration, (15) skin O Smoothness, (16) skin tightness, and any combination (d) any combination thereof. thereof. 7. The method of claim 1, wherein: 3. The method of claim 1, wherein the nanoemulsion has a (a) the nanoemulsion is in a dosage form selected from the Viscosity selected from the group consisting of greater than group consisting of liquids, ointments, creams, oils, about 12 centipoise (cP), greater than about 15 cl, greater emulsions, lotions, gels, liquids, bioadhesive gels, than about 20 cp greater than about 25 cF. greater than about sprays, shampoos, aerosols, pastes, foams, Sunscreens, 30 cp, greater than about 35 cF. greater than about 40 cp. capsules, microcapsules, in the form of an article or greater than about 45 cF. greater than about 50 cp greater than carrier, such as a bandage, insert, Syringe-like applica US 2012/0064136 A1 Mar. 15, 2012 24

tor, pessary, powder, talc or other Solid, shampoo, 2 years, up to about 2.5 years, up to about 3 years, up to cleanser, day creams, night creams, make-up removal about 3.5 years, up to about 4 years, up to about 4.5 creams, foundation creams, make-up removal formula years, up to about 5 years, up to about 5.5 years, up to tions, protective or skin care body milks, skin care about 6 years, up to about 6.5 years, and up to about 7 lotions, gels, or foams, bath compositions, deodorant years; or compositions, aftershave and pre-shave gels or lotions; (d) any combination thereof. (b) the nanoemulsion is a controlled release formulation, 13. The method of claim 1, wherein the organic solvent: Sustained release formulation, immediate release formu (a) is selected from the group consisting of C-C alcohol, lation; or diol, triol, dialkyl phosphate, tri-alkyl phosphate, semi (c) any combination thereof. synthetic derivatives thereof, and combinations thereof; 8. The method of claim 1, wherein the nanoemulsion fur (b) is an alcohol which is selected from the group consist ther comprises at least one drug active agent, at least one ing of a nonpolar solvent, a polar solvent, a protic Sol non-drug active agent, at least one active agent having anti vent, and an aprotic solvent; aging and/or anti-wrinkle properties, at least one active cos (c) is selected from the group consisting of ethanol, metha metic Substance, at least one antiviral active agent, at least one nol, isopropyl alcohol, glycerol, medium chain triglyc anti-acne active agent, or any combination thereof. erides, diethyl ether, ethyl acetate, acetone, dimethyl 9. The method of claim 8, wherein the agent is selected sulfoxide (DMSO), acetic acid, n-butanol, butylene gly from the group consisting of skin lightening agents, tanning col, perfumers alcohols, isopropanol, n-propanol, for agents, skin conditioning agents, skin protectants, Sunscreen mic acid, propylene glycols, glycerol, Sorbitol, indus agent, emollients, humectants, Botulinum toxin type A, a trial methylated spirit, triacetin, hexane, benzene, retinoid, vitamin A derivatives, retinol, retinal, tretinoin, ret toluene, diethyl ether, chloroform, 1,4-dixoane, tetrahy inoic acid, isotretinoin, alitretinoin, etretinate, acitretin, taZ drofuran, dichloromethane, acetone, acetonitrile, dim arotene, bexarotene, and adapalene, alpha hydroxy acids, ethylformamide, dimethyl sulfoxide, formic acid, semi beta hydroxy acids, polyhydroxy acids, hydroxyl acids, kine synthetic derivatives thereof, and any combination tin, coenzyme Q10, copper peptides, tea extracts, green tea thereof; or extracts, black tea extracts, oolong tea extracts, antioxidants, (d) any combination thereof. ascorbic acid, glutathione, melatonin, tocopherols, C-toco 14. The method of claim 1, wherein the oil: pherol, tocotrienols, vitamin E, lipoic acid, uric acid, car (a) is any cosmetically or pharmaceutically acceptable oil: otenes, ubiquinone (coenzyme Q), thioredoxin, Polyphenolic antioxidants, resveratrol, flavonoids, and carotenoids. (b) is non-volatile; 10. The method of claim 1, wherein the nanoemulsion (c) is selected from the group consisting of animal oil, comprises: Vegetable oil, natural oil, synthetic oil, hydrocarbon oils, (a) an aqueous phase; silicone oils, and semi-synthetic derivatives thereof; (d) is selected from the group consisting of mineral oil, (b) about 1% oil to about 80% oil; squalene oil, flavor oils, silicon oil, essential oils, water (c) about 0.1% organic solvent to about 50% organic sol insoluble vitamins, Isopropyl Stearate, Butyl Stearate, vent; Octyl palmitate, Cetyl palmitate, Tridecyl behenate, (d) at least one surfactant present in an amount of about Diisopropyl adipate, Dioctyl sebacate, Menthyl anthra 0.001% surfactant to about 10% surfactant; and nhilate, Cetyl octanoate, Octyl salicylate, Isopropyl (e) about 0.0005% to about 1.0% of a chelating agent. myristate, neopentyl glycol dicarpate cetols, Cera 11. The method of claim 10, wherein the nanoemulsion phyls.