Compositions and use thereof for treating a chemotherapy induced symptom, complication or side effect

Abstract

The disclosure relates generally to compositions comprising a CDA inhibitor, e.g., tetrahydrouridine or an analog or derivative thereof, and methods for treating, reducing or inhibiting a symptom, complication or side effect, such as palmar-plantar erythrodysesthesia, caused by chemotherapy, such as 5-fluorouracil chemotherapy, especially, capecitabine chemotherapy, by administering a CDA inhibitor, e.g., tetrahydrouridine or an analog or derivative thereof. The disclosure also relates to treating cancer by co-administering capecitabine and a CDA inhibitor, e.g., tetrahydrouridine or an analog or derivative thereof to a subject.

Description

Attorney Docket No.: 102577-000100WOPTCOMPOSITIONS AND USE THEREOF FOR TREATING A CHEMOTHERAPY INDUCED SYMPTOM, COMPLICATION OR SIDE EFFECTCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit under 35 U. S. C. § 119(e) of U. S. Provisional Application No. 63 / 572,701 filed April 1, 2024, the contents of which are incorporated herein by reference in their entireties.TECHNICAL FIELD

[0002] The disclosure relates generally to compositions, kits and methods for treating, reducing or inhibiting a symptom, complication or side effect caused by chemotherapy, such as 5-fluorouracil chemotherapy, especially, capecitabine chemotherapy.BACKGROUND

[0003] Thus, there is a need in the art for composition and methods for treating, reducing or inhibiting a symptom, complication or side effect for chemotherapy induced by chemotherapy, such as those due to 5-fluorouracil chemotherapy, and especially, those induced by capecitabine chemotherapy. The present disclosure addresses this need.SUMMARY

[0004] In one aspect, provided herein is a composition comprising a CDA inhibitor and formulated for topical administration, e.g., for applying to the skin of a subject. In some embodiments, the topical formulation is in the form of a lotion, cream, solution, gel, emugel, oil, serum, powder, ointment, suspension, slurry, paste, spray, dispersion, or foam. For example, the topical formulation is in form of a dermatological ointment. In some embodiments, the topical formulation is in the form of a transdermal patch or a controlled-release patch.

[0005] In another aspect, provided herein a composition comprising a CDA inhibitor and capecitabine, and formulated for oral administration to a subject.

[0006] In yet another aspect, provided herein is method for treating, reducing or inhibiting a symptom, complication or side effect caused by chemotherapy, e.g., caused by 5-FU chemotherapy, such as caused by capecitabine chemotherapy. The method comprises: administering an effective amount of a CDA inhibitor to a subject in need thereof. It is noted, the CDA inhibitor can be administered locally, (e.g., applied topically4922-4270-5705 1 1Attorney Docket No.: 102577-000100WOPTto the skin, such as applied topically to the skin of the hands or feet) or systemically (e.g., administered orally) to the subject in need.

[0007] In still another aspect, provided herein is a method for treating a cancer, treating cancer. The method comprises co-administering an effective amount of capecitabine and an effective amount of a CDA inhibitor to a subject in need thereof.

[0008] In yet still another aspect, provided herein is a method for treating palmar-plantar erythrodysesthesia, e.g., chemotherapy induced palmar-plantar erythrodysesthesia. The method comprises administering an effective amount of a CDA inhibitor to a subject in need thereof. In some embodiments, the palmar-plantar erythrodysesthesia is 5-fluorouracil chemotherapy induced palmar-plantar erythrodysesthesia. For example, the palmar-plantar erythrodysesthesia is capecitabine chemotherapy induced palmar-plantar erythrodysesthesia.

[0009] In another aspect, provided herein is a kit comprising: (i) a CDA inhibitor: and (ii) a and (ii) at least one of capecitabine, an anti-inflammatory agent, or an agent for treating a side effect of capecitabine.

[0010] Any CDA inhibitor known in the art can be used in the compositions and methods described herein. Exemplary CDA inhibitors are described, for example, in US Pat. No. 8,268,800; No. 5,223,608, No. 5,521,294; No. 5,530,110; No. 5,594,124; No.5,606,048; No. 5,637,688; No. 5,821,357; No. 5,932,719; and No. 7,125,983, contents of all of which are incorporated herein by reference in their entireties. In embodiments of the various aspects described herein, the CDA inhibitor can be tetrahydrouridine (THU); THU analog or derivative; ASTX727 (E7727); 5-methyl-2',3'-dideoxy-3'-azidocytidine (5mAZC); 5-methyl-2',3'-dideoxycytidine; 5-ethyl-2',3'dideoxy-3'-azidocytidine; 5-propyl-2',3'-dideoxycytidine; 5-propyl-2',3'-dideoxy-3'-azidocytidine; 5-propene-2',3'-dideoxy-3'-azidocytidine; 5-propyne-2',3'-dideoxy-3'-azidocytidine; 5-propyne-2',3'-dideoxy-3'-azidocytidine; Zebularine; or any combination thereof. For example, the CDA inhibitor is tetrahydrouridine, or a fluorinated derivative thereof. In some embodiments of any one of the aspects described herein, the CDA inhibitor is tetrahydrouridine, 2'-fluoro-2’-deoxytetrahydrouridine, or 2’-deoxy-2',2'-difluorotetrahydrouridine. For example, the CDA inhibitor can be tetrahydrouridine; 2',2'-difluoro-dihydrouridine (DFDHU); 2', 2'-difluoro-tetrahydrouridine (DFTHU); 2'(R)-fluoro-2’-deoxy-tetrahydrouridine; 2'(R)-fluoro-2’-deoxy-dihydrouridine ((R)-FDHU); 2'(S)-fluoro-2’-deoxy-tetrahydrouridine; 2'(S)-fluoro-2’-deoxy-dihydrouridine ((S)-FDHU); 2'(S)-fluoro-2’-deoxy-tetrahydrouridine ((S)-FTHU); 2’-deoxy-2',2'-difluoro-5,6-dihydrouridine; (4R)-2’-deoxy-2',2'-difluoro-3, 4,5,6-tetrahydrouridine; (4S)-2’-deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine; 1 -(2-Deoxy-2,2-4922-4270-5705 1 2Attorney Docket No.: 102577-000100WOPTdifluoro-p-D-erythro-pentofuranosyl)-tetrahydro-2(1H)-pyrimidinone; 2’-deoxy-2'-fluoro-5,6-dihydrouridine; (4R)-2’-deoxy-2'-fluoro-3,4,5,6-tetrahydrouridine; (4S)-2’-deoxy-2'-fluoro-3,4,5,6-tetrahydrouridine; 1 -(2-deoxy-2-fluoro-(3-D-ribofuranosyl)tetrahydro-2(1 H)-pyrimidinone; 1 -(2-deoxy-2-fluoro-p-D-arabinofuranosyl)dihydro-2,4-(1 H,3H)-pyrimidinedione; (4R)-1-(2-deoxy-2-fluoro-(3-D-arabinofuranosyl)tetrahydro-4-hydroxy-2(1 H)-pyrimidinone; (4S)-1 -(2-deoxy-2-fluoro-(3-D-arabinofuranosyl)tetrahydro-4-hydroxy-2(1H)-pyrimidinone; or any combination thereof. In some embodiments of any one of the aspects described herein, the CDA inhibitor is tetrahydrouridine. In some embodiments, the CDA inhibitor is (4R)-2'-Deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 is a schematic showing capecitabine conversion into the active chemotherapeutic 5FU requires cytidine deaminase (CDA). Without wishing to be bound by a theory, CDA can be locally and reversibly inhibited by small molecule CDA-inhibitors, e.g., tetrahydrouridine (THU).

[0012] FIG. 2 shows the relationship between pharmacokinetics of oral THU 10 mg / kg and the pharmacodynamic effect of CDA-inhibition, measured by cytidine levels. THU and cytidine levels were measured by liquid chromatography-tandem mass spectrometry at the indicated time-points after ingestion of a single oral dose of THU 750 mg (~10 mg / kg) in 10 human subjects. Cytidine synthesized by the liver is normally rapidly deaminated into uridine by cytidine deaminase in the liver and other tissues; therefore, systemic inhibition of CDA by oral THU increases plasma cytidine levels, in a pattern that corresponds to THU pharmacokinetics.DETAILED DESCRIPTION

[0013] It should be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such can vary. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims.

[0014] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, and treatises, are hereby expressly incorporated by reference in their entirety for any purpose.4922-4270-5705 1 3Attorney Docket No.: 102577-000100WOPTTopical formulations

[0015] Topical formulations descried herein, generally have a pH of from about 4.5 to about 9.5. For example, the formulation has a pH of from about 5 to about 9, from about 5.5 to about 8.5, from about 6 to about 8, or from about 6.5 to about 7.5. In some embodiments, the formulation has a neutral pH. In some embodiments, the formulation has an acidic pH, e.g., the formulation has a pH of about 6.5, about 6, about 5.5, about 5, about 4.5, about 4 or lower. In some embodiments, the formulation has a basic pH, e.g., the formulation has a pH of about 7.5, about 8, about 8.5, about 9, about 9.5, about 10, about 10.5, about 11 or higher.

[0016] A topical formulation described herein can take any of a wide variety of forms, and include, for example, creams, lotions, solutions, sprays, gels, ointments, pastes and the like. For instance, creams, as is well known in the arts of pharmaceutical and cosmeceutical formulation, are viscous liquids or semisolid emulsions, either oil-in-water or water-in-oil. Cream bases are water-washable, and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, also called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant.

[0017] Lotions, which are preferred for delivery of cosmetic agents, are preparations to be applied to the skin surface without friction, and are typically liquid or semi-liquid preparations in which solid particles, including the active agent, are present in a water or alcohol base. Lotions are usually suspensions of solids, and preferably comprise a liquid oily emulsion of the oil-in-water type. Lotions are preferred formulations herein for treating large body areas, because of the ease of applying a more fluid composition. It is generally preferred that the insoluble matter in a lotion be finely divided. Lotions will typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin, e.g., methylcellulose, sodium carboxymethyl-cellulose, or the like.

[0018] Solutions are homogeneous mixtures prepared by dissolving one or more chemical substances (salutes) in a liquid such that the molecules of the dissolved substance are dispersed among those of the solvent. The solution may contain other pharmaceutically acceptable and / or cosmeceutically acceptable chemicals to buffer, stabilize or preserve the solute. Common examples of solvents used in preparing4922-4270-5705 1 4Attorney Docket No.: 102577-000100WOPTsolutions are ethanol water propylene glycol or any other pharmaceutically acceptable and / or cosmeceutically acceptable vehicles.

[0019] Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably, contain an alcohol, and, optionally, an oil. Preferred “organic macromolecules," i.e., gelling agents, may be chemically crosslinked polymers such as crosslinked acrylic acid polymers, for instance, the “carbomer” family of polymers, e.g., carboxypolyalkylenes, that may be obtained commercially under the Carbopoi® trademark. Also preferred in certain embodiments may be hydrophilic polymers such as polyethylene oxides, polyo.xyethylene-polyoxypropylene copolymers and polyvinylalcohol; cellulosic polymers such as hydroxypropyi cellulose, hydroxyethyi cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methyl cellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing or stirring, or combinations thereof.

[0020] Ointments, as also well known in the art, are semisoiid preparations that are typically based on petrolatum or other petroleum derivatives. The specific ointment base to be used, as will be appreciated by those skilled in the art, is one that will provide for a number of desirable characteristics, e.g., emoiliency or the like. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating, and nonsensitizing. As explained in Remington: The Science and Practice of Pharmacy, 19th Ed. (Easton, Pa.: Mack Publishing Co., 1995), at pages 1399 1404, ointment bases may be grouped in four classes: oleaginous bases: emulsifiable bases; emulsion bases; and water-soluble bases. Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin, and hydrophilic petrolatum. Emulsion ointment bases are either water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weight. See, for example, Remington: The Science and Practice of Pharmacy (23rded., Academic Press, Cambridge, MA, 2020), contents of which are incorporated herein by reference in their entireties.4922-4270-5705 1 5Attorney Docket No.: 102577-000100WOPT

[0021] Pastes are semisoiid dosage forms in which the active agent is suspended in a suitable base. Depending on the nature of the base, pastes are divided between fatty pastes er those made from single-phase aqueous geis. The base in a fatty paste is generally petroiaturn or hydrophilic petrolatum or the like. The pastes made from single-phase aqueous gels generally incorporate carboxymethylceiluiese or the like as a base.

[0022] Generally, the topical formulation comprises the CDA inhibitor in an amount from about 0.0005% to about 30% (w / w or w / v). For example, the topical formulation comprises the CDA inhibitor in an amount from about 0.001 % to about 25% (w / w or w / v), from about 0.0015% to about 25% (w / w or w / v), from 0.002% to about 15% (w / w or w / v), from about 0.0025% to about 10% (w / w or w / v), or any amount between 0.0005% to about 30% (w / w or w / v).

[0023] In some embodiments, the topical formulation comprises the CDA inhibitor in an amount from about 0.05% to about 30% (w / w or w / v). For example, the topical formulation comprises the CDA inhibitor in an amount from about 0.075% to about 25%, from about 0.1% to about 20%, from about 0.15% to about 15%, about 0.2% to about 10%, or any amount between 0.05% to about 30% (w / w or w / v). In some embodiments, the topical formulation comprises the CDA inhibitor in an amount about 0.05%, about 0.075%, about 0.1%, about 0.15%, about 0.175%, about 0.2%, about 0.25%, about 0.275%, about 0.3%, about 0.35%, about 0.375%, about 0.4%, about 0.45%, about 0.475%, about 0.5%, about 0.55%, about 0.575%, about 0.6%, about 0.65%, about 0.675%, about 0.7%, about 0.75%, about 0.775%, about 0.8%, about 0.85%. about 0.875%, about 0.9%, about 0.95%, about 0.975%, about 1%, about 1.05%, about 1.075%, about 1.1%, about 1.15%, about 1.175%, about 1.2%, about 1.25%, about 1.275%, about 1.3%, about 1.35%, about 1.375%, about 1.4%, about 1.45%, about 1.475%, about 1.5%, about 1.55%, about 1.575%, about 1.6%, about 1.65%, about 1.675%, about 1.7%, about 1.75%, about 1.775%, about 1.8%, about 1.85%, about 1.875%, about 1.9%, about 1.95%, about 1.975%, about 2%, about 2.05%, about 2.075%, about 2.1%, about 2.15%, about 2.175%, about 2.2%, about 2.25%, about 2.275%, about 2.3%, about 2.35%, about 2.375%, about 2.4%, about 2.45%, about 2.475%, about 2.5%, about 2.55%, about 2.575%, about 2.6%, about 2.65%, about 2.675%, about 2.7%, about 2.75%, about 2.775%, about 2.8%, about 2.85%, about 2.875%, about 2.9%, about 2.95%, about 2.975%, about 3%, about 3.05%, about 3.075%, about 3.1%, about 3.15%, about 3.175%, about 3.2%, about 3.25%, about 3.275%, about 3.3%, about 3.35%, about 3.375%, about 3.4%, about 3.45%, about4922-4270-5705 1 6Attorney Docket No.: 102577-000100WOPT3.475%, about 3.5%, about 3.55%, about 3.575%, about 3.6%, about 3.65%, about 3.675%, about 3.7%, about 3.75%, about 3.775%, about 3.8%, about 3.85%, about 3.875%, about 3.9%, about 3.95%, about 3.975%, about 4%, about 4.05%, about 4.075%, about 4.1%, about 4.15%, about 4.175%, about 4.2%, about 4.25%, about 4.275%, about 4.3%, about 4.35%, about 4.375%, about 4.4%, about 4.45%, about 4.475%, about 4.5%, about 4.55%, about 4.575%, about 4.6%, about 4.65%, about 4.675%, about 4.7%, about 4.75%, about 4.775%, about 4.8%, about 4.85%, about 4.875%, about 4.9%, about 4.96%, about 4.975%, about 5%, about 5.05%, about 5.075%, about 5.1%, about 5.15%, about 5.175%, about 5.2%, about 5.25%, about 5.275%, about 5.3%, about 5.35%, about 5.375%, about 5.4%, about 5.45%, about 5.475%, about 5.5%, about 5.55%, about 5.575%, about 5.6%, about 5.65%, about 5.675%, about 5.7%, about 5.75%, about 5.775%, about 5.8%, about 5.85%, about 5.875%, about 5.9%, about 5.95%, about 5.975%, about 6%, about 6.05%, about 6.075%, about 6.1%, about 6.15%, about 6.175%, about 6.2%, about 6.25%, about 6.275%, about 6.3%, about 6.35%, about 6.375%, about 6.4%, about 6.45%, about 6.475%, about 6.5%, about 6.55%, about 6.575%, about 6.6%, about 6.65%, about 6.675%, about 6.7%, about 6.75%, about 6.775%, about 6.8%, about 6.85%, about 6.875%, about 6.9%, about 6.95%, about 6.975%, about 7%, about 7.05%, about 7.075%, about 7.1%, about 7.15%, about 7.175%, about 7.2%, about 7.25%, about 7.275%, about 7.3%, about 7.35%, about 7.375%, about 7.4%, about 7.45%, about 7.475%, about 7.5%, about 7.55%, about 7.575%, about 7.6%, about 7.65%, about 7.675%, about 7.7%, about 7.75%, about 7.775%, about 7.8%, about 7.85%, about 7.875%, about 7.9%, about 7.95%, about 7.975%, about 8%, about 8.05%, about 8.075%, about 8.1%, about 8.15%, about 8.175%, about 8.2%, about 8.25%, about 8.275%, about 8.3%, about 8.35%, about 8.375%, about 8.4%, about 8.45%, about 8.475%, about 8.5%, about 8.55%, about 8.575%, about 8.6%, about 8.65%, about 8.675%, about 8.7%, about 8.75%, about 8.775%, about 8.8%, about 8.85%, about 8.875%, about 8.9%, about 8.95%, about 8.975%, about 9%, about 9.05%, about 9.075%, about 9.1%, about 9.15%, about 9.175%, about 9.2%, about 9.25%, about 9.275%, about 9.3%, about 9.35%, about 9.375%, about 9.4%, about 9.45%, about 9.475%, about 9.5%, about 9.55%, about 9.575%, about 9.6%, about 9.65%, about 9.675%, about 9.7%, about 9.75%, about 9.775%, about 9.8%, about 9.85%, about 9.875%, about 9.9%, about 9.95%, about 9.975%, or about 10% (w / w orw / v).