(R), Decyl oleate, diisopropyl adipate, C2-s alkyl comprises: lactates, Cetyl lactate, Lauryl lactate, IsoStearyl neopen (a) at least one non-ionic Surfactant present in an amount of tanoate, Myristyl lactate, Isocetyl Stearoyl Stearate, about 0.1% to about 10%; and Octyldodecyl stearoyl stearate, Hydrocarbon oils, Iso (b) at least one cationic agent present in an amount of about paraffin, Fluid paraffins, Isododecane, Petrolatum, 0.01% to about 2%. Argan oil, Canola oil, Chile oil, Coconut oil, corn oil, 12. The method of claim 1, wherein: Cottonseed oil, Flaxseed oil, Grape seed oil, Mustard (a) the nanoemulsion is stable at about 40° C. and about oil, Olive oil, Palm oil, Palm kernel oil, Peanut oil, Pine 75% relative humidity for a time period selected from seed oil, Poppy seed oil, Pumpkin seed oil, Rice bran oil, the group consisting of up to about 1 month, up to about Safflower oil, Tea oil, Truffle oil, Vegetable oil, Apricot 3 months, up to about 6 months, up to about 12 months, (kernel) oil, Jojoba oil (simmondsia chinensis seed oil), up to about 18 months, up to about 2 years, up to about Grapeseed oil, Macadamia oil. Wheat germ oil, Almond 2.5 years, and up to about 3 years; oil, Rapeseed oil, Gourd oil, Soybean oil, Sesame oil, (b) the nanoemulsion is stable at about 25° C. and about Hazelnut oil, Maize oil, Sunflower oil, Hemp oil, Bois 60% relative humidity for a time period selected from oil, Kuki nut oil, Avocado oil, Walnut oil, Fish oil, berry the group consisting of up to about 1 month, up to about oil, allspice oil, juniper oil, seed oil, almond seed oil, 3 months, up to about 6 months, up to about 12 months, anise seed oil, celery seed oil, cumin seed oil, nutmeg up to about 18 months, up to about 2 years, up to about seed oil, leafoil, basil leafoil, bay leafoil, cinnamon leaf 2.5 years, up to about 3 years, up to about 3.5 years, up oil, common sage leaf oil, eucalyptus leaf oil, lemon to about 4 years, up to about 4.5 years, and up to about 5 grass leaf oil, melaleuca leaf oil, oregano leaf oil, years; patchouli leaf oil, peppermint leaf oil, pine needle oil, (c) the nanoemulsion is stable at about 4°C. for a time rosemary leaf oil, spearmint leaf oil, tea tree leaf oil, period selected from the group consisting of up to about thyme leaf oil, wintergreen leaf oil, flower oil, chamo 1 month, up to about 3 months, up to about 6 months, up mile oil, clary sage oil, clove oil, geranium flower oil, to about 12 months, up to about 18 months, up to about hyssop flower oil, jasmine flower oil, lavenderflower oil, US 2012/0064136 A1 Mar. 15, 2012 25

manuka flower oil, Marhoram flower oil, orange flower Glyceryl caprylate, Glyceryl cocate, Glyceryl erucate, oil, rose flower oil, ylang-ylang flower oil, Bark oil, Glyceryl hydroxysterate, Glyceryl isostearate, Glyceryl cassia Bark oil, cinnamon bark oil, Sassafras Bark oil, lanolate, Glyceryl laurate, Glyceryl linolate, Glyceryl Wood oil, camphor wood oil, cedar wood oil, rosewood myristate, Glyceryl oleate, Glyceryl PABA, Glyceryl oil, Sandalwood oil), rhizome (ginger) wood oil, resin palmitate, Glyceryl ricinoleate, Glyceryl Stearate, Glyc oil, frankincense oil, myrrh oil, peel oil, bergamot peel eryl thighlycolate, Glyceryl dilaurate, Glyceryl dioleate, oil, grapefruit peel oil, lemon peel oil, lime peel oil, Glyceryl dimyristate, Glyceryl disterate, Glyceryl sesui orange peel oil, tangerine peel oil, root oil, Valerian oil, oleate, Glyceryl Stearate lactate, Polyoxyethylene cetyl/ Oleic acid, Linoleic acid, Oleyl alcohol, Isostearyl alco stearyl ether, Polyoxyethylene cholesterol ether, Poly hol, semi-synthetic derivatives thereof, and combina oxyethylene laurate or dilaurate, Polyoxyethylene tions thereof, or Stearate or distearate, polyoxyethylene fatty ethers, (e) any combination thereof. Polyoxyethylene lauryl ether, Polyoxyethylene stearyl 15. The method of claim 1, wherein the nanoemulsion ether, polyoxyethylene myristyl ether, a steroid, Choles comprises a volatile oil, wherein: terol, Betasitosterol, Bisabolol, fatty acid esters of alco (a) the volatile oil can be the organic solvent, or the volatile hols, isopropyl myristate, Aliphati-isopropyl n-butyrate, oil can be present in addition to an organic solvent; Isopropyl n-hexanoate, Isopropyl n-decanoate, Isoprop (b) the Volatile oil is a terpene, monoterpene, sesquiter pyl palmitate, Octyldodecyl myristate, alkoxylated alco pene, carminative, azulene, semi-synthetic derivatives hols, alkoxylated acids, alkoxylated amides, alkoxy thereof, or combinations thereof; lated sugar derivatives, alkoxylated derivatives of (c) the Volatile oil is selected from the group consisting of natural oils and waxes, polyoxyethylene polyoxypropy a terpene, monoterpene, sesquiterpene, carminative, lene block copolymers, nonoxynol-14, PEG-8 laurate, aZulene, menthol, camphor, thujone, thymol, nerol, lina PEG-6 Cocoamide, PEG-20 methylglucose sesquistear lool, limonene, geraniol, perillyl alcohol, nerolidol, far ate, PEG40 lanolin, PEG-40 castor oil, PEG-40 hydro neSol, ylangene, bisabolol, farmesene, ascaridole, che genated castor oil, polyoxyethylene fatty ethers, glyc nopodium oil, citronellal, citral, citronellol, eryl diesters, polyoxyethylene stearyl ether, chamaZulene, yarrow, guaiaZulene, chamomile, semi polyoxyethylene myristyl ether, and polyoxyethylene synthetic derivatives thereof, and combinations thereof lauryl ether, glyceryl dilaurate, glyceryl dimyState, glyc O eryl distearate, semi-synthetic derivatives thereof, and (d) any combination thereof. mixtures thereof; 16. The method of claim 1, wherein the surfactant is: (e) a non-ionic lipid selected from the group consisting of (a) a pharmaceutically acceptable ionic Surfactant, a phar glyceryl laurate, glyceryl myristate, glyceryl dilaurate, maceutically acceptable nonionic Surfactant, a pharma glyceryl dimyristate, semi-synthetic derivatives thereof, ceutically acceptable cationic Surfactant, a pharmaceu and mixtures thereof tically acceptable ionic Surfactant, a pharmaceutically (f) a polyoxyethylene fatty ether having a polyoxyethylene acceptable anionic Surfactant, or a pharmaceutically head group ranging from about 2 to about 100 groups; acceptable Zwitterionic Surfactant; (g) an alkoxylated alcohol having the structure shown in (b) a pharmaceutically acceptable ionic polymeric Surfac formula I below: tant, a pharmaceutically acceptable nonionic polymeric Surfactant, a pharmaceutically acceptable cationic poly Rs (OCH2CH2), OH Formula I meric Surfactant, a pharmaceutically acceptable anionic wherein Rs is a branched or unbranched alkyl group having polymeric Surfactant, or a pharmaceutically acceptable from about 6 to about 22 carbon atoms and y is between Zwitterionic polymeric Surfactant; about 4 and about 100, and preferably, between about 10 (c) a polymeric Surfactant which is selected from the group and about 100: consisting of a graft copolymer of a poly(methyl meth (h) analkoxylated alcohol which is an ethoxylated deriva acrylate) backbone with at least one polyethylene oxide tive of lanolin alcohol; (PEO) side chain, polyhydroxystearic acid, an alkoxy (i) is nonionic and is selected from the group consisting of lated alkyl phenol formaldehyde condensate, a poly nonoxynol-9, an ethoxylated Surfactant, an alcohol alkylene glycol modified polyester with fatty acid ethoxylated, an alkyl phenol ethoxylated, a fatty acid hydrophobes, a polyester, semi-synthetic derivatives ethoxylated, a monoalkaolamide ethoxylated, a Sorbitan thereof, and combinations thereof; ester ethoxylated, a fatty amino ethoxylated, an ethylene (d) selected from the group consisting of ethoxylated non oxide-propylene oxide copolymer, Bis(polyethylene ylphenol comprising 9 to 10 units of ethyleneglycol, glycol bisimidazoyl carbonyl), BrijR 35, BrijR 56, ethoxylated undecanol comprising 8 units of ethyleneg BrijR 72, Brij(R 76, BrijR 92V, Brij.R. 97, BrijR 58P. lycol, polyoxyethylene (20) Sorbitan monolaurate, poly Cremophor R EL, Decaethylene glycol monododecyl oxyethylene (20) Sorbitan monopalmitate, polyoxyeth ether, N-Decanoyl-N-methylglucamine, n-Decyl alpha ylene (20) sorbitan monostearate, polyoxyethylene (20) D-glucopyranoside, Decyl beta-D-maltopyranoside, Sorbitan monooleate, Sorbitan monolaurate, Sorbitan n-Dodecanoyl-N-methylglucamide, n-Dodecyl alpha monopalmitate, Sorbitan monostearate, Sorbitan D-maltoside, n-Dodecyl beta-D-maltoside, Heptaethyl monooleate, ethoxylated hydrogenated ricin oils, ene glycol monodecyl ether, Heptaethylene glycol sodium laurylsulfate, a diblock copolymer of ethyl monotetradecyl ether, Heptaethylene glycol monodode eneoxyde and propyleneoxyde, Ethylene Oxide-Propy cyl ether, n-Hexadecyl beta-D-maltoside, Hexaethylene lene Oxide Block Copolymers, and tetra-functional glycol monododecyl ether, Hexaethylene glycol mono block copolymers based on ethylene oxide and propy hexadecyl ether, Hexaethylene glycol monooctadecyl lene oxide, Glyceryl monoesters, Glyceryl caprate, ether, Hexaethylene glycol monotetradecyl ether, Igepal US 2012/0064136 A1 Mar. 15, 2012 26