[0024] n some embodiments, the topical formulation comprises the CDA inhibitor in an amount from about 0.05 mg / g to about 30 mg / g of the total weigh of the formulation.4922-4270-5705 1 7Attorney Docket No.: 102577-000100WOPTFor example, the topical formulation comprises the CDA inhibitor in an amount from about 0.075 mg / g to about 25 mg / g, from about 0.1 mg / g to about 20 mg / g, from about 0.15 mg / g to about 15 mg / g, about 0.2 mg / g to about 10 mg / g, or any amount between 0.05 mg / g to about 30 mg / g of the total weigh of the formulation. In some embodiments, the topical formulation comprises the CDA inhibitor in an amount about 0.05mg / g, about 0.075 mg / g, about 0.1 mg / g, about 0.15mg / g, about 0.175 mg / g, about 0.2 mg / g, about 0.25mg / g, about 0.275 mg / g, about 0.3 mg / g, about 0.35mg / g, about 0.375 mg / g, about 0.4mg / g, about 0.45mg / g, about 0.475 mg / g, about 0.5 mg / g, about 0.55mg / g, about 0.575 mg / g, about 0.6 mg / g, about 0.65mg / g, about 0.675 mg / g, about 0.7 mg / g, about 0.75mg / g, about 0.775 mg / g, about 0.8 mg / g, about 0.85mg / g, about 0.875 mg / g, about 0.9 mg / g, about 0.95mg / g, about 0.975 mg / g, about 1 mg / g, about 1.05mg / g, about 1.075 mg / g, about 1.1 mg / g, about 1.15mg / g, about 1.175 mg / g, about 1.2 mg / g, about 1.25mg / g, about 1.275 mg / g, about 1.3 mg / g, about 1.35mg / g, about 1.375 mg / g, about 1.4mg / g, about 1.45mg / g, about 1.475 mg / g, about 1.5 mg / g, about 1.55mg / g, about 1.575 mg / g, about 1.6 mg / g, about 1.65mg / g, about 1.675 mg / g, about 1.7 mg / g, about 1.75mg / g, about 1.775 mg / g, about 1.8 mg / g, about 1.85mg / g, about 1.875 mg / g, about 1.9 mg / g, about 1.95mg / g, about 1.975 mg / g, about 2 mg / g, about 2.05mg / g, about 2.075 mg / g, about 2.1 mg / g, about 2.15mg / g, about 2.175 mg / g, about 2.2 mg / g, about 2.25mg / g, about 2.275 mg / g, about 2.3 mg / g, about 2.35mg / g, about 2.375 mg / g, about 2.4mg / g, about 2.45mg / g, about 2.475 mg / g, about 2.5 mg / g. about 2.55mg / g, about 2.575 mg / g. about 2.6 mg / g, about 2.65mg / g, about 2.675 mg / g, about 2.7 mg / g, about 2.75mg / g, about 2.775 mg / g, about 2.8 mg / g, about 2.85mg / g, about 2.875 mg / g, about 2.9 mg / g, about 2.95mg / g, about 2.975 mg / g, about 3 mg / g, about 3.05mg / g, about 3.075 mg / g. about 3.1 mg / g, about 3.15mg / g, about 3.175 mg / g, about 3.2 mg / g, about 3.25mg / g, about 3.275 mg / g, about 3.3 mg / g, about 3.35mg / g, about 3.375 mg / g, about 3.4mg / g, about 3.45mg / g, about 3.475 mg / g, about 3.5 mg / g, about 3.55mg / g, about 3.575 mg / g, about 3.6 mg / g, about 3.65mg / g, about 3.675 mg / g, about 3.7 mg / g, about 3.75mg / g, about 3.775 mg / g, about 3.8 mg / g, about 3.85mg / g, about 3.875 mg / g, about 3.9 mg / g, about 3.95mg / g, about 3.975 mg / g, about 4 mg / g, about 4.05mg / g, about 4.075 mg / g, about 4.1 mg / g, about 4.15mg / g, about 4.175 mg / g, about 4.2 mg / g, about 4.25mg / g, about 4.275 mg / g, about 4.3 mg / g, about 4.35mg / g, about 4.375 mg / g, about 4.4mg / g, about 4.45mg / g, about 4.475 mg / g, about 4.5 mg / g, about 4.55mg / g, about 4.575 mg / g, about 4.6 mg / g, about 4.65mg / g, about 4.675 mg / g, about 4.7 mg / g, about 4.75mg / g, about 4.775 mg / g, about 4.8 mg / g, about 4.85mg / g, about 4.8754922-4270-5705 1 8Attorney Docket No.: 102577-000100WOPTmg / g, about 4.9 mg / g, about 4.95mg / g, about 4.975 mg / g, about 5 mg / g, about 5.05mg / g, about 5.075 mg / g, about 5.1 mg / g, about 5.15mg / g, about 5.175 mg / g, about 5.2 mg / g, about 5.25mg / g, about 5.275 mg / g, about 5.3 mg / g, about 5.35mg / g, about 5.375 mg / g, about 5.4mg / g, about 5.45mg / g, about 5.475 mg / g, about 5.5 mg / g, about 5.55mg / g, about 5.575 mg / g, about 5.6 mg / g, about 5.65mg / g, about 5.675 mg / g, about 5.7 mg / g, about 5.75mg / g, about 5.775 mg / g, about 5.8 mg / g, about 5.85mg / g, about 5.875 mg / g, about 5.9 mg / g, about 5.95mg / g, about 5.975 mg / g, about 6 mg / g, about 6.05mg / g, about 6.075 mg / g, about 6.1 mg / g, about 6.15mg / g, about 6.175 mg / g, about 6.2 mg / g, about 6.25mg / g, about 6.275 mg / g, about 6.3 mg / g, about 6.35mg / g, about 6.375 mg / g, about 6.4mg / g, about 6.45mg / g, about 6.475 mg / g, about 6.5 mg / g, about 6.55mg / g, about 6.575 mg / g, about 6.6 mg / g, about 6.65mg / g, about 6.675 mg / g, about 6.7 mg / g, about 6.75mg / g, about 6.775 mg / g, about 6.8 mg / g, about 6.85mg / g, about 6.875 mg / g, about 6.9 mg / g, about 6.95mg / g, about 6.975 mg / g, about 7 mg / g, about 7.05mg / g, about 7.075 mg / g, about 7.1 mg / g, about 7.15mg / g, about 7.175 mg / g, about 7.2 mg / g, about 7.25mg / g, about 7.275 mg / g, about 7.3 mg / g, about 7.35mg / g, about 7.375 mg / g, about 7.4mg / g, about 7.45mg / g, about 7.475 mg / g, about 7.5 mg / g, about 7.55mg / g, about 7.575 mg / g, about 7.6 mg / g, about 7.65mg / g, about 7.675 mg / g, about 7.7 mg / g, about 7.75mg / g, about 7.775 mg / g, about 7.8 mg / g, about 7.85mg / g, about 7.875 mg / g, about 7.9 mg / g, about 7.95mg / g, about 7.975 mg / g, about 8 mg / g, about 8.05mg / g, about 8.075 mg / g, about 8.1 mg / g, about 8.15mg / g, about 8.175 mg / g, about 8.2 mg / g, about 8.25mg / g, about 8.275 mg / g, about 8.3 mg / g, about 8.35mg / g, about 8.375 mg / g, about 8.4mg / g, about 8.45mg / g, about 8.475 mg / g, about 8.5 mg / g, about 8.55mg / g, about 8.575 mg / g, about 8.6 mg / g, about 8.65mg / g, about 8.675 mg / g, about 8.7 mg / g, about 8.75mg / g, about 8.775 mg / g, about 8.8 mg / g, about 8.85mg / g, about 8.875 mg / g, about 8.9 mg / g, about 8.95mg / g, about 8.975 mg / g, about 9 mg / g, about 9.05mg / g, about 9.075 mg / g, about 9.1 mg / g, about 9.15mg / g, about 9.175 mg / g, about 9.2 mg / g, about 9.25mg / g, about 9.275 mg / g, about 9.3 mg / g, about 9.35mg / g, about 9.375 mg / g, about 9.4mg / g, about 9.45mg / g, about 9.475 mg / g, about 9.5 mg / g, about 9.55mg / g, about 9.575 mg / g, about 9.6 mg / g, about 9.65mg / g, about 9.675 mg / g, about 9.7 mg / g, about 9.75mg / g, about 9.775 mg / g, about 9.8 mg / g, about 9.85mg / g, about 9.875 mg / g, about 9.9 mg / g, about 9.95mg / g, about 9.975 mg / g, or about 10 mg / g of the total weigh of the formulation.4922-4270-5705 1 9Attorney Docket No.: 102577-000100WOPT

[0025] Generally, the topical formulation comprises a pharmaceutically acceptable topical carrier or excipient in an amount from about 5% to about 99.9955% (w / w or w / v).

[0026] A topical formulation described herein can include one or more ingredients found in topical formulations in the art. For example, the topical formulation can comprise one or more of a penetration enhancer, emollient, emulsifier, humectant, viscosity modifier, rheology modifier or thickening agent (gelling agent), surfactant, occlusive agent, colorant, preservative, exfoliating agent, antioxidant, chelating agent, isotonic agent, cooling agent, ultraviolet (UV) light absorbing or scattering agent, fragrance / perfume, soothing agent, solvent, pH modifier, opacifier or pearlizing agent, skin conditioner, or any combination thereof.

[0027] In some embodiments, the topical formulation comprises a solvent. For example, the formulation comprises a volatile solvent. In some embodiments, the solvent has a viscosity at 25°C in the range of about 1 to about 1,000 mm2 / sec. Suitable solvents, e.g., volatile solvents include volatile solvents, organic liquids (oils and solvents), silicones and mixtures thereof. Solvents can include volatile liquids such as alcohols (e.g., methyl, ethyl, isopropyl alcohols and methylene chloride); ketones (e.g., acetone); aromatic hydrocarbons such as benzene derivatives (e.g., xylenes and toluenes); lower molecular weight alkanes and cycloalkanes (e.g., hexanes, heptanes and cyclohexanes); and alkanoic acid esters (e.g., ethyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate, isobutyl isobutyrate, hexyl acetate, 2-ethylhexyl acetate or butyl acetate); and combinations and mixtures thereof.

[0028] Typically, the solvent, e.g., volatile solvent is an organic liquid. Organic liquids include oils and solvents. The organic liquids are exemplified by, but not limited to, aromatic hydrocarbons, aliphatic hydrocarbons, alcohols, aldehydes, ketones, amines, esters, ethers, glycols, glycol ethers, alkyl halides and aromatic halides. Hydrocarbons include, isododecane, isohexadecane, Isopar L (C11-C13), Isopar H (C11-C12), hydrogentated polydecene. Ethers and esters include, isodecyl neopentanoate, neopentylglycol heptanoate, glycol distearate, dicaprylyl carbonate, diethylhexyl carbonate, propylene glycol n butyl ether, ethyl-3 ethoxypropionate, propylene glycol methyl ether acetate, tridecyl neopentanoate, propylene glycol methylether acetate (PGMEA), propylene glycol methylether (PGME). octyldodecyl neopentanoate, diisobutyl adipate, diisopropyl adipate, propylene glycol dicaprylate / dicaprate, and octyl palmitate. Additional volatile solvents suitable as a standalone compound or as an ingredient to the carrier fluid include fats, oils, fatty acids,4922-4270-5705 1 10Attorney Docket No.: 102577-000100WOPTand fatty alcohols.

[0029] The solvent can also be a low viscosity organopolysiloxane or a volatile methyl siloxane or a volatile ethyl siloxane or a volatile methyl ethyl siloxane having a viscosity at 25°C in the range of about 1 to about 1,000 mm2 / sec, exemplified by hexamethylcyclotrisiloxane, octamethyleyelotetrasiloxane, decamethylcyclopentasiloxane, dodecamethylcyclohexasiloxane, octamethyltrisiloxane, decamethyltetrasiloxane, dodecamethylpentasiloxane, tetradecamethylhe xasiloxane, hexadeamethylheptasiloxane, heptamethyl-3-{(trimethylsilyl)oxy)}trisiloxane, hexa methyl-3,3,bis{(trimethlylsilyl)oxy}trisiloxane pentamethyl{(trimethylsilyl)oxy}cyclotrisiloxane as well as polydimethylsiloxanes, polyethylsiloxanes, polymethylethylsiloxanes, polymethylphenylsiloxanes, polydiphenylsiloxanes.

[0030] In some embodiments, the formulation comprises a solvent in an amount from about an amount from about 10% to about 99.99% (w / w or w / v).

[0031] In some embodiments, the topical formulation comprises a penetration enhancer. The term “penetration enhancer” as used herein includes an agent or combination of agents that facilitates the transport of molecules, e.g., CDA inhibitor, through the major skin barrier, the stratum comeum. Generally, the formulation comprises the penetration enhancer in an amount from about 0.1% to about 10% (w / w or w / v).

[0032] The penetration enhancer can be selected from the group consisting of fatty acids, fatty acid esters, glycerol tri-esters, glycerol di-esters, glycerol monoesters, fatty alcohols, short chain alcohols, diols, polyols, pyrrolidones, bile salts, sulfoxides, chelating agents, surfactants, triacetin, amine oxides, and any combinations thereof. Some exemplary penetration enhancer include, but are not limited to, decyl alcohol, undecyl alcohol, dodecyl alcohol, oleyl alcohol, lauryl alcohol, isopropyl myristate, oleyl oleate, levulinic acid, ethanol, glycerol monooleate, methyl laurate, sorbitan monooleate, triacetin, aloe vera oil, benzethonium chloride, cetyl dimethylamine oxide, cetyl alcohol, cetyl lactate, cocamidopropyl betaine, cocoamine oxide diethanolamine, dimethyloctylamine oxide, 2-dodecoxyethyldimethylamine oxide, dimethyl-decylamine oxide, dimethylhexadecylamine oxide, dimethyl-tetradecylamine oxide, dimethyl isosorbide, dipropylene glycol, ethyl hexyl lactate, glycolic acid, 3-dodecoxy-2-hydroxypropyldi(3-hydroxypropyl)amine oxide, lactic acid, lauramine oxide, lauryl betaine, lauryl lactate, lauryl laurate, isopropyl palmitate, macrogol 15 hydroxystearate (Solutol HS 15), menthol, menthyl lactate, myristyl alcohol, myristal lactate,4922-4270-5705 1 11Attorney Docket No.: 102577-000100WOPToctyldodecanol, octyl salicylate, oleamine oxide, oleic acid, oleyl betaine, oleyldi(2-hydroxyethyl) amine oxide, PEG 1000, pentadecalactone, propylene glycol, salicylic acid, stearyl alcohol, stearyl lactate, 3,6,9-trioxaheptadecyl di ethyl amine oxide, di(2-hydroxyethyl)-tetradecylamine oxide, triethanolamine triacetate, dimethyl sulfoxide, isopropyl myristate, propylene glycol, polyethylene glycol, alkyl pyrrolidones, diethoxy glycol (Transcutol), lecithin, and any combination thereof.

[0033] In some embodiments of any one of the aspects described herein, the topical formulation comprises an emollient. As used herein, the term “emoSHent” refers to one or more water-immiscible substances used in cosmetic formulations. Without wishing to be bound by a theory, emollients help to retain moisture in the skin and also helps to control the rate of evaporation and viscosity of the composition. Additionally, emollients provide a soothing or softening effect on the skin's surface. The emollient can be selected from the group consisting of natural oils, plant-derived oils, mineral oils, silicone oils (e.g., dimethyl silicone, polysiloxane, polydimethylsiloxane, and mixtures thereof), polyunsaturated fatty acids, paraffins, beeswaxes, squalenes, cetyl oil, petrolatum, lanolin and its derivatives, and any combinations thereof.

[0034] Exemplary emollients include, but are not limited to, arachidyl propionate, C1-C4 glycols, caprylic / capric triglyerides, caprylyl glycol, castor oil, ceteareth-20, ceteareth-30, cetearyl alcohol, ceteth 20, cetostearyl alcohol, cetyl acetate, cetyl alcohol, cetyl lactate, cetyl ricinoleate, cetyl stearyl alcohol, cocoa butter, cocoyl caprylocarprate, cyclomethicone, decyl oleate, diisopropyl adipate, diisopropyl dimerate, dimethicones, dormin, fatty acid glycols, fatty acids, fruit oils, glycerides, glycerols, glyceryl monostearate, glyceryl stearate, glycol esters, gyceryl monooleate, hydrogenated lanolin, isononyl isononanoate, isopropyl isostearate, isopropyl lanolate, isopropyl myristate, isopropyl palmitate, isosteric acid, isotridecyl isononanoate, jojoba oil, lanolin, lanolin alcohol, linoleic acid, liquid paraffins, long chain alcohols, maleated soybean oil, medium chain triglycerides, methicone, mineral oil, myristate derivatives like butyl myristate and myristyl myristate, myristyl lactate, myristyl myristate, neopentylglycol dicaprylate / dicaprate, nut oils, octyl dodecanol, octyl hydroxystearate, octyl palmitate, octyldodecanol, oleate derivates, oleic acid, oleyl alcohol, olive oil, paraffin, pentaerythrityl tetrastearate, polyethylene glycol, polyoxyethylene glycol fatty alcohol ethers, polyoxypropylene 15-stearyl ether, propylene glycol, propylene glycol dicaprylate, propylene glycol ricinoleate, propylene glycol stearate, rapeseed oil, soybean oil, squalane, steareth-2 or -100, stearic acid, stearyl alcohol, sucrose esters of fatty acids, tocopheryl acetate, tocopheryl linoleate, urea, vegetable oils, wheat germ4922-4270-5705 1 12Attorney Docket No.: 102577-000100WOPTglycerides, white petrolatum, urea, glycerol, propylene glycol, lactic acid, lanolin, liquid paraffin wax, aloe vera topical, glycerin topical, salicylic acid / urea topical, vitamin a & d topical, ammonium lactate topical, emollients topical, ammonium lactate / urea topical, hydrocortisone / urea topical, lactic acid / urea topical, petrolatum topical, vitamin a, vitamin d, vitamin e, aquaphor, bag balm, dimethicone, or any combinations thereof.

[0035] The formulation can comprise the emollient in an amount from about 0.1% to about 50% (w / w or w / v).

[0036] In some embodiments, the topical formulation comprises a humectant. The term “humectant”, as used herein, means a compound that promotes retention and absorption of moisture. The term “humectant” includes an agent that absorbs water from the air. Humectants are characterized as having several hydrophilic functional groups. When a humectant is present, it is present in an amount of from about 0.01% to about 50% (w / w or w / v). In some embodiments, the humectant is present in an amount of from about 1% to about 20% by weight. In some embodiments, the humectant is present in an amount of from about 5% to about 15% by weight.

[0037] Exemplary humectants include, but are not limited to, acetamide MEA (acetyl ethanolamine), agarose, alkyl dimethicone, allatoin, aloe vera gel, arginine, arginine PCA (arginine 2-pyrrolidone carboxylate), asparagus cochinchinensis, beeswax, benzyl hyaluronate, butylene glycol, carboxylic acid amides, chitosan, chitosan PCA, copper, copper PCA, corn glycerides, dimethyl imidazolidinone, fatty acid esters, fructose, gluconolactone, glucosamine, glucose glutamate, glucose Sodium ammonia, glucuronic acid, glutamic acid, glycerin, glycerin, glyceryl polyether-12, glyceryl polyether-20, glyceryl polyether-26, glyceryl polyether-7, hexylene glycol, honey, hydrogenated starch hydrolysate, hydrogenated vegetable oils, hydrolyzed corn starch, hydrolyzed keratin, hydroxyethyl urea, isomerized sugar, kombucha, lactamide MEA, lactic acid, lactobionic acid, lactose, lactose lysine PCA, lanolin alcohol, lysine, maltitol, maltose, mannitol, methyl glutamic polyether-10, methyl glutamic polyether-20, mineral oil, mucopolysaccharides, n-acetylethanolamine, panthenol, PCA (2-pyrrolidone carboxylate), PEG-10 propylene glycol, PEG-2 lactamide, petrolatum, polyamino acids, polyamino sugar condensates, trehalose, polysaccharides, potassium PCA, hyaluronic acid, glycerin, propylene glycol, propylene glycol citrate, quaternized nitrogen moisturizers, sodium aspartate, sodium lactate, sodium PCA (sodium 2-pyrrolidone carboxylate), sorbitol, sugar hydrolysates, TEA-lactate, TEA-PCA, tocopherol esters, triacetin, urea, vegetable oils, xylitol,, or any combinations thereof. In some embodiments, the humectant is propylene glycol, sorbitol, butylene glycol, hexylene4922-4270-5705 1 13Attorney Docket No.: 102577-000100WOPTglycol, acetamide MEA, honey, and sodium PCA, sorbitol, triacetin, or any combination thereof. In some embodiments, the humectant is selected from propylene glycol and polyols such as sorbitol, maltitol glycerine, glyceryl triacetate, polydextrose and other polyols such as polymeria polyols including polydextrose.

[0038] In some embodiments of any one of the aspects described herein, the topical formulation comprises a viscosity modifier. The term “viscosity modifier1’ refers to a viscosity-regulating agent, e.g., a thickener or gelling agent. Non-limiting examples of viscosity modified include, but are not limited to, cellulose and derivatives thereof, polysaccharides, carbomers, polyvinyl alcohol, povidone, colloidal silicon dioxide, cetyl alcohols, stearic acid, beeswax, petrolatum, triglycerides, lanolin, inorganic salts, polymers, gums, organic solvents, and the like. The viscosity modifier can be present in an amount from about 0.01 % to about 50% (w / w or w / v).

[0039] In some embodiments, the viscosity modifier is selected from the group consisting of collagen, gellan, guar and guar derivatives, xanthum gum, carbohydrate gel-forming polymers, carob bean gum, locust bean gum, carrageenan, alginates (e.g., alginic acid, sodium alginate, potassium alginate, ammonium alginate, and calcium alginate), agar, guar gum, xanthan gum, carboxymethyl cellulose, clear starch, pectin, gelatin, arrowroot, cornstarch, katakuri starch, potato starch, sago, tapioca, furcellaran, sodium pyrophosphate, polyacrylates, cellulose, cellulose derivative (e.g., hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, and the like), cellulose gum,, carbopol, sodium hyaluronate, sodium chloride, calcium chloride, sodium sulfate, magnesium sulfate, alcohols, glycol ethers, magnesium aluminum silicate, hydrogenated castor oil, and any combinations thereof.

[0040] The topical formulation can also comprise a rheology modifier or thickening agent. As used herein, the term " thUckenmg agent " means a substance that increases the viscosity of a solution or the like Some non-limiting examples of thickening agents include, but are not limited to, polymers, cellulose, cellulose polymers, cellulose derivatives, carbomer polymers, carbomer derivatives, polyvinyl alcohol, poloxamers, polysaccharides, natural gums, finely divided silica, laponite, colloidal magnesium aluminum silicate, and any combinations thereof. When present, the formulation can comprise the rheology modifier or thickening agent in an amount from about 0.01 % to about 50% (w / w or w / v).

[0041] In some embodiments of any one of ths aspects described herein, the rheology modifier or thickening agent selected from the group consisting of aluminum silica gel, arabiya gum, Bee gum, carbopol, carboxyvinyl polymer, carrageenan, ethylene4922-4270-5705 1 14Attorney Docket No.: 102577-000100WOPTglycol, glycerin, guar gum, gum Arabic, hydroxyethyl cellulose, hydroxypropyl cellulose, karaya gum, lactol, laponite, locust bean gum, maltitol, methylcellulose, polyacrylic acid crosslinked with polyallyl sucrose or polyallyl pentaerythritol, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, propylene glycol, silica gel, sodium alginate, sodium hydroxyethylcellulose, sodium polyacrylate, sorbitol, thickening silica, tragacanth, tragacanth gum, water soluble salts of cellulose ethers (such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose), xanthan gum, xylitol, and any combinations thereof.

[0042] The topical formulation can also comprise a surfactant. The surfactant can be an anionic, non-ionic, cationic, zwitterionic or amphoteric surfactant. When present, the formulation can comprise the surfactant in an amount from about 0.01% to about 5% (w / w or w / v). Exemplary surfactants include, but are not limited to, sodium lauroyl sarcosine, potassium lauroyl sarcosine, aodium coco acylsarcosinate, cocoyl flesh Propylhomoserin potassium, sodium lauroylmethyl taurate, sodium cocoyl methyl sodium taurocholate, sodium lauroyl glutamate, lauryl trimethyl ammonium chloride, stearyl trimethyl ammonium chloride, benzethonium chloride, cetyl pyridinium chloride, cetyl pyridinium chloride benzalkonium chloride, stearyl dimethyl benzyl ammonium chloride, polyoxyethylene lauryl ether sodium sulfate, sodium lauryl sulfate, sodium myristyl sulfate, sodium N-lauroyl sarcosinate, sodium N-myristol sarcosine, sodium dodecylbenzene sulfonate, sodium coconut fatty acid monoglyceride monosulfate, sodium lauryl sulfoacetate, sodium a-olefin sulfonate, sodium N-palmitoyl glutamate, sodium N-methyl-N-acyl taurate, sucrose fatty acid ester, maltose fatty acid ester, maltitol fatty acid ester, lactol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan monostearate, polyoxyethylene higher alcohol ether, polyoxyethylene cured Castor oil, polyoxyethylene polyoxypropylene copolymer, polyoxyethylene polyoxypropylene fatty acid ester, polyglycerin fatty acid ester, coconut oil fatty acid amidopropyl betaine, lauryldimethylaminoacetic acid betaine, lauryldimethylamine oxide, 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolium betaine, N-lauryldiaminoethylglycine, N-myristyldiaminoethylglycine, sodium N-alkyl-1-hydroxyethylimidazoline betaine, or any combination thereof.

[0043] In some embodiments, the topical formulation comprises an occlusive agent. The term "occlusive agent" means a material that delivers the function of occlusivity when incorporated in a skin care product. The occlusive agents typically have relatively high occlusivity. As used herein, the term ’'occlusivity" refers to covering the skin with a film and thus preventing moisture evaporation from the skin. The occlusive agent can4922-4270-5705 1 15Atorney Docket No.: 102577-000100WOPTbe present in the formulation in an amount from about 1 % to about 50% (w / w or w / v). Some exemplary occlusive agents include, but are not limited to, petrolatum, shea butter, dimethicones, plant and animal oils such as avocado, canola, cod liver, and com, mineral oil, olive oil, soybean oil, lanolin, glycerides, beeswax, triglycerides, long chain fatty alcohols, cocoa butter, coconut oil, jojoba oil, propylene glycol, and their derivatives, and the like. Some additional non-limiting examples of occlusive agents include arachidyl behenate, butter, canola oil, cottonseed oil, dimethicone, glycol dilaurate, hydrogenated shea butter, isocetyl behenate, lauryl stearate, methicone, neopentyl glycol stearate, octyldodecyl myristate, prunus amygdalua dulcis (sweet almond) oil, ricinus communis (castor) seed oil, shea butter cetyl esters, squalane, tocopherol, zea mays (com) oil, or any combination thereof.

[0044] The formulation can also comprise a colorant or coloring agent. The coloring agent can be present in an amount in an amount from about 0.01% to about 1% (w / w or w / v). For example, the coloring agent can be present in an amount upto about 0.75% (w / w or w / v). In some embodiments, the formulation can can comprise a coloring agent an amount from about 0.01% to about 0.75% (w / w or w / v). Some exemplary coloring agents include, but are not limited to, FD& C Blue No. 1 (Brilliant Blue), FD& C Blue No. 2 (Indigotine), FD& C Green No. 3 (Fast Green), FD& C Red No. 3 (Erythrosine), FD& C Red No. 40 (Allura Red), FD& C Yellow No. 5 (Tartrazine), FD& C Yellow No. 6 (Sunset Yellow), annatto extract, anthocyanis, aronia / redfhiit, beet juice, beet powder, beia-carotene, beta-apo-8- carotenal, black currant, burnt sugar, canthaxanthin, caramel, carbo medicinalis, carmine, carmine / beta-carotene, carmine blue, carminic acid, carrot, carrot oils, chlorophyll, chlorophyllin, cochineal extract, copper-chlorophyll, copper-chlorophyll in, curcumin, curcumin / Cu-chlorophyllin, elderberry, grape, grape skin extracts, hibiscus, lutein, mixed carotenoids, paprika, paprika extract, paprika oieoresin, riboflavin, saffron, spinach, stinging nettle, titanium dioxide, turmeric, and combinations thereof. Preferred coloring agents according to the present invention are FD& C Blue No.1 (Brilliant Blue), FD& C Blue No. 2 (Indigotine), FD& C Green No. 3 (Fast Green), FD& C Red No. 3 (Erythrosine), FD& C Red No. 4, FD& C Red No. 33, FD& C Red No. 40 (Allura Red), FD& C Yellow No. 5 (Tartrazine), FD& C Yellow No. 6 (Sunset Yellow), FD& C Yellow No. 10, FD& C Orange No. 4, D& C blue No. 1, D& C blue No. 4, D& C brown No.1, D& C green No. 5 through No. 8, D& C orange No. 4 through No. 11, D& C yellow No. 2 through No. 11, D& C red No. 6 through No. 40, and any combinations thereof.

[0045] In some embodiments, the formulation can further comprise one or more preservatives. Exemplary preservatives include, for example, antioxidants, chelating4922-4270-5705 1 16Attorney Docket No.: 102577-000100WOPTagents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. When present, the preservative can be present in an amount from about 0.01% to about 10 % (w / w or w / v). For example, the formulation can comprise a preservative in an amount from about 0.01% to about 7.5 % (w / w or w / v), from about 0.01% to about 5 % (w / w or w / v), from about 0.01% to about 4 % (w / w or w / v), from about 0.01% to about 3 % (w / w or w / v), from about 0.01% to about 2.5 % (w / w or w / v), from about 0.01% to about 2 % (w / w or w / v), from about 0.01% to about 1.5 % (w / w or w / v), or from about 0.01% to about 1 % (w / w or w / v).

[0046] Exemplary preservative include, but are not limit to, benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, p-hydroxybenzoic acid, methyl p-hydroxybenzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chlorocylenol, ethanol, glycerin, hexetidine, imidourea, phenol, phenoxyethanol, phenylethyl alcohol, phenyl mercuric nitrate, propylene glycol, sodium propionate, thimerosyl, methyl paraben, ethyl paraben, butyl paraben, isobutyl paraben, benzyl paraben, citric acid, trisodium citrate, sorbic acid, dichlorinated phenol, phumeotassium sorbate, phenoxyethanol, parabens (such as methylparaben and propylparaben), propylene glycols, sorbates, urea derivatives (such as diazolindinyl urea) and any combination thereof.

[0047] In some embodiments, the preservative can be an antimicrobial agent. The antimicrobial agent can be, for example, substances which have fungicidal activity (fungicidal agents) and / or substances which have bactericidal activity (bactericidal agents). Exemplary antimicrobial agents include, but are not limited to, parabens, isothiazolinone, phenolics, acidic preservatives, halogenated compounds, quarternia, and alcohol. Exemplary parabens can include, but are not limited to, parabens and paraben salts. Exemplary isothiazolinones can include, but are not limited to, methylchloroisothiazolinone, methylisothiazolinone, benzisothiazolinone ProCiin 150, ProCiin 200, ProCiin 300, and ProCiin 950. Exemplary phenolic types can include, but are not limited to, phenoxyethanol, benzyl alcohol, and phenethyl alcohol. Exemplary acidic preservatives can include, but are not limited to, dehydroacetic acid, benzoic acid, sorbic acid, salicylic acid, formic acid, propionic acid. Exemplary halogenated compounds can include, but are not limited to, 2-bromo-2-nitropropane-1, 3-diol, chloroacetamide, chlorobutanol, chloroxylenol, chlorphenesin, dichlorobenzyl alcohol, iodopropynyl butylcarbamate, methyldibromo glutaronitrile. Exemplary quaternia can include, but are not limited to, benzalkonium chloride, benzethonium chloride,4922-4270-5705 1 17Attorney Docket No.: 102577-000100WOPTchlorhexidine, hexamidine diisethionate, and polyaminopropyl biguanide. Exemplary alcohols can include, but are not limited to, ethyl alcohol and isopropyl alcohol. Examples thereof include, but are not limited to, triazine antimicrobial agents, thiazole bactericidal agents (for example, benzisothiazolone etc.), pyrithione, pyridine bactericidal agents (for example, 1 -hydroxy pyridine-2-thiosodium etc.), 2-phenoxyethanol, and the like. In some embodiments, the antimicrobial agent is methylparaben. In other embodiments, the preferred antimicrobial is propylparaben.

[0048] In some embodiments of any one of the aspects described herein, the formulation comprises an exfoliating agent. As used herein, the term "exfoliating agent" means any compound capable of acting: (i) either directly on desquamation by¬ promoting exfoliation: or (ii) on the enzymes involved in desquamation or decomposition of the corneodesmosomes, such as glycosidases, stratum corneum chymotryptic enzyme (SCCE) or indeed even other proteases (trypsin, chymotrypsin-like). Exemplary exfoliating agents include, but are not limited to alpha-hydroxyacids, beta hydroxyacids, oxaacids, oxadiacids, and their derivatives such as esters, anhydrides, and salts thereof. When present, the exfoliating agent can be in an amount from about 0.001% to about 20% (w / w or w / v).