CA-630, Methyl-6-O-(N-heptylcarbamoyl)-alpha-D- Dodecyltrimethylammonium bromide, Ethylhexade glucopyranoside, Nonaethylene glycol monododecyl cyldimethylammonium bromide, Girard's reagent T. ether, N-Nonanoyl-N-methylglucamine, Octaethylene Hexadecyltrimethylammonium bromide, N,N',N'-Poly glycol monodecyl ether, Octaethylene glycol mon oxyethylene(10)-N-tallow-1,3-diaminopropane, ododecyl ether, Octaethylene glycol monohexadecyl Thonzonium bromide, Trimethyl(tetradecyl)ammo ether, Octaethylene glycol monooctadecyl ether, Octa nium bromide, 1,3,5-Triazine-1,3,5(2H4H.6H)-trietha ethylene glycol monotetradecyl ether, Octyl-beta-D- nol, 1-Decanaminium, N-decyl-N,N-dimethyl-, chlo glucopyranoside, Pentaethylene glycol monodecyl ride, Didecyl dimethyl ammonium chloride, 2-(2-(p- ether, Pentaethylene glycol monododecyl ether, Penta (Diisobutyl)cresoSXy)ethoxy)ethyl dimethyl benzyl ethylene glycol monohexadecyl ether, Pentaethylene ammonium chloride, 2-(2-(p-(Diisobutyl)phenoxy) glycol monohexyl ether, Pentaethylene glycol monooc ethoxy)ethyl dimethyl benzyl ammonium chloride, tadecyl ether, Pentaethylene glycol monooctyl ether, Alkyl 1 or 3 benzyl-1-(2-hydroxethyl)-2-imidazolinium Polyethylene glycol diglycidyl ether, Polyethylene gly chloride, Alkyl bis(2-hydroxyethyl)benzyl ammonium col ether W-1, Polyoxyethylene 10 tridecyl ether, Poly chloride, Alkyl demethyl benzyl ammonium chloride, oxyethylene 100 stearate, Polyoxyethylene 20 isohexa Alkyl dimethyl 3,4-dichlorobenzyl ammonium chloride decyl ether, Polyoxyethylene 20 oleyl ether, (100% C12), Alkyl dimethyl 3,4-dichlorobenzyl ammo Polyoxyethylene 40 stearate, Polyoxyethylene 50 stear nium chloride (50% C14, 40% C12, 10% C16), Alkyl ate, Polyoxyethylene 8 stearate, Polyoxyethylene bis dimethyl 3,4-dichlorobenzyl ammonium chloride (55% (imidazolyl carbonyl), Polyoxyethylene 25 propylene C14, 23% C12, 20% C16), Alkyl dimethyl benzyl glycol stearate, Saponin from Quillaja bark, SpanR 20, ammonium chloride, Alkyl dimethylbenzyl ammonium Span R 40, Span(R) 60, Span(R) 65, Span R 80, Span(R) 85, chloride (100% C14), Alkyl dimethyl benzyl ammo Tergitol, Tergitol, Type 15-S-12, Tergitol, Type 15-S-30, nium chloride (100% C16), Alkyl dimethyl benzyl Tergitol, Type 15-S-5, Tergitol, Type 15-S-7, Tergitol, ammonium chloride (41% C14, 28% C12), Alkyl dim Type 15-S-9, Tergitol, TypeNP-10, Tergitol, Type NP-4, ethylbenzyl ammonium chloride (47% C12, 18% C14), Tergitol, Type NP-40, Tergitol, Type NP-7, Tergitol, Alkyl dimethylbenzyl ammonium chloride (55% C16, Type NP-9, Tergitol, Type TMN-10, Tergitol, Type 20% C14), Alkyl dimethylbenzyl ammonium chloride TMN-6, Tetradecyl-beta-D-maltoside, Tetraethylene (58% C14, 28% C16), Alkyl dimethyl benzyl ammo glycol monodecyl ether, Tetraethylene glycol mon nium chloride (60% C14, 25% C12), Alkyl dimethyl ododecyl ether, Tetraethylene glycol monotetradecyl benzyl ammonium chloride (61% C11, 23% C14), Alkyl ether, Triethylene glycol monodecyl ether, Triethylene dimethyl benzyl ammonium chloride (61% C12, 23% glycol monododecyl ether, Triethylene glycol mono C14), Alkyl dimethylbenzyl ammonium chloride (65% hexadecyl ether, Triethylene glycol monooctyl ether, C12, 25% C14), Alkyl dimethyl benzyl ammonium Triethylene glycol monotetradecyl ether, Triton CF-21, chloride (67% C12, 24% C14), Alkyl dimethylbenzyl Triton CF-32, Triton DF-12, Triton DF-16, Triton ammonium chloride (67% C12, 25% C14), Alkyl dim GR-5M, Triton QS-15, Triton QS-44, TritonX-100, Tri ethylbenzyl ammonium chloride (90% C14, 5% C12), ton X-102, Triton X-15, Triton X-151, Triton X-200, Alkyl dimethylbenzyl ammonium chloride (93%. C14, Triton X-207, Triton X-114, Triton X-165, Triton 4% C12), Alkyl dimethyl benzyl ammonium chloride X-305, Triton X-405, Triton X-45, Triton X-705-70, (95%C16, 5% C18), Alkyl didecyl dimethylammonium TWEENR) 20, TWEENR 21, TWEENR 40, TWEENR) chloride, Alkyl dimethyl benzyl ammonium chloride 60, TWEENR 61, TWEENR) 65, TWEENR 80, (C12-16), Alkyl dimethyl benzyl ammonium chloride TWEENR 81, TWEENR 85, Tyloxapol, n-Undecyl (C12-18), dialkyl dimethylbenzyl ammonium chloride, beta-D-glucopyranoside, Poloxamer 101, Poloxamer Alkyl dimethyl dimethybenzyl ammonium chloride, 105, Poloxamer 108, Poloxamer 122, Poloxamer 123, Alkyl dimethyl ethyl ammonium bromide (90% C14, Poloxamer 124, Poloxamer 181, Poloxamer 182, Polox 5% C16, 5% C12), Alkyl dimethyl ethyl ammonium amer 183, Poloxamer 184, Poloxamer 185, Poloxamer bromide (mixed alkyl and alkenyl groups as in the fatty 188, Poloxamer 212, Poloxamer 215, Poloxamer 217, acids of