[0049] In some embodiments of any one of the aspects described herein, the exfoliating agent is glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, 2-hydroxyalkanoic acid, mandelic acid, salicylic acid, 5-n-octanoylsalicylic acid, urea, gentisic acid, oligofucoses, cinnamic acid; extract of Saphara japonica, resveratrol, jasmonic acid derivatives, N-(2-hydroxyethyl)piperazine-N-2-ethanesulfonic acid (HEPES), 2-oxothiazolidine-4-carboxylic acid (procysteine) derivatives, derivatives of a- amino acids of glycine type, and also sodium methyl glycine diacetate sold by BASF under the trade name Trilon M); honey; sugar derivatives such as O-octanoyl-6-D-maitose and N-acetylgluccsamine, and the like.

[0050] In some embodiments of any one of the aspects described herein, the topical formulation comprises an antioxidant. For example, the formulation comprises an antioxidant in an amount from about 0.01% to about 10 % (w / w or w / v). Exemplary antioxidants include, but are not limited to, sodium metabisulfite, sodium sulfite, sodium bisulfite, sodium thiosulfate, vitamin C (ascorbic acid), vitamin E, vitamin E isomers (such as -, p-, y-, and 5- tocopherols and a-, [3-, y-, and 5-tocotrienols;) vitamin A, B vitamins (e.g. vitamin B6), flavonoids, selenium, carotenoids (e.g. beta-carotene), esters of gallic acid (e.g., propyl, octyl and dodecyl esters of gallic acid), butylated hydroxyanisole (BHA) (e.g., 2-tert-butyl-4-hydroxyanisole and 3-tert- butyl-4-4922-4270-5705 1 18Attorney Docket No.: 102577-000100WOPThydroxyanisole), butylated hydroxytoluene (BHT), nordihydroguairetic acid, alkylated parabens, cysteine, glutathione, dihydrolipoic acid, 2-mercaptoethane sulfonic acid, 2-mercaptobenzimidazole sulfonic acid, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, polyphenols (such as 2-tert-butyl-4- methyl phenol, 2-tert-butyl-5-methyl phenol, and 2-tert-butyl-6-methyl phenol), tert-butylhydroquinone (TBHQ), ascorbyl palmitate, n-propyl gallate, or any combination thereof.

[0051] The topical formulation can also comprise a chelating agent. Accordingly, in some embodiments, the topical formulation comprises a chelating agent, e.g., a metal chelator. For example, the topical formulation comprises a chelating agent in an amount from about 0.01% to about 10 % (w / w or w / v). In some embodiments, the formulation comprises a chelating agent selected form the group consisting of ethylenediaminetetraacetic acid (EDTA), citrate, ethylene glycol tetraacetic acid (EGTA), 1,2-bis(o-aminophenoxy)ethane-N, N, N', N'-tetraacetic acid (BAPTA), diethylene triamine pentaacetic acid (DTPA), 2,3-dimercapto-l-propanesulfonic acid (D PS), dimercaptosuccinic acid (DMSA), a-lipoic acid, salicylaldehyde isonicotinoyl hydrazone (SIH), hexyl thioethylamine hydrochloride (HTA), desferoxamine, and any combination thereof.

[0052] In some embodiments, the topical formulation comprises an isotonic agent. For example, the formulation comprises an isotonic agent in an amount from about 0.01% to 10% (w / w or w / v). As used herein, the term “isotonic agent” refers to a compound that serves to modify the osmotic pressure of a composition comprising same, i.e., to regulate the osmotic pressure of a composition. Some exemplary isotonic agents include, but are not limited to, polyhydric sugar alcohols, trihydric sugar alcohols, inorganic salts, and combination thereof. In some embodiments, the formulation comprises an isotonic agent selected from the group consisting of glycerol, erythritol, arabitol, xylitol, sorbitol, mannitol, glucose, trehalose, lactose, fructose, xylitol, glycerin, polyethyleneglycol, propylene glycol, sodium chloride, potassium chloride, calcium chloride, and any combination thereof.

[0053] A topical formulation described herein can also include a cooling agent. As used herein, the term "cooling agent" refers to molecules which provide a sensation of cooling on application. Some exemplary cooling agents include, but are not limited to, WS-3; WS-23; menthol; 3-substituted-P-menthanes; N-substituted-P-menthane-3- carboxamides; isopulegol; 3-(1- menthaxy)propane-1,2-diol; 3-(1~menthoxy)~2- methylpropane-1,2-diol; p-menthane-2,3-diol; p-menthane-3.8-diol; 6-isopropyl-9-methyl- 1,4-dioxaspiro[4,5]decane-2-methanol; menthyl succinate and its alkaline earth metal4922-4270-5705 1 19Atorney Docket No.: 102577-000100WOPTsalts; trimethylcyclohexanol; N-ethyl-2-isopropyl-5-methylcyclohexanecarboxamlde; Japanese mint ail; peppermint ail; menthone; menthane glycerol ketal; menthyl lactate; 3-(1 -menthoxy Jethan- 1-ol; 3-(1-menthoxy)propan-1-ol; 3-(1- menthoxy)butan-1-ol; 1- menthylacetlc add N-ethylamlde; 1 -menthyl-4-hydroxypentanoate; 1- menthyl-3- hydroxybutyrate; N^. S-trlmethyl-S-CI-methylethylJ-butanamlde; n-ethyl-t-2-c-6 nonadienamide; N. N-dimethyl menthyl succinamide; menthyl pyrrolidone carboxylate; and the like. When present, the formulation can comprise the cooling agent in an amount from about 0.01% to 10% (w / w or w / v).

[0054] The topical formulation can also comprise an UV absorbing or scattering agent. Accordingly, in some embodiments, the formulation comprises a UV absorbing or scattering agent in an amount from about 0.01% to 10% (w / w or w / v). Some exemplary UV absorbing or scattering agents include, but are not limited to, ultraviolet absorber of benzoic acid system such as para-aminobenzoic acid (hereinafter, abbreviated as PABA), PABA monoglycerin ester, N,N-dipropoxy PABA ethyl ester, N, N-diethoxy PABA ethyl ester, N. N-dimethyl PABA ethyl ester, N. N-dimethyl PABA butyl ester, and N. N-dimethyl PABA methyl ester and the like; ultraviolet absorber of anthranilic acid system such as homomenthyl-N-acetyl anthranilate and the like; ultraviolet absorber of salicylic acid system such as amyl salicylate, menthyl salicylate, homomenthyl salicylate, octyl salicylate, phenyl salicylate, benzyl salicylate, p-isopropanol phenyl salicylate and the like; ultraviolet absorber of cinnamic acid system such as octyl cinnamate, ethyl-4-isopropyl cinnamate, methyl-2,5'diisopropyl cinnamate, ethyl- 2,4-diisopropyl cinnamate, methyl-2,4-diisopropyl cinnamate, propyl-p-methoxy cinnamate, isopropyl-p-methoxy cinnamate, isoamyl-p-methoxy cinnamate, octyl- p-methoxy cinnamate(2-ethylhexyl-p-methoxy cinnamate), 2-ethoxyethyl-p- methoxy cinnamate, cyclohexyl-p-methoxy cinnamate, ethyl-a-cyano-p-phenyl cinnamate, 2-ethylhexyl-a-cyano-P-phenyl cinnamate, glyceryl mono-2- ethylhexanoyl-dipara-methoxy cinnamate, methyl-bis(trimethylsiloxane)silylisopentyl trimethoxy cinnamate and the like; 3-(4'-methylbenzylidene)~d.l-camphor; 3-benzylidene-d,l-camphor; urocanic acid, urocanic acid ethyl ester; 2-phenyl-5-methylbenzoxazole; 2,2'-hydroxy-5-methylphenylbenzotriazole; 2-(2?-hydroxy-5 '-t-octylphenyl)benzotriazole; 2-(2'- hydroxy-5'-methylphenylbenzotriazole; dibenzaladine; dianisoylmethane, 4- methoxy-4'-t-butyldibenzoylmethane; 5-(3,3-dimethyl-2-norbornylidene)-3- pentane-2-one; dimorpholinopyridazinone; powders such as titanium oxide, particulate titanium oxide, zinc oxide, particulate zinc oxide, ferric oxide, particulate ferric oxide, eerie oxide; and any combinations thereof.4922-4270-5705 1 20Attorney Docket No.: 102577-000100WOPT

[0055] The topical formulation can also include a fragrance. For example, the formulation comprises a fragrance in an amount from about 0.01% to 10% (w / w or w / v). Exemplary fragrances include, but are not limited to 2,4-dimethyl-3-cyclohexene-1-carbaldehyde; isocyclocitral; menthone; isomenthone; ROMASCONE® (methyl 2,2-dimethyl-6-methylene-1 -cyclohexanecarboxylate); nerone; terpineol; dihydroterpineol; terpenyl acetate; dihydroterpenyl acetate; dipentene; eucalyptol; hexylate; rose oxide; PERYCOROLLE® ((S)-1,8-p-menthadiene-7-ol); 1-p-menthene-4-ol; (1RS,3RS,4SR)-3-p-mentanyl acetate; (1R,2S,4R)-4,6,6-trimethyl-bicyclo[3,1,1]heptan-2-ol; DOREMOX® (tetrahydro-4-methyl-2-phenyl-2H-pyran); cyclohexyl acetate; cyclanol acetate; Fructalate (1,4-cyclohexane diethyldicarboxylate); KOUMALACTONE® ((3ARS,6SR,7ASR)-perhydro-3,6-dimethyl-benzo[B]furan-2-one); Natactone ((6R)-perhydro-3,6-dimethyl-benzo[B]furan-2-one); 2,4,6-trimethyl-4-phenyl-1,3-dioxane; 2,4,6-trimethyl-3-cyclohexene-1-carbaldehyde; (E)-3-methyl-5-(2,2,3-trimethyl-3-cyclopenten- 1-yl)-4-penten-2-ol; (1'R, E)-2-ethyl-4-(2',2',3'-trimethyl-3'-cyclopenten-T-yl)-2-buten-1-ol; POLYSANTOL® ((1'R, E)-3,3-dimethyl-5-(2',2',3'-trimethyl-3'-cyclopenten-T-yl)-4-penten- 2-ol); fleuramone; PARADISONE® (methyl-(1R)-cis-3-oxo-2-pentyl-1 -cyclopentane acetate); Veloutone (2, 2, 5-Trimethyl-5-pentyl-1 -cyclopentanone); NIRVANOL® (3,3-dimethyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)-4-penten-2-ol); 3-methyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-pentanol; damascenes; NEOBUTENONE® (1-(5,5-dimethyl-1 -cyclohexen-1 -yl)-4-penten-1 -one); nectalactone ((1 'R)-2-[2-(4'-methyl-3'-cyclohexen-1'-yl)propyl]cyclopentanone); alpha-ionone; beta-ionone; damascenone; DYNASCONE® (mixture of 1-(5,5-dimethyl-1 -cyclohexen-1 -yl)-4-penten-1 -one and 1-(3,3-dimethyl-1 -cyclohexen-1 -yl)-4-penten-1 -one); DORINONE® beta (1-(2,6,6-trimethyl-1 -cyclohexen-1 -yl)-2-buten-1 -one); ROMANDOLIDE® ((1 S, 1'R)-[1 -(3',3'-Dimethyl-1 '-cyclohexyl)ethoxycarbonyl]methyl propanoate); 2-tert-butyl-1 -cyclohexyl acetate; LIMBANOL® (1-(2,2,3,6-tetramethyl-cyclohexyl)-3-hexanol); trans-1-(2,2,6-trimethyl-1-cyclohexyl)-3-hexanol; (E)-3-methyl-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3-buten-2-one; terpenyl isobutyrate; LORYSIA® (4-(1, 1 -dimethylethyl)-1 -cyclohexyl acetate); 8-methoxy-1-p-menthene; HELVETOLIDE® ((1S,1'R)-2-[1-(3',3'-dimethyl-1'-cyclohexyl) ethoxy]-2-methylpropyl propanoate); para tert-butylcyclohexanone; menthenethiol; 1-methyl-4-(4-methyl-3-pentenyl)-3-cyclohexene-1 -carbaldehyde; allyl cyclohexylpropionate; cyclohexyl salicylate; Methyl cedryl ketone; Verdylate; vetyverol; vetyverone; 1-(octahydro-2, 3, 8, 8-tetramethyl-2-naphtalenyl)-1 -ethanone; (5RS,9RS,10SR)-2,6,9,10-tetramethyl-1-oxaspiro[4.5]deca-3,6-diene and the (5RS,9SR,10RS) isomer; 6-ethyl-2,10,10-trimethyl-1 -oxaspiro[4.5]deca-3,6-diene; 1,2,3,5,6,7-hexahydro-1, 1,2,3,3-4922-4270-5705 1 21Attorney Docket No.: 102577-000100WOPTpentamethyl-4-indenone; HIVERNAL® (a mixture of 3-(3,3-dimethyl-5-indanyl)propanal and 3-(1,1-dimethyl-5-indanyl)propanal); Rhubofix® (3',4-dimethyl-tricyclo[6.2.1.0(2,7)]undec-4-ene-9-spiro-2'-oxirane); 9 / 10-ethyldiene-3-oxatricyclo[6.2.1,0(2,7)]undecane; POLYWOOD® (perhydro-5,5,8A-trimethyl-2-naphthalenyl acetate); octalynol; CETALOX® (dodecahydro-3a,6,6,9a-tetramethyl-naphtho[2,1-b]furan); tricyclo[5.2.1.0(2,6)]dec-3-en-8-yl acetate and tricyclo[5.2.1.0(2,6)]dec-4-en-8-yl acetate as well as tricyclo[5.2.1.0(2,6)]dec-3-en-8-yl propanoate and tricyclo[5.2.1.0(2,6)]dec-4-en-8-yl propanoate; camphor; borneol; isobornyl acetate; 8-isopropyl-6-methyl-bicyclo[2.2.2]oct-5-ene-2-carbaldehyde; camphopinene; cedramber (8-methoxy-2,6,6,8-tetramethyl-tricyclo[5.3.1.0(1,5)]undecane); cedrene; cedrenol; cedrol; FLOREX® (mixture of 9-ethylidene-3-oxatricyclo[6.2.1,0(2,7)]undecan-4-one and 10-ethylidene-3-oxatricyclo[6.2.1.0(2,7)]undecan-4-one); 3-methoxy-7,7-dimethyl-10-methylene-bicyclo[4.3.1 ]decane; CEDROXYDE® (trimethyl-13-oxabicyclo-[10.1,0]-trideca-4,8-diene); Ambrettolide LG ((E)-9-hexadecen-16-olide); HABANOLIDE® (pentadecenolide); muscenone (3-methyl-(4 / 5)-cyclopentadecenone); muscone; EXALTOLIDE® (pentadecanolide); EXALTONE® (cyclopentadecanone); (1-ethoxyethoxy)cyclododecane; Astrotone; LILIAL®; rosinol; or any combination thereof.

[0056] In some embodiments of any one of the aspects described herein, the topical formulation comprises a soothing agent. As used herein, the term "soothing agent" means a molecule which helps in reducing the discomfort of the skin and / or scalp, for example by soothing the feelings of itching. Exemplary soothing agents include, but are not limited to, aloe, avocado oil, green tea extract, hops extract, chamomile extract, colloidal oatmeal, calamine, cucumber extract, sodium palmate, sodium palm kernelate, butyrospermum parkii (i.e., shea butter), menthe piperita (i.e., peppermint) leaf oil, sericin, pyridoxine (a form of vitamin B6), retinyl palmitate and / or other forms of vitamin A, tocopheryl acetate and / or other forms of vitamin E, lauryl laurate, hyaluronic acid, aloe barbadensis leaf juice powder, euterpe oleracea (i.e., acai berry) fruit extract, riboflavin (i.e., vitamin B2), thiamin HCI and / or other forms of vitamin B1, and / any combinations thereof. In some embodiments, the formulation comprises the soothing agent in an amount from about 0.01% to 10% (w / w or w / v).

[0057] In some embodiments, the topical formulation also comprises a skin conditioner. As used herein, the term ’’skin conditioner” refers to substances capable of maintaining the equilibrium of the epithelial tissue and facilitating its permanence in a good condition. When present, the formulation can comprise the skin conditioner in an4922-4270-5705 1 22Attorney Docket No.: 102577-000100WOPTamount from about 0.5% to about 29% (w / w or w / v). Some exemplary skin conditioner include, but are not limited to, hyaluronic acid, alpha hydroxyl acids (i.e.: glycolic acid, lactic acid, ascorbic acid), polyhydroxy acids (i.e.: gluconolactone, lactobionic acid), beta hydroxyl acids, dipate esters, alkyl benzoates, fatty acid esters of C8or greater, esterified erucates, laurates, neopentanoates, salicylates, stearates, triglycerides, carbonates, glycols, glycerin, mineral oils, phytantriol, panthenyl ethyl ether, primula veris extract, chamomi, sambucus nigra flower extract, panthenol, polyquaternium-51, cetyl alcohol, glycolic acid, stearyl alcohol, sodium lauryl sulfate, sodium dioctyl sulfide succinate, sodium stearate, sorbitan esters, ethoxylated fatty acids, ethoxylated fatty alcohols such as tride Cess-9 and PEG-5 ethyl hexanoate, sorbitol, mannitol, propylene lanolin, and combinations therefore.