soybean oil), Alkyl dimethyl ethylbenzyl Poloxamer 231, Poloxamer 234, Poloxamer 235, Polox ammonium chloride, Alkyl dimethyl ethylbenzyl amer 237, Poloxamer 238, Poloxamer 282, Poloxamer ammonium chloride (60% C14), Alkyl dimethyl isopro 284, Poloxamer 288, Poloxamer 331, Poloxamer 333, pylbenzyl ammonium chloride (50% C12, 30% C14, Poloxamer 334, Poloxamer 335, Poloxamer 338, Polox 17% C16, 3% C18), Alkyl trimethyl ammonium chlo amer 401, Poloxamer 402, Poloxamer 403, Poloxamer ride (58% C18, 40% C16, 1% C14, 1% C12), Alkyl 407, Poloxamer 105 Benzoate, Poloxamer 182 Diben trimethyl ammonium chloride (90% C18, 10% C16), Zoate, semi-synthetic derivatives thereof, and combina Alkyldimethyl(ethylbenzyl) ammonium chloride (C12 tions thereof; 18), Di-(C8-10)-alkyl dimethyl ammonium chlorides, () the Surfactant is cationic and is selected from the group Dialkyl dimethyl ammonium chloride, Dialkyl methyl consisting of a quarternary ammonium compound, an benzyl ammonium chloride, Didecyl dimethyl ammo alkyl trimethyl ammonium chloride compound, a nium chloride, Diisodecyl dimethyl ammonium chlo dialkyl dimethyl ammonium chloride compound, Ben ride, Dioctyl dimethyl ammonium chloride, Dodecyl Zalkonium chloride, Benzyldimethylhexadecylammo bis(2-hydroxyethyl) octyl hydrogen ammonium chlo nium chloride, Benzyldimethyltetradecylammonium ride, Dodecyl dimethyl benzyl ammonium chloride, chloride, Benzyldodecyldimethylammonium bromide, Dodecylcarbamoyl methyl dimethylbenzyl ammonium Benzyltrimethylammonium tetrachloroiodate, cetylpy chloride, Heptadecyl hydroxyethylimidazolinium chlo ridinium chloride, Dimethyldioctadecylammonium ride, Hexahydro-1,3,5-tris(2-hydroxyethyl)-s-triazine, bromide, Dodecylethyldimethylammonium bromide, Myristalkonium chloride (and) Quat RNIUM 14, N.N- US 2012/0064136 A1 Mar. 15, 2012 27

Dimethyl-2-hydroxypropylammonium chloride poly (c) the concentration of the cationic surfactant is selected mer, n-Tetradecyl dimethylbenzyl ammonium chloride from the group consisting of less than about 5%, less monohydrate, Octyl decyl dimethyl ammonium chlo than about 4.5%, less than about 4.0%, less than about ride, Octyl dodecyl dimethyl ammonium chloride, 3.5%, less than about 3.0%, less than about 2.5%, less Octyphenoxyethoxyethyl dimethyl benzyl ammonium than about 2.0%, less than about 1.5%, less than about chloride, Oxydiethylenebis(alkyl dimethyl ammonium 1.0%, less than about 0.90%, less than about 0.80%, less chloride), Trimethoxysily propyl dimethyl octadecyl than about 0.70%, less than about 0.60%, less than about ammonium chloride, Trimethoxysilyl quats, Trimethyl 0.50%, less than about 0.40%, less than about 0.30%, dodecylbenzyl ammonium chloride, semi-synthetic less than about 0.20%, less than about 0.10%, greater derivatives thereof, and combinations thereof; than about 0.002%, greater than about 0.003%, greater (k) the Surfactant is anionic and is selected from the group than about 0.004%, greater than about 0.005%, greater consisting of a carboxylate, a sulphate, a sulphonate, a than about 0.006%, greater than about 0.007%, greater phosphate, Chenodeoxycholic acid, Chenodeoxycholic than about 0.008%, greater than about 0.009%, greater acid sodium salt, Cholic acid, ox or sheep bile, Dehy than about 0.010%, and greater than about 0.001%; or drocholic acid, Deoxycholic acid, Deoxycholic acid (d) any combination thereof. methyl ester, Digitonin, Digitoxigenin, N,N-Dimethyl 19. The method of claim 1, wherein the nanoemulsion dodecylamine N-oxide, Docusate sodium salt, Glyco comprises at least one cationic surfactant and at least one chenodeoxycholic acid sodium salt, Glycocholic acid non-cationic surfactant. hydrate, synthetic, Glycocholic acid sodium salt 20. The method of claim 19, wherein: hydrate, synthetic, Glycodeoxycholic acid monohy (a) the non-cationic surfactant is a nonionic surfactant; drate, Glycodeoxycholic acid sodium salt, Glycolitho (b) the non-cationic surfactant is a nonionic surfactant cholic acid 3-sulfate disodium salt, Glycolithocholic which is a polysorbate; acid ethyl ester, N-Lauroylsarcosine sodium salt, (c) the non-cationic surfactant is a nonionic surfactant N-Lauroylsarcosine solution, Lithium dodecyl sulfate, which is polysorbate 20 or polysorbate 80 or polysorbate Lugol solution, Niaproof 4. Type 4.1-Octanesulfonic 60; acid sodium salt, Sodium 1-butanesulfonate, Sodium (d) the non-cationic surfactant is a nonionic surfactant and 1-decanesulfonate, Sodium 1-dodecanesulfonate, the non-ionic surfactant is present in a concentration of Sodium 1-heptanesulfonate anhydrous, Sodium about 0.05% to about 7.0%: 1-nonanesulfonate, Sodium 