[0058] The topical formulation can also comprise an opacifier or pearlizing agent. Thus, in some embodiments, the formulation comprises the opacifier or pearlizing agent in an amount from about 0.5% to about 10% (w / w or w / v). Exemplary opacifiers and pearlizing agents include, but are not limited to, titanium dioxide, zinc oxide, kaolin clay, calcined kaolin clay, montmorillonite clay, calcined montmorillonite clay, talc, barium sulfate, bentonite clays, silicates, silicas, calcium carbonate, precipitated calcium carbonate, zirconates (e.g., strontium zirconate, and mica substrates coated with titanium dioxide and / or metal oxides like iron oxide or tin oxide), calcium carbonate, carbon black or carbon based opacifiers, iron oxides, metal phthalocyanines, styrene / vinyl pyrrolidone copolymers, styrene / acrylic copolymers, stryrene / acrylamide copolymers, ethylene glycol monostearate, ethylene glycol distearate, or combinations thereof.

[0059] In some embodiments of any one of the aspects described herein, the topical formulation comprises a carrier oil. For example, the formulation comprises a carrier oil in an amount from about 1% to about 99.99% (w / w or w / v). In some embodiments, the carrier oil is coconut oil, jojoba oil, shea butter, primrose oil, arnica oil, argan oil, rosehip seed oil, tamanu oil, avocado oil, grape seed oil, safflower oil, sunflower oil, vegetable oil, canola oil, or any combinations thereof.

[0060] In some embodiments of any one of the aspects described herein, the topical formulation comprises an essential oil. For example, the formulation comprises an essential oil in an amount from about 1% to about 99.99% (w / w or w / v). In some embodiments, the essential oil is peppermint, frankincense, menthol, spearmint, wintergreen, copaiba, chamomile, lavender, marjoram, eucalyptus, rosemary, thyme, coconut oil, olive oil, clary sage, sandalwood, juniper, ginger, yarrow, vetiver,4922-4270-5705 1 23Attorney Docket No.: 102577-000100WOPThelichrysum, black pepper oil, lemongrass, rose geranium, bergamot, clove, jojoba, sweet almond, or any combinations thereof.

[0061] In some embodiments of any one of the aspects described herein, the topical formulation comprises a silicone-based carrier or excipient. The silicone-based carrier or excipient can be any silicone-containing polymer material, including a silicone elastomer blend, a silicone organic elastomer blend, a silicone resin, a silicone elastomer, a pressure sensitive adhesive, a silicone gum, a silicone wax, an elastomer base sealant, adhesive or any combination thereof. The silicone-based carrier or excipient can be a dimethicone cross polymer, a dimethicone / bis-isobutyl propylene glycol cross polymer, a polyethylene glycol-12 dimethicone / bis-isobutyl propylene glycol-20 cross polymer, or any combination thereof.

[0062] Silicones are a class of compounds based on polydialkylsiloxanes. Silicones have been used extensively to enhance aesthetics of personal care formulations by providing a unique sensory profile upon application. Silicone elastomer gels are generally obtained by a crosslinking hydrosilylation reaction of a SiH polysiloxane with another polysiloxane containing an unsaturated hydrocarbon substituent, such as a vinyl functional polysiloxane, or by crosslinking a SiH polysiloxane with a hydrocarbon diene. The silicone elastomers may be formed in the presence of a carrier fluid, such as a volatile silicone, resulting in a gelled formulation.

[0063] The silicone-based carrier or excipient can be a pressure sensitive adhesive (PSA). The PSA may be the reaction product of a hydroxyl end-blocked polydimethylsiloxane polymer and a hydroxy functional silicate resin. The polymer and resin react in a condensation reaction to form the PSA. The advantage of using the PSA as the silicone component is the substantivity that the PSA provides. The substantivity is particularly advantageous in human and veterinary applications that require significant substantivity for the active agent to provide sustained pharmacological effects.

[0064] For purposes of the present disclosure, the terms “silicone rubber” and “silicone elastomer” are synonymous, at least to the extent that both silicone components are capable of elongation and recovery. The silicone elastomers may be contained in a carrier fluid such as cyclopentasiloxane, isododecane, isodecylneopentanoate, caprylyl methicone, or other suitable carrier fluids. Silicone rubbers and silicone elastomers are generally crosslinked or reacted silicone polymers. In contrast, silicone gums are capable of being stretched, but they do not generally snap back. Silicone gums are the high molecular weight, generally linear,4922-4270-5705 1 24Attorney Docket No.: 102577-000100WOPTpolydiorganosiloxanes that can be converted from their highly viscous plastic state into a predominately elastic state by crosslinking. Silicone gums are often used as one of the main components in the preparation of silicone rubbers and silicone elastomers.

[0065] The silicone resins can include MQ resins. The acronym MQ as it relates to silicone resins is derived from the symbols M, D, T, and Q each of which represent a functionality of different types of structural units which may be present in silicone resins containing siloxane units joined by Si— O— Si bonds. Monofunctional (M) unit represents (CH3)3SiOi / 2. Difunctional (D) unit represents (CH3)2SiO2 / 2. Trifunctional (T) unit represents CH3SiC>3 / 2 and results in the formation of branched linear siloxanes. Tetrafunctional (Q) unit represents SiC>4 / 2 which results in the formation of crosslinked and resinous silicone compositions. Hence, MQ is used when the siloxane contains all monofunctional M and tetrafunctional Q units, or at least a high percentage of M and Q units such as to render the silicone resinous.

[0066] Silicone resins resins include non-linear siloxane resins having a glass transition temperature (Tg) above about 0°C. Glass transition temperature is the temperature at which an amorphous material such as a higher silicone polymer changes from a brittle vitreous state to a plastic state. The silicone resin generally has the formula R'aSiO(4-a) / 2 wherein R' is a monovalent hydrocarbon group with 1-6 carbon atoms or a functionally substituted hydrocarbon group with 1-6 carbon atoms, and a has an average value of 1-1.8. The silicone resin will preferably include monofunctional (M) units R"3SiO1 / 2and tetrafunctional (Q) units SiO4 / 2, in which R" is the monovalent hydrocarbon group having 1-6 carbon atoms, most preferably the methyl group. The number ratio of M groups to Q groups may be in the range of 0.5:1 to 1.2:1, so as to provide an equivalent wherein a in the formula R'aSiO(4-a) / 2has an average value of 1.0-1.63. The number ratio of M groups to Q groups may also be between about 0.6:1 to about 0.9:1. Silicone MQ resins in which the number of Q units per molecule is higher than 1 or higher than 5 may also be used.

[0067] The silicone resin can also contain between about 1 to about 5% by weight of silicon-bonded hydroxyl radicals such as a dimethylhydroxysiloxy unit (HO)(CH3)2SiO1 / 2. If desired, the silicone resin may contain minor amounts of difunctional (D) units and / or trifunctional (T) units. Silicone resins having a viscosity of at least 100,000,000 (100 million) centistoke (mmf2 / s) and a softening temperature of less than about 200°C may also be used. The silicone resin may include (i) silicone resins of the type MxQywhere x and y have values such that the silicone resin contains at least more than 5 Q units per molecule; (ii) silicone resins of the type MxTywhere x and y have values such that the4922-4270-5705 1 25Attorney Docket No.: 102577-000100WOPTsilicone resin contains at least more than 5 T units per molecule; and (iii) silicone resins of the type MxDyTpQqwhere x, y, p, and q have values such that the sum of Q and T units is at least more than 5 units per molecule, and the number of D units varies from 0-100.

[0068] In some embodiments, the formulation comprises a silicone-based carrier or excipient in an amount from about 1% to about 99.99% (w / w or w / v).Second active agent

[0069] Embodiments of the various aspects described herein include a second active agent. The second active agent can be a known active agent for treating, reducing or inhibiting a symptom, complication or side effect caused by chemotherapy, e.g., 5-fluororidine chemotherapy, such as capecitabine chemotherapy. Some exemplary treatments for chemotherapy induced symptom, complication or side effects include antiinflammatory agents (e.g., non-steroidal anti-inflammatory drugs (NSAIDs)), phosphodiesterase 5 (PDE5) inhibitors, corticosteroids urea, and pyridoxine (vitamin B6). Thus, in some embodiments, the second agent can be an anti-inflammatory agent, a PDE5 inhibitor, a corticosteroid urea, pyridoxine (vitamin B6), or any combination thereof.

[0070] Exemplary anti-inflammatory agents include, but are not limited to, steroidal anti-inflammatory agents, non-steroidal anti-inflammatory drugs (NSAIDs, such as COX inhibitors, e.g., COX-1 or COX nonspecific inhibitors, and selective COX-2 inhibitors), corticosteroids (including glucocorticoids, e.g. cortisol, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, and beclometasone), anti-malarial medication (such as hydrochloroquine), methotrexrate, sulfasalazine, leflunomide, anti-TNF medications, cyclophosphamise, pro-resolving drugs, mycophenolate, dexamethasone, rosiglitazone, prednisolone, corticosterone, budesonide, estrogen, estradiol, sulfasalazine, fenfibrate, pravastatin, simvastatin, proglitazone, acetylsalicylic acid, mycophenolic acid, mesalamine, hydroxyurea, opiates (e.g., endorphins, enkephalins, dynorphin, barbiturates, oxycodone, morphine, lidocaine and the like), steroids, sirolimus, everolimus, biolimus (A9), zotarolimus (ABT-578), tacrolimus, pimecrolimus, genistein, and any combinations thereof.

[0071] In some embodiments, the anti-inflammatory agent is selected from the group consisting of salicylic acid derivatives such as aspirin, sodium salicylate, choline magnesium trisalicylate, salicylate, diflunisal, sulfasalazine and olsalazine; paraaminophenol derivatives such as acetaminophen; indole and indene acetic acids such4922-4270-5705 1 26Attorney Docket No.: 102577-000100WOPTas indomethacin and sulindac; heteroaryl acetic acids such as tolmetin, dicofenac and ketorolac; arylpropionic acids such as ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen and oxaprozin; anthranilic acids (fenamates) such as mefenamic acid and meloxicam; enolic acids such as the oxicams (piroxicam, meloxicam); alkanones such as nabumetone; diarylsubstituted furanones such as refecoxib; diaryl-substituted pyrazoles such as celecoxib; indole acetic acids such as etodolac and sulfonanilides such as nimesulide; and analogues and derivatives thereof.

[0072] Exemplary PDE5 inhibitors include, but are not limited to, sildenafil, vardenafil, tadalafil, avanafil, mirodenafil, udenafil, gisadenafil, yonkenafil (tunodafil), lodenafil fenspiride, MBCQ, zaprinast, icariin, NS-0200, or any combination thereof.

[0073] Exemplary corticosteroids include, but are not limited to, beclomethasone, beclomethasone dipropionate, betamethasone, budesonide, ciclesonide, cortisone, dexamethasone, dexamethasone, fludrocortisone acetate, flunisolide, flunisolide hemihydrate, fluocinolone, fluticasone, fluticasone propionate, furoate monohydrate, hydrocortisone, methylprednisolone, mometasone, mometasone furoate monohydrate, prednisolone, prednisone, triamcinolone, triamcinolone acetonide, and triamincinoione.

[0074] In some embodiments, the second active agent is selected from the group consisting of corticosteroids, urea, pyridoxine (vitamin B6), 2-hydroxy-1,4-naphthoquinone, glycosides, antiarrhythmics, glucosamine sulfate, Boswellia, hyaluronic acid, rutin, MSM, trypsin, bromelain, chondroitin sulfate, glucosamine HCL, curcumin, turmeric, resveratrol, polyphenol classes, UC-II Collagen, Black pepper extract, 5-Loxin, Calcium, horsetail leaf extract, omega-3 fatty acids, Vitamin C, cetyl myristoleate, Gelatin, silicon dioxide, titanium dioxide, magnesium stearate, amitriptyline, nortriptyline, duloxetine, venlafaxine, willow bark, clover, prickly ash bark, Corydalis yanhusuo, lobelia, California poppy, metformin, carbamazepine, topiramate, pregabalin, gabapentin, duloxetine, desvenlafaxine, amitriptyline, azathioprine, cyclosporine, melatonin, fish oil, ginseng root, Ginkgo biloba extract, coenzyme Q10, St. John's Wort, S-adenosyl methionine, hypericin, pseudohypericin, xanthones, folic acid, vitamin B6, vitamin B12, Butterbur, cayenne, Zyflamend, acetaminophen, vitamin K, Epsom salt, proline, glycine, glutamine, phosphorus, silicon, Sulphur, Earl Grey, Tanacetum parthenium, Filipendula ulmaria, Boswellia serrata, Harpagophytum procumbens, Alpinia officinarum Uncaria tomentosa, Foeniculum vulgare, Origanum vulgare ssp. Hirtum, Rosmarinus officinalis, Thymus vulgaris, Antelaea azadirachta, Azadirachta indica, Melia azadirachta, Rumex crispus, Crocus sativus, Passiflora incarnata, Pedicularis canadensis, Lactuca virosa, Curcuma longa, Tabebuia avellanedae,4922-4270-5705 1 27Attorney Docket No.: 102577-000100WOPTBupleurum spp., Commiphora mukul, Yucca spp., Dioscorea villosa, Salix caprea, flower of water hyacinth, Flower of Henna (fragrance), Bitter Orange, Sweet Orange, Vanilla and combinations thereof. For example, the second active agent is selected from the group consisting of corticosteroids, urea, pyridoxine (vitamin B6), 2-hydroxy-1,4-naphthoquinone, glycosides, and any combinations thereof.

[0075] In some embodiments, the topical formulation comprises a steroid. For example, the formulation comprises a steroid in an amount from about 0.005% to about 5% (w / w or w / v). Exemplary steroids include, but are not limited to. clobetasol propionate, halobetasol propionate, augmented betamethasone dipropionate, diflorasone diacetate, betamethasone dipropionate, betamethasone valerate, fluocinonide, fluticasone propionate, mometasone furoate, desoximetasone, amcinonide, topicort, hydrocortisone valerate, triamcinolone acetonide, alclometasone dipropionate, triamcinolone diacetate, desonide, hydrocortisone acetate, dexamethasone, prednisolone, methylprednisolone, hydrocortisone, betamethasone dipropionate, clobetasol propionate, diflorasone diacetate, fluocinonide, flurandrenolid, halobetasol, amcinonide ointment, desoximetasone, diflorasone diacetate, halcinonide, amcinonide, fluticasone propionate, triamcinolone acetonide, betamethasone valerate, desoximetasone, hydrocortisone 17-butyrate, hydrocortisone probutate, hydrocortisone valerate, fluocinolone acetonide, fluticasone propionate, mometasone furoate, triamcinolone acetonide, triamcinolone acetonide, alclometasone dipropionate, desonide, fluocinolone acetonide, diflorasone topical, prednicarbate topical, clocortolone topical, halcinonide topical, fluocinolone topical, fluticasone topical, amcinonide topical, ammonium lactate / halobetasol topical, mometasone topical, clobetasol topical, flurandrenolide topical, desonide topical, betamethasone topical, desoximetasone topical, fluocinonide topical, prednisolone, dexamethasone, prednisone, triamcinolone, prednisolone, methylprednisolone, budesonide, triamcinolone, dexamethasone, cortisone, deflazacort, or any combinations thereof.

[0076] In some embodiments, the topical formulation comprises a glycoside. For example, the formulation comprises a glycoside in an amount from about 0.005% to about 5% (w / w or w / v). Exemplary glycosides include, but are not limited to. steroidal glycosides, anthraquinones glycosides, cardiac glycosides, saponin glycosides, tetracyclic triterpenoids saponins, pentacyclic Ttriterpenoid saponins, coumarin glycosides, furocoumarin glycosides, cyanophore glycosides, flavonoids glycosides, flavone glycosides, flavanol glycosides, flavanone glycosides, chalone glycosides,4922-4270-5705 1 28Attorney Docket No.: 102577-000100WOPTisoflavonoid glycoside, anthocyanidin glycosides, isothiocyanate glycosides, phenol glycoside, aldehyde glycosides, bitter glycosides, and combinations thereof.

[0077] Various aspects of the disclosure can be embodied in any of the embodiments described herein, including, but not limited to, the following numbered embodiments:

[0078] Embodiment 1: A topical formulation comprising a cytidine deaminase inhibitor (CDA) inhibitor and, optionally, a pharmaceutically acceptable topical carrier or excipient.

[0079] Embodiment 2: The topical formulation of Embodiment 1, wherein the CDA inhibitor is tetrahydrouridine (THU); THU analog or derivative; ASTX727 (E7727); 5-methyl-2',3'-dideoxy-3'-azidocytidine (5mAZC); 5-methyl-2',3'-dideoxycytidine; 5-ethyl-2',3'dideoxy-3'-azidocytidine; 5-propyl-2',3'-dideoxycytidine; 5-propyl-2',3'-dideoxy-3'-azidocytidine; 5-propene-2',3'-dideoxy-3'-azidocytidine; 5-propyne-2',3'-dideoxy-3'-azidocytidine; 5-propyne-2',3'-dideoxy-3'-azidocytidine; Zebularine; or any combination thereof.

[0080] Embodiment 3: The topical formulation of Embodiment 1 or 2, wherein the CDA inhibitor is tetrahydrouridine, or a fluorinated derivative thereof.

[0081] Embodiment 4: The topical formulation of any one of Embodiments 1-3, wherein the CDA inhibitor is tetrahydrouridine, 2'-fluoro-2’-deoxytetrahydrouridine, or 2’-deoxy-2',2'-difluorotetrahydrouridine.

[0082] Embodiment 5: The topical formulation of any one of Embodiments 1-3, wherein the CDA inhibitor is tetrahydrouridine; 2',2'-difluoro-dihydrouridine (DFDHU); 2',2'-difluoro-tetrahydrouridine (DFTHU); 2'(R)-fluoro-2’-deoxy-tetrahydrouridine; 2'(R)-fluoro-2’-deoxy-dihydrouridine ((R)-FDHU); 2'(S)-fluoro-2’-deoxy-tetrahydrouridine; 2'(S)-fluoro-2’-deoxy-dihydrouridine ((S)-FDHU); 2'(S)-fluoro-2’-deoxy-tetrahydrouridine ((S)-FTHU); 2’-deoxy-2',2'-difluoro-5,6-dihydrouridine; (4R)-2’-deoxy-2',2'-difluoro-3, 4,5,6-tetrahydrouridine; (4S)-2’-deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine; 1-(2-Deoxy-2,2-difluoro-p-D-erythro-pentofuranosyl)-tetrahydro-2(1H)-pyrimidinone; 2’-deoxy-2'-fluoro-5,6-dihydrouridine; (4R)-2’-deoxy-2'-fluoro-3,4,5,6-tetrahydrouridine; (4S)-2’-deoxy-2'-fluoro-3,4,5,6-tetrahydrouridine; 1 -(2-deoxy-2-fluoro-(3-D-ribofuranosyl)tetrahydro-2(1 H)-pyrimidinone; 1-(2-deoxy-2-fluoro-p-D-arabinofuranosyl)dihydro-2,4-(1H,3H)-pyrimidinedione; (4R)-1-(2-deoxy-2-fluoro-(3-D-arabinofuranosyl)tetrahydro-4-hydroxy-2(1 H)-pyrimidinone; (4S)-1 -(2-deoxy-2-fluoro-(3-D-arabinofuranosyl)tetrahydro-4-hydroxy-2(1H)-pyrimidinone; or any combination thereof.4922-4270-5705 1 29Attorney Docket No.: 102577-000100WOPT

[0083] Embodiment 6: The topical formulation of any one of Embodiments 1-5, wherein the CDA inhibitor is tetrahydrouridine or (4R)-2'-Deoxy-2',2'-difluoro-3, 4,5,6-tetrahydrouridine.

[0084] Embodiment 7: The topical formulation of any one of Embodiments 1-6, wherein the formulation comprises the CDA inhibitor in an amount from about 0.0005% to about 30% (w / w or w / v), e.g., from about 0.05mg / g to about 30 mg / g (w / w).

[0085] Embodiment 8: The topical formulation of any one of Embodiments 1-7, wherein the formulation comprises the CDA inhibitor in an amount from about 0.001% to about 0.01% (w / w or w / v), e.g., from about 0.1 mg / g to 10mg / g (w / w).

[0086] Embodiment 9: The topical formulation of any one of Embodiments 1-8, wherein the formulation further comprises a second active agent.

[0087] Embodiment 10: The topical formulation of Embodiment 9, wherein the second active agent is for treating, reducing or inhibiting a symptom, complication or side effect caused by capecitabine in a subject undergoing treatment with capecitabine.

[0088] Embodiment 11: The topical formulation of Embodiment 9 or 10, wherein said second active agent is an anti-inflammatory agent, a phosphodiesterase 5 (PDE5) inhibitor, a corticosteroid, urea, or pyridoxine (vitamin B6).

[0089] Embodiment 12: The topical formulation of Embodiment 11, wherein said second active agent is an anti-inflammatory agent.

[0090] Embodiment 13: The topical formulation of Embodiment 12, wherein the antiinflammatory agent is selected from the group consisting of steroidal anti-inflammatory agents, non-steroidal anti-inflammatory drugs (NSAIDs, such as COX inhibitors, e.g., COX-1 or COX nonspecific inhibitors, and selective COX-2 inhibitors), corticosteroids (including glucocorticoids, e.g. cortisol, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, and beclometasone), anti-malarial medication (such as hydrochloroquine), methotrexrate, sulfasalazine, leflunomide, anti-TNF medications, cyclophosphamise, pro-resolving drugs, mycophenolate, dexamethasone, rosiglitazone, prednisolone, corticosterone, budesonide, estrogen, estradiol, sulfasalazine, fenfibrate, pravastatin, simvastatin, proglitazone, acetylsalicylic acid, mycophenolic acid, mesalamine, hydroxyurea, opiates (e.g., endorphins, enkephalins, dynorphin, barbiturates, oxycodone, morphine, lidocaine and the like), steroids, sirolimus, everolimus, biolimus (A9), zotarolimus (ABT-578), tacrolimus, pimecrolimus, genistein, and any combinations thereof.

[0091] Embodiment 14: The topical formulation of Embodiment 13, wherein the antiinflammatory agent is selected from the group consisting of salicylic acid derivatives4922-4270-5705 1 30Attorney Docket No.: 102577-000100WOPTsuch as aspirin, sodium salicylate, choline magnesium trisalicylate, salicylate, diflunisal, sulfasalazine and olsalazine; para-aminophenol derivatives such as acetaminophen; indole and indene acetic acids such as indomethacin and sulindac; heteroaryl acetic acids such as tolmetin, diclofenac and ketorolac; arylpropionic acids such as ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen and oxaprozin; anthranilic acids (fenamates) such as mefenamic acid and meloxicam; enolic acids such as the oxicams (piroxicam, meloxicam); alkanones such as nabumetone; diarylsubstituted furanones such as refecoxib; diaryl-substituted pyrazoles such as celecoxib; indole acetic acids such as etodolac and sulfonanilides such as nimesulide; and analogues and derivatives thereof.

[0092] Embodiment 15: The topical formulation of Embodiment 11, said second active agent is a PDE5 inhibitor.

[0093] Embodiment 16: The topical formulation of Embodiment 15, wherein PDE5 inhibitor is sildenafil, vardenafil, tadalafil, avanafil, mirodenafil, udenafil, gisadenafil, yonkenafil (tunodafil), lodenafil fenspiride, MBCQ, zaprinast, icariin, NS-0200, or any combination thereof.

[0094] Embodiment 17: The topical formulation of Embodiment 9, wherein the second active agent is selected from the group consisting of corticosteroids, urea, pyridoxine (vitamin B6), 2-hydroxy-1,4-naphthoquinone, glycosides, antiarrhythmics, glucosamine sulfate, Boswellia, hyaluronic acid, rutin, MSM, trypsin, bromelain, chondroitin sulfate, glucosamine HCL, curcumin, turmeric, resveratrol, polyphenol classes, UC-II Collagen, Black pepper extract, 5-Loxin, Calcium, horsetail leaf extract, omega-3 fatty acids, Vitamin C, cetyl myristoleate, Gelatin, silicon dioxide, titanium dioxide, magnesium stearate, amitriptyline, nortriptyline, duloxetine, venlafaxine, willow bark, clover, prickly ash bark, Corydalis yanhusuo, lobelia, California poppy, metformin, carbamazepine, topiramate, pregabalin, gabapentin, duloxetine, desvenlafaxine, amitriptyline, azathioprine, cyclosporine, melatonin, fish oil, ginseng root, Ginkgo biloba extract, coenzyme Q10, St. John's Wort, S-adenosyl methionine, hypericin, pseudohypericin, xanthones, folic acid, vitamin B6, vitamin B12, Butterbur, cayenne, Zyflamend, acetaminophen, vitamin K, Epsom salt, proline, glycine, glutamine, phosphorus, silicon, Sulphur, Earl Grey, Tanacetum parthenium, Filipendula ulmaria, Boswellia serrata, Harpagophytum procumbens, Alpinia officinarum Uncaria tomentosa, Foeniculum vulgare, Origanum vulgare ssp. Hirtum, Rosmarinus officinalis, Thymus vulgaris, Antelaea azadirachta, Azadirachta indica, Melia azadirachta, Rumex crispus, Crocus sativus, Passiflora incarnata, Pedicularis canadensis, Lactuca virosa, Curcuma4922-4270-5705 1 31Attorney Docket No.: 102577-000100WOPTlonga, Tabebuia avellanedae, Bupleurum spp., Commiphora mukul, Yucca spp., Dioscorea villosa, Salix caprea, flower of water hyacinth, Flower of Henna (fragrance), Bitter Orange, Sweet Orange, Vanilla and combinations thereof.

[0095] Embodiment 18: The topical formulation of any one of Embodiments 1-17, wherein the formulation comprises a penetration enhancer, emollient, emulsifier, humectant, viscosity modifier, rheology modifier or thickening agent (gelling agent), surfactant, occlusive agent, colorant, preservative, exfoliating agent, antioxidant, chelating agent, isotonic agent, cooling agent, ultraviolet (UV) light absorbing or scattering agent, fragrance / perfume, soothing agent, solvent, pH modifier, opacifier or pearlizing agent, skin conditioner, or any combination thereof.

[0096] Embodiment 19: The topical formulation of any one of Embodiments 1-18, wherein the formulation comprises a penetration enhancer.

[0097] Embodiment 20: The topical formulation of Embodiment 19, wherein the penetration enhancer is selected from the group consisting of fatty acids, fatty acid esters, glycerol tri-esters, glycerol di-esters, glycerol monoesters, fatty alcohols, short chain alcohols, diols, polyols, pyrrolidones, bile salts, sulfoxides, chelating agents, surfactants, triacetin, amine oxides, and any combinations thereof.

[0098] Embodiment 21: The topical formulation of Embodiment 19 or 20, wherein the penetration enhancer is decyl alcohol, undecyl alcohol, dodecyl alcohol, oleyl alcohol, lauryl alcohol, isopropyl myristate, oleyl oleate, levulinic acid, ethanol, glycerol monooleate, methyl laurate, sorbitan monooleate, triacetin, aloe vera oil, benzethonium chloride, cetyl dimethylamine oxide, cetyl alcohol, cetyl lactate, cocamidopropyl betaine, cocoamine oxide diethanolamine, dimethyloctylamine oxide, 2-dodecoxyethyldimethylamine oxide, dimethyl-decylamine oxide, dimethylhexadecylamine oxide, dimethyl-tetradecylamine oxide, dimethyl isosorbide, dipropylene glycol, ethyl hexyl lactate, glycolic acid, 3-dodecoxy-2-hydroxypropyldi(3-hydroxypropyl)amine oxide, lactic acid, lauramine oxide, lauryl betaine, lauryl lactate, lauryl laurate, isopropyl palmitate, macrogol 15 hydroxystearate (Solutol HS 15), menthol, menthyl lactate, myristyl alcohol, myristal lactate, octyldodecanol, octyl salicylate, oleamine oxide, oleic acid, oleyl betaine, oleyldi(2-hydroxyethyl) amine oxide, PEG 1000, pentadecalactone, propylene glycol, salicylic acid, stearyl alcohol, stearyl lactate, 3,6,9-trioxaheptadecyl di ethyl amine oxide, di(2-hydroxyethyl)-tetradecylamine oxide, triethanolamine triacetate, dimethyl sulfoxide, isopropyl myristate, propylene glycol, polyethylene glycol, alkyl pyrrolidones, diethoxy glycol (Transcutol), lecithin, and any combination thereof.4922-4270-5705 1 32Attorney Docket No.: 102577-000100WOPT

[0099] Embodiment 22: The topical formulation of any one of Embodiments 19-21, wherein the formulation comprises the penetration enhancer in an amount from about 0.1% to about 10% (w / w or w / v).

[0100] Embodiment 23: The topical formulation of any one of Embodiments 1-22, wherein the formulation comprises an emollient.

[0101] Embodiment 24: The topical formulation of Embodiment 23, wherein the emollient is selected from the group consisting of natural oils, plant-derived oils, mineral oils, silicone oils (e.g., dimethyl silicone, polysiloxane, polydimethylsiloxane, and mixtures thereof), polyunsaturated fatty acids, paraffins, beeswaxes, squalenes, cetyl oil, petrolatum, lanolin and its derivatives, and any combinations thereof.

[0102] Embodiment 25: The topical formulation of Embodiments 23 or 24, wherein the emollient is arachidyl propionate, C1-C4 glycols, caprylic / capric triglyerides, caprylyl glycol, castor oil, ceteareth-20, ceteareth-30, cetearyl alcohol, ceteth 20, cetostearyl alcohol, cetyl acetate, cetyl alcohol, cetyl lactate, cetyl ricinoleate, cetyl stearyl alcohol, cocoa butter, cocoyl caprylocarprate, cyclomethicone, decyl oleate, diisopropyl adipate, diisopropyl dimerate, dimethicones, dormin, fatty acid glycols, fatty acids, fruit oils, glycerides, glycerols, glyceryl monostearate, glyceryl stearate, glycol esters, gyceryl monooleate, hydrogenated lanolin, isononyl isononanoate, isopropyl isostearate, isopropyl lanolate, isopropyl myristate, isopropyl palmitate, isosteric acid, isotridecyl isononanoate, jojoba oil, lanolin, lanolin alcohol, linoleic acid, liquid paraffins, long chain alcohols, maleated soybean oil, medium chain triglycerides, methicone, mineral oil, myristate derivatives like butyl myristate and myristyl myristate, myristyl lactate, myristyl myristate, neopentylglycol dicaprylate / dicaprate, nut oils, octyl dodecanol, octyl hydroxystearate, octyl palmitate, octyldodecanol, oleate derivates, oleic acid, oleyl alcohol, olive oil, paraffin, pentaerythrityl tetrastearate, polyethylene glycol, polyoxyethylene glycol fatty alcohol ethers, polyoxypropylene 15-stearyl ether, propylene glycol, propylene glycol dicaprylate, propylene glycol ricinoleate, propylene glycol stearate, rapeseed oil, soybean oil, squalane, steareth-2 or -100, stearic acid, stearyl alcohol, sucrose esters of fatty acids, tocopheryl acetate, tocopheryl linoleate, urea, vegetable oils, wheat germ glycerides, white petrolatum, urea, glycerol, propylene glycol, lactic acid, lanolin, liquid paraffin wax, aloe vera topical, glycerin topical, salicylic acid / urea topical, vitamin a & d topical, ammonium lactate topical, emollients topical, ammonium lactate / urea topical, hydrocortisone / urea topical, lactic acid / urea topical, petrolatum topical, vitamin a, vitamin d, vitamin e, aquaphor, bag balm, dimethicone, or any combinations thereof.4922-4270-5705 1 33Attorney Docket No.: 102577-000100WOPT

[0103] Embodiment 26: The topical formulation of any one of Embodiments 23-25, wherein the formulation comprises the emollient in an amount from about 0.1% to about 50% (w / w or w / v).

[0104] Embodiment 27: The topical formulation of any one of Embodiments 1-26, wherein the formulation comprises a humectant.

[0105] Embodiment 28: The topical formulation of Embodiment 27, wherein the humectant is acetamide MEA (acetyl ethanolamine), agarose, alkyl dimethicone, allatoin, aloe vera gel, arginine, arginine PCA (arginine 2-pyrrolidone carboxylate), asparagus cochinchinensis, beeswax, benzyl hyaluronate, butylene glycol, carboxylic acid amides, chitosan, chitosan PCA, copper, copper PCA, corn glycerides, dimethyl imidazolidinone, fatty acid esters, fructose, gluconolactone, glucosamine, glucose glutamate, glucose Sodium ammonia, glucuronic acid, glutamic acid, glycerin, glycerin, glyceryl polyether-12, glyceryl polyether-20, glyceryl polyether-26, glyceryl polyether-7, hexylene glycol, honey, hydrogenated starch hydrolysate, hydrogenated vegetable oils, hydrolyzed corn starch, hydrolyzed keratin, hydroxyethyl urea, isomerized sugar, kombucha, lactamide MEA, lactic acid, lactobionic acid, lactose, lactose lysine PCA, lanolin alcohol, lysine, maltitol, maltose, mannitol, methyl glutamic polyether-10, methyl glutamic polyether-20, mineral oil, mucopolysaccharides, n-acetylethanolamine, panthenol, PCA (2-pyrrolidone carboxylate), PEG-10 propylene glycol, PEG-2 lactamide, petrolatum, polyamino acids, polyamino sugar condensates, trehalose, polysaccharides, potassium PCA, hyaluronic acid, glycerin, propylene glycol, propylene glycol citrate, quaternized nitrogen moisturizers, sodium aspartate, sodium lactate, sodium PCA (sodium 2-pyrrolidone carboxylate), sorbitol, sugar hydrolysates, TEA-lactate, TEA-PCA, tocopherol esters, triacetin, urea, vegetable oils, xylitol,, or any combinations thereof.