1-propanesulfonate mono (e) the non-cationic surfactant is a nonionic surfactant and hydrate, Sodium 2-bromoethanesulfonate, Sodium cho the non-ionic surfactant is present in a concentration of late hydrate, Sodium choleate, Sodium deoxycholate, about 0.5% to about 4%; Sodium deoxycholate monohydrate, Sodium dodecyl (f) the cationic surfactant is present in a concentration of Sulfate, Sodium hexanesulfonate anhydrous, Sodium about 0.5% to about 2%, or octyl sulfate, Sodium pentanesulfonate anhydrous, (f) any combination thereof. Sodium taurocholate, Taurochenodeoxycholic acid 21. The method of claim 1, wherein the nanoemulsion Sodium salt, Taurodeoxycholic acid sodium salt mono further comprises: hydrate, Taurohyodeoxycholic acid sodium salt hydrate, (a) at least one preservative; Taurolithocholic acid 3-sulfate disodium salt, Taurour (b) at least one a pH adjuster; Sodeoxycholic acid sodium salt, Trizma(R) dodecyl sul (c) at least pharmaceutically acceptable buffer; fate, Ursodeoxycholic acid, semi-synthetic derivatives (d) at least one chelating agent; thereof, and combinations thereof; (e) at least one silicone component; or (1) the surfactant is Zwitterionic and is selected from the (d) any combination thereof. group consisting of an N-alkyl betaine, lauryl amindo 22. The method of claim 21, wherein: propyl dimethyl betaine, an alkyl dimethylglycinate, an (a) the preservative is selected from the group consisting of N-alkyl amino propionate. CHAPS, minimum 98%, cetylpyridinium chloride, benzalkonium chloride, ben CHAPS, minimum 98%. CHAPS, for electrophoresis, Zyl alcohol, chlorhexidine, imidazolidinyl urea, phenol, minimum 98%. CHAPSO, minimum 98%, CHAPSO, potassium sorbate, benzoic acid, bronopol, chlorocre CHAPSO, for electrophoresis, 3-(Decyldimethylam Sol, paraben esters, phenoxyethanol, sorbic Acid, alpha monio)propanesulfonate inner salt, 3-(Dodecyldim tocophernol, ascorbic acid, ascorbyl palmitate, buty ethylammonio)propanesulfonate inner salt, inner salt, lated hydroxyanisole, butylated hydroxytoluene, 3-(N,N-Dimethylmyristylammonio)propanesulfonate, Sodium ascorbate, sodium metabisulphite, citric acid, 3-(N,N-Dimethyloctadecylammonio)propane edetic acid, semi-synthetic derivatives thereof, and com sulfonate, 3-(N,N-Dimethyloctylammonio)propane binations thereof; sulfonate inner salt, 3-(N,N-Dimethylpalmitylammo (b) the pH adjuster is selected from the group consisting of nio)propanesulfonate, semi-synthetic derivatives diethyanolamine, lactic acid, monoethanolamine, tri thereof, and combinations thereof; or ethylanolamine, sodium hydroxide, sodium phosphate, (m) any combination thereof. semi-synthetic derivatives thereof, and combinations 17. The method of claim 1, wherein the nanoemulsion thereof; comprises at least one cationic surfactant. (c) the buffer is selected from the group consisting of 18. The method of claim 17, wherein the nanoemulsion 2-Amino-2-methyl-1,3-propanediol, 299.5% (NT), comprises a cationic surfactant, and wherein: 2-Amino-2-methyl-1-propanol, 299.0% (GC), L-(+)- (a) the cationic surfactant is cetylpyridinium chloride; Tartaric acid, 299.5% (T), ACES, 299.5% (T), ADA, (b) the concentration of the cationic surfactant is less than 299.0% (T), Acetic acid, 299.5% (GC/T), Acetic acid, about 5.0% and greater than about 0.001%; for luminescence, 299.5% (GC/T), Ammonium acetate US 2012/0064136 A1 Mar. 15, 2012 28

solution, for molecular biology, ~5 M in H2O, Ammo in H2O, Potassium acetate solution, for molecular biol nium acetate, for luminescence, 299.0% (calc. on dry ogy, ~1 M in HO, Potassium acetate, 299.0% (NT), substance. T), Ammonium bicarbonate, 299.5% (T), Potassium acetate, for luminescence, 299.0% (NT), Ammonium citrate dibasic, 299.0% (T), Ammonium Potassium acetate, for molecular biology, 299.0% formate solution, 10 M in HO, Ammonium formate, (NT), Potassium bicarbonate, 299.5% (T), Potassium 299.0% (calc. based on dry substance, NT). Ammo carbonate, anhydrous, 299.0% (T), Potassium chloride, nium oxalate monohydrate, 299.5% (RT), Ammonium 299.5% (AT), Potassium citrate monobasic, 299.0% phosphate dibasic solution, 2.5 M in H2O, Ammonium (dried material, NT), Potassium citrate tribasic solution, phosphate dibasic, 299.0% (T), Ammonium phosphate 1 M in H2O, Potassium formate solution, 14 Min H2O, monobasic solution, 2.5 M in HO. Ammonium phos Potassium formate, 299.5% (NT), Potassium oxalate phate monobasic, 299.5% (T), Ammonium sodium monohydrate, 299.0% (RT), Potassium phosphate phosphate dibasic tetrahydrate, 299.5% (NT), Ammo dibasic, anhydrous, 299.0% (T), Potassium phosphate nium sulfate solution, for molecular biology, 3.2 M in dibasic, for luminescence, anhydrous, 299.0% (T), H2O, Ammonium tartrate dibasic solution, 2 M in HO Potassium phosphate dibasic, for molecular biology, (colorless solution at 20° C.), Ammonium tartrate diba anhydrous, 299.0% (T), Potassium phosphate monoba sic, 299.5% (T), BES buffered saline, for molecular sic, anhydrous, 299.5% (T), Potassium phosphate biology, 2x concentrate, BES, 299.5% (T), BES, for monobasic, for molecular biology, anhydrous, 299.5% molecular biology, 299.5% (T), BICINE buffer Solu (T), Potassium phosphate tribasic monohydrate, 2.95% tion, for molecular biology, 1 M in HO, BICINE, 299. (T), Potassium phthalate monobasic, 299.5% (T), 5% (T), BIS-TRIS, 299.0% (NT), Bicarbonate buffer Potassium sodium tartrate solution, 1.5 M in H.O. solution, 20.1 M NaCO, 20.2 M NaHCO Boric Potassium sodium tartrate tetrahydrate, 299.5% (NT), acid, 299.5% (T), Boric acid, for molecular biology, Potassium tetraborate tetrahydrate, 299.0% (T), Potas 299.5% (T), CAPS, 299.0% (TLC), CHES, 299.5% sium tetraoxalate dihydrate, 299.5% (RT), Propionic (T), Calcium acetate hydrate, 299.0% (calc. on dried acid solution, 1.0 M in HO, STE buffer solution, for material, KT), Calcium carbonate, precipitated, 299. molecular biology, pH 7.8, STET buffer solution, for 0% (KT), Calcium citrate tribasic tetrahydrate, 298.0% molecular biology, pH 8.0, Sodium 5,5-diethylbarbitu (calc. on dry substance, KT), Citrate Concentrated Solu rate, 299.5% (NT), Sodium acetate solution, for tion, for molecular biology, 1 M in H2O, Citric acid, molecular biology, ~3 M in HO, Sodium acetate trihy anhydrous, 299.5% (T), Citric acid, for luminescence, drate, 299.5% (NT), Sodium acetate, anhydrous, 299. anhydrous, 299.5% (T), Diethanolamine, 299.5% 0% (NT), Sodium acetate, for luminescence, anhydrous, (GC), EPPS, 299.0% (T), Ethylenediaminetetraacetic 299.0% (NT), Sodium acetate, for molecular biology, acid disodium salt dihydrate, for molecular biology, anhydrous, 299.0% (NT), Sodium bicarbonate, 299. 299.0% (T), Formic acid solution, 1.0 M in HO, Gly 5%. (T), Sodium bitartrate monohydrate, 299.0% (T), Gly-Gly, 299.0% (NT), Gly-Gly, 299.5% (NT), Gly Sodium carbonate decahydrate, 299.5% (T), Sodium cine, 299.0% (NT), Glycine, for luminescence, 299. carbonate, anhydrous, 299.5% (calc. on dry substance, 0% (NT), Glycine, for molecular biology, 299.0% T), Sodium citrate monobasic, anhydrous, 299.5% (T), (NT), HEPES buffered saline, for molecular biology, 2x Sodium citrate tribasic dihydrate, 299.0% (NT), concentrate, HEPES, 299.5% (T), HEPES, for molecu Sodium citrate tribasic dihydrate, for luminescence, lar biology, 299.5% (T), Imidazole buffer Solution, 1 M 299.0% (NT), Sodium citrate tribasic dihydrate, for in H.O., Imidazole, 299.5% (GC), Imidazole, for lumi molecular biology, 299.5% (NT), Sodium formate nescence, 299.5% (GC), Imidazole, for molecular biol solution, 8 M in HO, Sodium oxalate, 299.5% (RT), ogy, 299.5% (GC), Lipoprotein Refolding Buffer, Sodium phosphate dibasic dihydrate, 299.0% (T), Lithium acetate dihydrate, 299.0% (NT), Lithium cit Sodium phosphate dibasic dihydrate, for luminescence, rate tribasic tetrahydrate, 299.5% (NT), MES hydrate, 299.0% (T), Sodium phosphate dibasic dihydrate, for 299.5% (T), MES monohydrate, for luminescence, molecular biology, 299.0% (T), Sodium phosphate 299.5% (T), MES solution, for molecular biology, 0.5 dibasic dodecahydrate, 299.0% (T), Sodium phosphate M in HO, MOPS, 299.5% (T), MOPS, for lumines dibasic solution, 0.5M in HO, Sodium phosphate diba cence, 299.5% (T),MOPS, for molecular biology, 299. sic, anhydrous, 299.5% (T), Sodium phosphate dibasic, 5%. (T), Magnesium acetate solution, for molecular biol for molecular biology, 299.5% (T), Sodium phosphate ogy, ~1 M in H2O, Magnesium acetate tetrahydrate, monobasic dihydrate, 299.0% (T), Sodium phosphate 299.0% (KT), Magnesium citrate tribasic nonahydrate, monobasic dihydrate, for molecular biology, 299.0% 298.0% (calc. based on dry substance, KT), Magne (T), Sodium phosphate monobasic monohydrate, for sium formate solution, 0.5M in HO, Magnesium phos molecular biology, 299.5% (T), Sodium phosphate phate dibasic trihydrate, 298.0% (KT), Neutralization monobasic solution, 5 M in HO, Sodium pyrophos solution for the in-situ hybridization for in-situ hybrid phate dibasic, 299.0% (T), Sodium pyrophosphate tet ization, for molecular biology, Oxalic acid dihydrate, rabasic decahydrate, 299.5% (T), Sodium tartrate diba 299.5% (RT), PIPES,299.5% (T), PIPES, for molecu sic dihydrate, 299.0% (NT), Sodium tartrate dibasic lar biology, 299.5% (T), Phosphate buffered saline, solution, 1.5 M in HO (colorless solution at 20° C.), solution (autoclaved), Phosphate buffered saline, wash Sodium tetraborate decahydrate, 299.5% (T), TAPS, ing buffer for peroxidase conjugates in Western Blot 299.5% (T), TES, 299.5% (calc. based on dry sub ting, 10x concentrate, piperazine, anhydrous, 299.0% stance, T), TM buffer solution, for molecular biology, (T), Potassium D-tartrate monobasic, 299.0% (T), pH 7.4, TNT buffer solution, for molecular biology, pH Potassium acetate solution, for molecular biology, 8.0, TRIS Glycine buffer solution, 10x concentrate, Potassium acetate solution, for molecular biology, 5 M TRIS acetate—EDTA buffer solution, for molecular US 2012/0064136 A1 Mar. 15, 2012 29