[0106] Embodiment 29: The topical formulation of Embodiment 27 or 28, wherein the humectant is propylene glycol, sorbitol, butylene glycol, hexylene glycol, acetamide MEA, honey, and sodium PCA, sorbitol, triacetin, or any combination thereof.

[0107] Embodiment 30: The topical formulation of Embodiments 27-29, wherein the formulation comprises the humectant in an amount from about 0.01% to about 50% (w / w or w / v).

[0108] Embodiment 31: The topical formulation of any one of Embodiments 1-30, wherein the formulation comprises a viscosity modifier.

[0109] Embodiment 32: The topical formulation of Embodiment 31, wherein the viscosity modifier is selected from the group consisting of inorganic salts, polymers, gums, organic solvents.4922-4270-5705 1 34Attorney Docket No.: 102577-000100WOPT

[0110] Embodiment 33: The topical formulation of Embodiments 31 or 32, wherein the viscosity modifier is selected from the group consisting of collagen, gellan, guar and guar derivatives, xanthum gum, carbohydrate gel-forming polymers, carob bean gum, locust bean gum, carrageenan, alginates (e.g., alginic acid, sodium alginate, potassium alginate, ammonium alginate, and calcium alginate), agar, guar gum, xanthan gum, carboxymethyl cellulose, clear starch, pectin, gelatin, arrowroot, cornstarch, katakuri starch, potato starch, sago, tapioca, furcellaran, sodium pyrophosphate, polyacrylates, cellulose, cellulose derivative (e.g., hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, and the like), cellulose gum,, carbopol, sodium hyaluronate, sodium chloride, calcium chloride, sodium sulfate, magnesium sulfate, alcohols, glycol ethers, magnesium aluminum silicate, hydrogenated castor oil, and any combinations thereof.

[0111] Embodiment 34: The topical formulation of any one of Embodiments 31-33, wherein the formulation comprises the viscosity modifier in an amount from about 0.01% to about 50% (w / w or w / v).

[0112] Embodiment 35: The topical formulation of any one of Embodiments 1-34, wherein the formulation comprises a rheology modifier or thickening agent.

[0113] Embodiment 36: The topical formulation of Embodiment 35, wherein the rheology modifier or thickening agent is selected from the groups consisting of polymers, cellulose, cellulose polymers, cellulose derivatives, carbomer polymers, carbomer derivatives, polyvinyl alcohol, poloxamers, polysaccharides, natural gums, finely divided silica, laponite, colloidal magnesium aluminum silicate, and any combinations thereof.

[0114] Embodiment 37: The topical formulation of Embodiment 35 or 36, wherein the rheology modifier or thickening agent selected from the group consisting of aluminum silica gel, arabiya gum, Bee gum, carbopol, carboxyvinyl polymer, carrageenan, ethylene glycol, glycerin, guar gum, gum Arabic, hydroxyethyl cellulose, hydroxypropyl cellulose, karaya gum, lactol, laponite, locust bean gum, maltitol, methylcellulose, polyacrylic acid crosslinked with polyallyl sucrose or polyallyl pentaerythritol, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, propylene glycol, silica gel, sodium alginate, sodium hydroxyethylcellulose, sodium polyacrylate, sorbitol, thickening silica, tragacanth, tragacanth gum, water soluble salts of cellulose ethers (such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose), xanthan gum, xylitol, and any combinations thereof.4922-4270-5705 1 35Attorney Docket No.: 102577-000100WOPT

[0115] Embodiment 38: The topical formulation of any one of Embodiments 35-27, wherein the formulation comprises the rheology modifier or thickening agent in an amount from about 0.01 % to about 50% (w / w or w / v).

[0116] Embodiment 39: The topical formulation of any one of Embodiments 1-38, wherein the formulation comprises a surfactant.

[0117] Embodiment 40: The topical formulation of Embodiment 39, wherein the surfactant is an anionic, non-ionic, cationic, zwitterionic or amphoteric surfactant.

[0118] Embodiment 41: The topical formulation of Embodiment 39 or 40, wherein the surfactant is selected from the group consisting of sodium lauroyl sarcosine, potassium lauroyl sarcosine, aodium coco acylsarcosinate, cocoyl flesh Propylhomoserin potassium, sodium lauroylmethyl taurate, sodium cocoyl methyl sodium taurocholate, sodium lauroyl glutamate, lauryl trimethyl ammonium chloride, stearyl trimethyl ammonium chloride, benzethonium chloride, cetyl pyridinium chloride, cetyl pyridinium chloride benzalkonium chloride, stearyl dimethyl benzyl ammonium chloride, polyoxyethylene lauryl ether sodium sulfate, sodium lauryl sulfate, sodium myristyl sulfate, sodium N-lauroyl sarcosinate, sodium N-myristol sarcosine, sodium dodecylbenzene sulfonate, sodium coconut fatty acid monoglyceride monosulfate, sodium lauryl sulfoacetate, sodium a-olefin sulfonate, sodium N-palmitoyl glutamate, sodium N-methyl-N-acyl taurate, sucrose fatty acid ester, maltose fatty acid ester, maltitol fatty acid ester, lactol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan monostearate, polyoxyethylene higher alcohol ether, polyoxyethylene cured Castor oil, polyoxyethylene polyoxypropylene copolymer, polyoxyethylene polyoxypropylene fatty acid ester, polyglycerin fatty acid ester, coconut oil fatty acid amidopropyl betaine, lauryldimethylaminoacetic acid betaine, lauryldimethylamine oxide, 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolium betaine, N-lauryldiaminoethylglycine, N-myristyldiaminoethylglycine, sodium N-alkyl-1-hydroxyethylimidazoline betaine, and any combination thereof.

[0119] Embodiment 42: The topical formulation of any one of Embodiments 39-41, wherein the formulation comprises the surfactant in an amount from about 0.01% to about 5% (w / w or w / v).

[0120] Embodiment 43: The topical formulation of any one of Embodiments 1-42, wherein the formulation comprises an occlusive agent.

[0121] Embodiment 44: The topical formulation of Embodiment 43, wherein the occlusive agent is selected from the group consisting of petrolatum, shea butter, dimethicones, plant and animal oils such as avocado, canola, cod liver, and com,4922-4270-5705 1 36Attorney Docket No.: 102577-000100WOPTmineral oil, olive oil, soybean oil, lanolin, glycerides, beeswax, triglycerides, long chain fatty alcohols, cocoa butter, coconut oil, jojoba oil, propylene glycol, and their derivatives, and any combinations thereof.

[0122] Embodiment 45: The topical formulation of Embodiment 43 or 44, wherein the occlusive agent is arachidyl behenate, butter, canola oil, cottonseed oil, dimethicone, glycol dilaurate, hydrogenated shea butter, isocetyl behenate, lauryl stearate, methicone, neopentyl glycol stearate, octyldodecyl myristate, prunus amygdalua dulcis (sweet almond) oil, ricinus communis (castor) seed oil, shea butter cetyl esters, squalane, tocopherol, zea mays (com) oil, or any combination thereof.

[0123] Embodiment 46: The topical formulation of any one of Embodiments 43-45, wherein the formulation comprises the occlusive agent in an amount from about 1 % to about 50% (w / w or w / v).

[0124] Embodiment 47: The topical formulation of any one of Embodiments 1-46, wherein the formulation comprises a colorant.

[0125] Embodiment 48: The topical formulation of Embodiment 47, wherein the colorant is selected from the group consisting of FD& C Blue No. 1 (Brilliant Blue), FD& C Blue No. 2 (Indigotine), FD& C Green No. 3 (Fast Green), FD& C Red No. 3 (Erythrosine), FD& C Red No. 40 (Allura Red), FD& C Yellow No. 5 (Tartrazine), FD& C Yellow No. 6 (Sunset Yellow), annatto extract, anthocyanis, aronia / redfhiit, beet juice, beet powder, beia-carotene, beta-apo-8- carotenal, black current, burnt sugar, canthaxanthin, caramel, carbo medicinalis, carmine, carmine / beta-carotene, carmine blue, carminic acid, carrot, carrot oils, chlorophyll, chlorophyllin, cochineal extract, copper-chlorophyll, copper- chlorophyll in, curcumin, curcumin / Cu-chlorophyllin, elderberry, grape, grape skin extracts, hibiscus, lutein, mixed carotenoids, paprika, paprika extract, paprika oieoresin, riboflavin, saffron, spinach, stinging nettle, titanium dioxide, turmeric, and combinations thereof. Preferred coloring agents according to the present invention are FD& C Blue No. 1 (Brilliant Blue), FD& C Blue No. 2 (Indigotine), FD& C Green No. 3 (Fast Green), FD& C Red No. 3 (Erythrosine), FD& C Red No. 4, FD& C Red No. 33, FD& C Red No. 40 (Allure Red), FD& C Yellow No. 5 (Tartrazine), FD& C Yellow No. 6 (Sunset Yellow), FD& C Yellow No. 10, FD& C Orange No. 4, D& C blue No. 1, D& C blue No. 4, D& C brown No. 1, D& C green No. 5 through No. 8, D& C orange No. 4 through No. 11, D& C yellow No. 2 through No. 11, D& C red No. 6 through No. 40, and any combinations thereof.4922-4270-5705 1 37Attorney Docket No.: 102577-000100WOPT

[0126] Embodiment 49: The topical formulation of Embodiment 47 or 48, wherein the formulation comprises the colorant in an amount from about 0.01% to about 1% (w / w or w / v).

[0127] Embodiment 50: The topical formulation of any one of Embodiments 1-49, wherein the formulation comprises a preservative.

[0128] Embodiment 51: The topical formulation of Embodiment 50, wherein the preservative is selected from the group consisting of benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, p-hydroxybenzoic acid, methyl p-hydroxybenzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chlorocylenol, ethanol, glycerin, hexetidine, imidourea, phenol, phenoxyethanol, phenylethyl alcohol, phenyl mercuric nitrate, propylene glycol, sodium propionate, thimerosyl, methyl paraben, ethyl paraben, butyl paraben, isobutyl paraben, benzyl paraben, citric acid, trisodium citrate, sorbic acid, dichlorinated phenol, phumeotassium sorbate, phenoxyethanol, parabens (such as methylparaben and propylparaben), propylene glycols, sorbates, urea derivatives (such as diazolindinyl urea) and any combination thereof.

[0129] Embodiment 52: The topical formulation of Embodiment 50 or 51, wherein the formulation comprises the preservative in an amount from about 0.01% to about 10 % (w / w or w / v).

[0130] Embodiment 53: The topical formulation of any one of Embodiments 1-52, wherein the formulation comprises an exfoliating agent.

[0131] Embodiment 54: The topical formulation of Embodiment 53, wherein the exfoliating agent is selected from the group consisting of alpha-hydroxyacids, beta hydroxyacids, oxaacids, oxadiacids, and their derivatives such as esters, anhydrides, and salts thereof.

[0132] Embodiment 54: The topical formulation of Embodiment 53 or 54, wherein the exfoliating agent is glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, 2-hydroxyalkanoic acid, mandelic acid, salicylic acid, or derivative thereof.

[0133] Embodiment 56: The topical formulation of any one of Embodiments 53-55, wherein the formulation comprises the exfoliating agent in an amount from about 0.001% to about 20% (w / w or w / v).

[0134] Embodiment 57: The topical formulation of any one of Embodiments 1-56, wherein the formulation comprises an antioxidant.

[0135] Embodiment 58: The topical formulation of Embodiment 57, wherein the antioxidant is sodium metabisulfite, sodium sulfite, sodium bisulfite, sodium thiosulfate,4922-4270-5705 1 38Attorney Docket No.: 102577-000100WOPTvitamin C (ascorbic acid), vitamin E, vitamin E isomers (such as p-, y-, and 5-tocopherols and a-, p-, y-, and 6-tocotrienols;) vitamin A, B vitamins (e.g. vitamin B6), flavonoids, selenium, carotenoids (e.g. beta-carotene), esters of gallic acid (e.g., propyl, octyl and dodecyl esters of gallic acid), butylated hydroxyanisole (BHA) (e.g., 2-tert-butyl-4-hydroxyanisole and 3-tert- butyl-4-hydroxyanisole), butylated hydroxytoluene (BHT), nordihydroguairetic acid, alkylated parabens, cysteine, glutathione, dihydrolipoic acid, 2-mercaptoethane sulfonic acid, 2-mercaptobenzimidazole sulfonic acid, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, polyphenols (such as 2-tert-butyl-4- methyl phenol, 2-tert-butyl-5-methyl phenol, and 2-tert-butyl-6-methyl phenol), tert-butylhydroquinone (TBHQ), ascorbyl palmitate, n-propyl gallate, or any combination thereof.

[0136] Embodiment 59: The topical formulation of Embodiment 57 or 58, the wherein the formulation comprises the antioxidant in an amount from about 0.01% to about 10 % (w / w or w / v).

[0137] Embodiment 60: The topical formulation of any one of Embodiments 1-59, wherein the formulation comprises a chelating agent.

[0138] Embodiment 61: The topical formulation of Embodiment 60, wherein the chelating agent is a metal chelator.

[0139] Embodiment 62: The topical formulation of Embodiment 60 or 61, wherein the chelating agent is ethylenediaminetetraacetic acid (EDTA), citrate, ethylene glycol tetraacetic acid (EGTA), 1,2-bis(o-aminophenoxy)ethane-N, N, N', N'-tetraacetic acid (BAPTA), diethylene triamine pentaacetic acid (DTPA), 2,3-dimercapto-l-propanesulfonic acid (D PS), dimercaptosuccinic acid (DMSA), a-lipoic acid, salicylaldehyde isonicotinoyl hydrazone (SIH), hexyl thioethylamine hydrochloride (HTA), desferoxamine, or any combination thereof.

[0140] Embodiment 63: The topical formulation of any one of Embodiments 60-62, the wherein the formulation comprises the chelating agent in an amount from about 0.01% to about 10 % (w / w or w / v).

[0141] Embodiment 64: The topical formulation of any one of Embodiments 1-63, wherein the formulation comprises an isotonic agent.

[0142] Embodiment 65: The topical formulation of Embodiment 64, wherein the isotonic agent is selected from the group consisting of polyhydric sugar alcohols, trihydric sugar alcohols, inorganic salts, and any combination thereof.

[0143] Embodiment 66: The topical formulation of Embodiment 64 or 65, wherein the isotonic agent is glycerol, erythritol, arabitol, xylitol, sorbitol, mannitol, glucose, trehalose,4922-4270-5705 1 39Attorney Docket No.: 102577-000100WOPTlactose, fructose, xylitol, glycerin, polyethyleneglycol, propylene glycol, sodium chloride, potassium chloride, calcium chloride, or any combination thereof.

[0144] Embodiment 67: The topical formulation of any one of Embodiments 64-66, the wherein the formulation comprises the isotonic agent in an amount from about 0.01% to 10% (w / w orw / v).

[0145] Embodiment 68: The topical formulation of any one of Embodiments 1-67, wherein the formulation comprises a cooling agent.

[0146] Embodiment 69: The topical formulation of Embodiment 68, wherein the cooling agent is WS-3; WS-23; menthol; 3-substituted-P-menthanes; N-suhstituted-P-menthane-3-carboxamides; isopulegol; 3-(1- menthoxy)propane-1,2-diol; 3-(1-menthoxy)-2-methylpropane-1,2-diol; p-menthane-2,3-diol; p-menthane-3,8-diol; 6-isopropyl-9-methyl-1,4-dioxaspiro[4,5]decane-2-methanol; menthyl succinate and its alkaline earth metal salts; trimethylcyclohexanol; N-ethyl-2-isopropyl-5-methylcyclohexanecarboxamide; Japanese mint oil; peppermint oil; menthone: menthone glycerol ketal; menthyl lactate; 3-(1-menthoxy)ethan-1-ol; 3-(1-menthoxy)propan-1-ol; 3-(1- menthoxy)butan-1-ol; 1 -menthylacetic acid N-ethylamide; 1-menthyl-4-hydroxypentanoate; 1- menthyl-3-hydroxybutyrate; N,2,3-trimethyl-2-(1-methylethyl)-butanamide; n-ethyl-t-2-c-6 nonadienamide; N, N-dimethyl menthyl succinamide; menthyl pyrrolidone carboxylate; or any combination thereof.

[0147] Embodiment 70: The topical formulation of any one of 68-69, the wherein the formulation comprises the cooling agent in an amount from about 0.01% to 10% (w / w or w / v).

[0148] Embodiment 71: The topical formulation of any one of Embodiments 1-70, wherein the composition comprises an UV absorbing or scattering agent.