biology, TRIS buffered saline, 10x concentrate, TRIS (iii) the silicone component is selected from the group glycine SDS buffer solution, for electrophoresis, 10x consisting of methylphenylpolysiloxane, simethi concentrate, TRIS phosphate EDTA buffer solution, cone, dimethicone, phenyltrimethicone (or an orga for molecular biology, concentrate, 10x concentrate, nomodified version thereof), alkylated derivatives of Tricine, 299.5% (NT), Triethanolamine, 299.5% polymeric silicones, cetyl dimethicone, lauryl trime (GC), Triethylamine, 299.5% (GC), Triethylammo thicone, hydroxylated derivatives of polymeric sili nium acetate buffer, volatile buffer, ~1.0 M in H.O. cones, such as dimethiconol, Volatile silicone oils, Triethylammonium phosphate solution, volatile buffer, cyclic and linear silicones, cyclomethicone, deriva ~1.0 M in HO, Trimethylammonium acetate solution, tives of cyclomethicone, hexamethylcyclotrisiloxane, volatile buffer, ~1.0 M in H2O, Trimethylammonium octamethylcyclotetrasiloxane, decamethylcyclopen phosphate solution, volatile buffer, ~1 M in HO, Tris tasiloxane, Volatile linear dimethylpolysiloxanes, iso EDTA buffer solution, for molecular biology, concen hexadecane, isoeicosane, isotetracosane, poly trate, 100x concentrate, Tris-EDTA buffer solution, for isobutene, isooctane, isododecane, semi-synthetic molecular biology, pH 7.4, Tris-EDTA buffer solution, derivatives thereof, and combinations thereof, or for molecular biology, pH 8.0, Trizma Racetate, 299. (f) any combination thereof. 0% (NT), Trizma(R) base, 299.8% (T), Trizma(R) base, 23. The method of claim 1, wherein the water is present in 299.8% (T), Trizma R base, for luminescence, 299.8% Phosphate Buffered Saline (PBS). (T), Trizma R base, for molecular biology, 299.8% (T), 24. The method of claim 1, wherein the nanoemulsion is Trizma(R) carbonate, 298.5% (T), Trizma Rhydrochlo topically applied: ride buffer solution, for molecular biology, pH 7.2, (a) in a single administration; Trizma(R) hydrochloride buffer solution, for molecular (b) for at least once a week, at least twice a week, at least biology, pH 7.4, Trizma Rhydrochloride buffer solution, once a day, at least twice a day, multiple times daily, for molecular biology, pH 7.6, Trizma(R) hydrochloride multiple times weekly, biweekly, at least once a month, buffer solution, for molecular biology, pH 8.0, Trizma(R) or any combination thereof; hydrochloride, 299.0% (AT), Trizma(R) hydrochloride, (c) for a period of time selected from the group consisting for luminescence, 299.0% (AT), Trizma(R) hydrochlo of about one week, about two weeks, about three weeks, ride, for molecular biology, 299.0% (AT), and Trizma(R) about one month, about two months, about three months, maleate, 299.5% (NT): about four months, about five months, about six months, (d) the chelating agent (i) is present in an amount of about about seven months, about eight months, about nine 0.0005% to about 1.0%; (ii) is selected from the group months, about ten months, about eleven months, about consisting of ethylenediamine, ethylenediaminetet one year, about 1.5 years, about 2 years, about 2.5 years, raacetic acid, and dimercaprol; or (iii) a combination about 3 years, about 3.5 years, about 4 years, about 4.5 thereof; years, and about 5 years; (e) the silicone component comprises at least one volatile (d) followed by washing the application area to remove any silicone oil, wherein: residual nanoemulsion; or (i) the volatile silicone oil can be the sole oil in the (f) any combination thereof. silicone component or it can be combined with other 25. The method of claim 1, wherein the nanoemulsion silicone and non-silicone oils, and wherein the other droplets enter the pilosebaeous gland (unit), hair follicle, oils can be volatile or non-volatile; epidermis, dermis, or a combination thereof. (ii) the volatile oil used in the silicone component is different than the oil in the oil phase; c c c c c