[0149] Embodiment 72: The topical formulation of Embodiment 71, wherein UV absorbing or scattering agent is selected from the group consisting of ultraviolet absorber of benzoic acid system such as para-aminobenzoic acid (hereinafter, abbreviated as PABA), PABA monoglycerin ester, N,N-dipropoxy PABA ethyl ester, N, N-diethoxy PABA ethyl ester, N, N-dimethyl PABA ethyl ester, N, N-dirnethyl PABA butyl ester, and N, N-dimethyl PABA methyl ester and the like; ultraviolet absorber of anthranilic acid system such as homomenthyl-N-acetyl anthranilate and the like; ultraviolet absorber of salicylic acid system such as amyl salicylate, menthyl salicylate, homomenthyl salicylate, octyl salicylate, phenyl salicylate, benzyl salicylate, p-isopropanol phenyl salicylate and the like; ultraviolet absorber of cinnamic acid system such as octyl cinnamate, ethyl-4-isopropyl cinnamate, methyl-2,5'diisopropyl cinnamate,4922-4270-5705 1 40Attorney Docket No.: 102577-000100WOPTethyl- 2,4-diisopropyl cinnamate, methyl-2,4-diisopropyl cinnamate, propyl-p-methoxy cinnamate, isopropyl-p-methoxy cinnamate, isoamyl-p-methoxy cinnamate, octyl- p-methoxy cinnamate(2-ethylhexyl-p-methoxy cinnamate), 2-ethoxyethyl-p- methoxy cinnamate, cyclohexyl-p-methoxy cinnamate, ethyl-a-cyano-p-phenyl cinnamate, 2-ethylhexyl-a-cyano-P-phenyl cinnamate, glyceryl mono-2- ethylhexanoyl-dipara-methoxy cinnamate, methyl- bis(trimethylsiloxane)silylisopentyl trimethoxy cinnamate and the like; 3-(4'- methylbenzylidene)~d.l-camphor; 3-benzylidene-d,l-camphor; urocanic acid, urocanic acid ethyl ester; 2-phenyl-5-methylbenzoxazole; 2,2'-hydroxy-5-methylphenylbenzotriazole; 2-(2?-hydroxy-5 '-t-octylphenyl)benzotriazole; 2-(2'- hydroxy-5'-methylphenylbenzotriazole; dibenzaladine; dianisoylmethane, 4- methoxy-4'-t-butyldibenzoylmethane; 5-(3,3-dimethyl-2-norbornylidene)-3- pentane-2-one; dimorpholinopyridazinone; powders such as titanium oxide, particulate titanium oxide, zinc oxide, particulate zinc oxide, ferric oxide, particulate ferric oxide, eerie oxide; and any combinations thereof.

[0150] Embodiment 73: The topical formulation of any one of 71-72, the wherein the formulation comprises the UV absorbing or scattering agent in an amount from about 0.01% to 10% (w / w orw / v).

[0151] Embodiment 74: The topical formulation of any one of Embodiments 1-73, wherein the formulation comprises a fragrance.

[0152] Embodiment 75: The topical formulation of Embodiment 74, wherein the fragrance is 2,4-dimethyl-3-cyclohexene-1-carbaldehyde; isocyclocitral; menthone; isomenthone; ROMASCONE® (methyl 2,2-dimethyl-6-methylene-1-cyclohexanecarboxylate); nerone; terpineol; dihydroterpineol; terpenyl acetate; dihydroterpenyl acetate; dipentene; eucalyptol; hexylate; rose oxide; PERYCOROLLE® ((S)-1,8-p-menthadiene-7-ol); 1-p-menthene-4-ol; (1RS,3RS,4SR)-3-p-mentanyl acetate; (1R,2S,4R)-4,6,6-trimethyl-bicyclo[3,1,1]heptan-2-ol; DOREMOX® (tetrahydro-4-methyl- 2-phenyl-2H-pyran); cyclohexyl acetate; cyclanol acetate; Fructalate (1,4-cyclohexane diethyldicarboxylate); KOUMALACTONE® ((3ARS,6SR,7ASR)-perhydro-3,6-dimethyl-benzo[B]furan-2-one); Natactone ((6R)-perhydro-3,6-dimethyl-benzo[B]furan-2-one); 2,4,6-trimethyl-4-phenyl-1,3-dioxane; 2,4,6-trimethyl-3-cyclohexene-1-carbaldehyde; (E)- 3-methyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)-4-penten-2-ol; (1 'R, E)-2-ethyl-4-(2',2',3'-trimethyl-3'-cyclopenten-1'-yl)-2-buten-1-ol; POLYSANTOL® ((1'R, E)-3,3-dimethyl-5-(2',2',3'-trimethyl-3'-cyclopenten-1 '-yl)-4-penten-2-ol); fleuramone; PARADISONE® (methyl-(1R)-cis-3-oxo-2-pentyl-1 -cyclopentane acetate); Veloutone (2,2,5-Trimethyl-5-pentyl-1 -cyclopentanone); NIRVANOL® (3,3-dimethyl-5-(2,2,3-trimethyl-3-cyclopenten-1-4922-4270-5705 1 41Attorney Docket No.: 102577-000100WOPTyl)-4-penten-2-ol); 3-methyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-pentanol; damascones; NEOBUTENONE® (1 -(5,5-dimethyl-1 -cyclohexen-1 -yl)-4-penten-1 -one); nectalactone ((1 'R)-2-[2-(4'-methyl-3'-cyclohexen-1 '-yl)propyl]cyclopentanone); alphaionone; beta-ionone; damascenone; DYNASCONE® (mixture of 1-(5,5-dimethyl-1-cyclohexen-1 -yl)-4-penten-1 -one and 1 -(3,3-dimethyl-1 -cyclohexen-1 -yl)-4-penten-1 -one); DORINONE® beta (1-(2,6,6-trimethyl-1 -cyclohexen-1 -yl)-2-buten-1 -one); ROMANDOLI DE® ((1 S, 1'R)-[1 -(3', 3'-Di methy I - 1 '-cyclohexyl)ethoxycarbonyl]methyl propanoate); 2-tert-butyl-1 -cyclohexyl acetate; LIMBANOL® (1 -(2,2,3, 6-tetramethyl-cyclohexyl)-3-hexanol); trans-1-(2,2,6-trimethyl-1-cyclohexyl)-3-hexanol; (E)-3-methyl-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3-buten-2-one; terpenyl isobutyrate; LORYSIA® (4-(1, 1 -dimethylethyl)-1 -cyclohexyl acetate); 8-methoxy-1-p-menthene; HELVETOLIDE® ((1S,1'R)-2-[1-(3',3'-dimethyl-T-cyclohexyl) ethoxy]-2-methylpropyl propanoate); para tert-butylcyclohexanone; menthenethiol; 1 -methyl-4-(4-methyl-3-pentenyl)-3-cyclohexene-1-carbaldehyde; allyl cyclohexylpropionate; cyclohexyl salicylate; Methyl cedryl ketone; Verdylate; vetyverol; vetyverone; 1 -(octahydro-2,3,8, 8-tetramethyl-2-naphtalenyl)-1 -ethanone; (5RS.9RS, 10SR)-2,6,9, 10-tetramethyl-1 -oxaspiro[4.5]deca-3,6-diene and the (5RS,9SR,10RS) isomer; 6-ethyl-2, 10, 10-trimethyl-1 -oxaspiro[4.5]deca-3,6-diene; 1,2,3,5,6,7-hexahydro-1, 1,2,3,3-pentamethyl-4-indenone; HI VERNAL® (a mixture of 3-(3,3-dimethyl-5-indanyl)propanal and 3-(1, 1 -dimethyl-5-indanyl)propanal); Rhubofix® (3',4-dimethyl-tricyclo[6.2.1,0(2,7)]undec-4-ene-9-spiro-2'-oxirane); 9 / 10-ethyldiene-3-oxatricyclo[6.2.1.0(2,7)]undecane; POLYWOOD® (perhydro-5,5,8A-trimethyl-2-naphthalenyl acetate); octalynol; CETALOX® (dodecahydro-3a,6,6,9a-tetramethyl-naphtho[2,1-b]furan); tricyclo[5.2.1.0(2,6)]dec-3-en-8-yl acetate and tricyclo[5.2.1.0(2,6)]dec-4-en-8-yl acetate as well as tricyclo[5.2.1.0(2,6)]dec-3-en-8-yl propanoate and tricyclo[5.2.1.0(2,6)]dec-4-en-8-yl propanoate; camphor; borneol; isobornyl acetate; 8-isopropyl-6-methyl-bicyclo[2.2.2]oct-5-ene-2-carbaldehyde; camphopinene; cedramber (8-methoxy-2,6,6,8-tetramethyl-tricyclo[5.3.1.0(1,5)]undecane); cedrene; cedrenol; cedrol; FLOREX® (mixture of 9-ethylidene-3-oxatricyclo[6.2.1,0(2,7)]undecan-4-one and 10-ethylidene-3-oxatricyclo[6.2.1.0(2,7)]undecan-4-one); 3-methoxy-7,7-dimethyl-10-methylene-bicyclo[4.3.1 ]decane; CEDROXYDE® (trimethyl-13-oxabicyclo-[10.1,0]-trideca-4,8-diene); Ambrettolide LG ((E)-9-hexadecen-16-olide); HABANOLIDE® (pentadecenolide); muscenone (3-methyl-(4 / 5)-cyclopentadecenone); muscone; EXALTOLIDE® (pentadecanolide); EXALTONE® (cyclopentadecanone); (1-ethoxyethoxy)cyclododecane; Astrotone; LILIAL®; rosinol; or any combination thereof.4922-4270-5705 1 42Attorney Docket No.: 102577-000100WOPT

[0153] Embodiment 76: The topical formulation of any one of 74-75, the wherein the formulation comprises the fragrance in an amount from about 0.01% to 10% (w / w or w / v).

[0154] Embodiment 77: The topical formulation of any one of Embodiments 1-76, wherein the formulation comprises a soothing agent.

[0155] Embodiment 78: The topical formulation of Embodiment 77, wherein the soothing agent is aloe, avocado oil, green tea extract, hops extract, chamomile extract, colloidal oatmeal, calamine, cucumber extract, sodium palmate, sodium palm kerneiate, butyrospermum parkii (i.e., shea butter), menthe piperita (i.e., peppermint) leaf oil, sericin, pyridoxine (a form of vitamin B6), retinyl paimitate and / or other forms of vitamin A, tocopheryl acetate and / or other forms of vitamin E, lauryl laurate, hyaluronic acid, aloe barbadensis leaf juice powder, euterpe oleracea (i.e., acai berry) fruit extract, riboflavin (i.e., vitamin B2), thiamin HCI lor other forms of vitamin B1, or any combination thereof.

[0156] Embodiment 79: The topical formulation of any one of 77-78, the wherein the formulation comprises the soothing agent in an amount from about 0.01% to 10% (w / w or w / v).

[0157] Embodiment 80: The topical formulation of any one of Embodiments 1-79, wherein the formulation comprises a solvent.

[0158] Embodiment 81: The topical formulation of any one of Embodiments 1-81, wherein the formulation comprises a solvent selected from the group consisting of water, alcohols (e.g., methyl, ethyl, isopropyl alcohols and methylene chloride); ketones (e.g., acetone); aldehydes; aromatic hydrocarbons such as benzene derivatives (e.g., xylenes and toluenes); aliphatic hydrocarbons; lower molecular weight alkanes and cycloalkanes (e.g., hexanes, heptanes and cyclohexanes); esters, such as alkanoic acid esters (e.g., ethyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate, isobutyl isobutyrate, hexyl acetate, 2-ethylhexyl acetate or butyl acetate); amines; ethers; glycols; glycol ethers; alkyl halides; aromatic halides; organopolysiloxanes, alkyl siloxanes; and any combinations and mixtures thereof.

[0159] Embodiment 82: The topical formulation of any one of Embodiments 80-81, wherein the solvent is water, dimethyl isosorbide, diethylene glycol monoethyl ether, PEG 400, propylene glycol, benzyl alcohol, isododecane, isohexadecane, Isopar L (C11-C13), Isopar H (C11-C12), hydrogentated polydecene, hexamethylcyclotrisiloxane, octamethyleyelotetrasiloxane, decamethylcyclopentasiloxane, dodecamethylcyclohexasiloxane, octamethyltrisiloxane, decamethyltetrasiloxane,4922-4270-5705 1 43Attorney Docket No.: 102577-000100WOPTdodecamethylpentasiloxane, tetradecamethyl he xasiloxane, hexadeamethylheptasiloxane, heptamethyl-3-{(trimethylsilyl)oxy)}trisiloxane, hexa methyl-3,3,bis{(trimethlylsilyl)oxy}trisiloxane, pentamethyl{(trimethylsilyl)oxy} cyclotrisiloxane, polydimethylsiloxanes, polyethylsiloxanes, polymethylethylsiloxanes, polymethylphenylsiloxanes, polydiphenylsiloxanes.

[0160] Embodiment 83: The topical formulation of any one of Embodiments 80-82, wherein the solvent is a volatile solvent.

[0161] Embodiment 84: The topical formulation of any one of Embodiments 80-83, wherein the solvent has a viscosity at 25°C in the range of about 1 to about 1,000 mm2 / sec.

[0162] Embodiment 85: The topical formulation of any one of Embodiments 80-84, wherein the formulation comprises the solvent in an amount from about 10% to about 80% (w / w or w / v).

[0163] Embodiment 86: The topical formulation of any one of Embodiments 1-85, wherein the formulation comprises an opacifier or pearlizing agent.

[0164] Embodiment 87: The topical formulation of Embodiment 86, wherein the opacifier or pearlizing agent is titanium dioxide, zinc oxide, kaolin clay, calcined kaolin clay, montmorillonite clay, calcined montmorillonite clay, talc, barium sulfate, bentonite clays, silicates, silicas, calcium carbonate, precipitated calcium carbonate, zirconates (e.g., strontium zirconate, and mica substrates coated with titanium dioxide and / or metal oxides like iron oxide or tin oxide), calcium carbonate, carbon black or carbon based opacifiers, iron oxides, metal phthalocyanines, styrene / vinyl pyrrolidone copolymers, styrene / acrylic copolymers, stryrene / acrylamide copolymers, ethylene glycol monostearate, ethylene glycol distearate, or combinations thereof.

[0165] Embodiment 88: The topical formulation of any one of Embodiments 86-87, wherein the formulation comprises the opacifier or pearlizing agent in an amount from about 0.5% to about 10% (w / w or w / v).

[0166] Embodiment 89: The topical formulation of any one of Embodiments 1-88, wherein the formulation comprises a skin conditioner.

[0167] Embodiment 90: The topical formulation of Embodiment 89, wherein the skin conditioner is selected from the group consisting of hyaluronic acid, alpha hydroxyl acids (i.e.: glycolic acid, lactic acid, ascorbic acid), polyhydroxy acids (i.e.: gluconolactone, lactobionic acid), beta hydroxyl acids, dipate esters, alkyl benzoates, fatty acid esters of Csor greater, esterified erucates, laurates, neopentanoates, salicylates, stearates, triglycerides, carbonates, glycols, glycerin, mineral oils, phytantriol, panthenyl ethyl4922-4270-5705 1 44Attorney Docket No.: 102577-000100WOPTether, primula veris extract, chamomi, sambucus nigra flower extract, panthenol, polyquaternium-51, cetyl alcohol, glycolic acid, stearyl alcohol, sodium lauryl sulfate, sodium dioctyl sulfide succinate, sodium stearate, sorbitan esters, ethoxylated fatty acids, ethoxylated fatty alcohols such as tride Cess-9 and PEG-5 ethyl hexanoate, sorbitol, mannitol, propylene lanolin, and combinations therefore.

[0168] Embodiment 91: The topical formulation of any one of Embodiments 89-91, wherein the formulation comprises the skin conditioner in an amount from about 0.5% to about 29% (w / w or w / v).

[0169] Embodiment 92: The topical formulation of any one of Embodiments 1-91, wherein the formulation comprises a steroid.

[0170] Embodiment 93: The topical formulation of Embodiment 92, wherein the steroid is selected from the group consisting of clobetasol propionate, halobetasol propionate, augmented betamethasone dipropionate, diflorasone diacetate, betamethasone dipropionate, betamethasone valerate, fluocinonide, fluticasone propionate, mometasone furoate, desoximetasone, amcinonide, topicort, hydrocortisone valerate, triamcinolone acetonide, alclometasone dipropionate, triamcinolone diacetate, desonide, hydrocortisone acetate, dexamethasone, prednisolone, methylprednisolone, hydrocortisone, betamethasone dipropionate, clobetasol propionate, diflorasone diacetate, fluocinonide, flurandrenolid, halobetasol, amcinonide ointment, desoximetasone, diflorasone diacetate, halcinonide, amcinonide, fluticasone propionate, triamcinolone acetonide, betamethasone valerate, desoximetasone, hydrocortisone 17-butyrate, hydrocortisone probutate, hydrocortisone valerate, fluocinolone acetonide, fluticasone propionate, mometasone furoate, triamcinolone acetonide, triamcinolone acetonide, alclometasone dipropionate, desonide, fluocinolone acetonide, diflorasone topical, prednicarbate topical, clocortolone topical, halcinonide topical, fluocinolone topical, fluticasone topical, amcinonide topical, ammonium lactate / halobetasol topical, mometasone topical, clobetasol topical, flurandrenolide topical, desonide topical, betamethasone topical, desoxi metasone topical, fluocinonide topical, prednisolone, dexamethasone, prednisone, triamcinolone, prednisolone, methylprednisolone, budesonide, triamcinolone, dexamethasone, cortisone, deflazacort and combinations thereof.

[0171] Embodiment 94: The topical formulation of any one of Embodiments 92-93, wherein the formulation comprises the steroid in an amount from about 0.005% to about 5% (w / w or w / v).4922-4270-5705 1 45Attorney Docket No.: 102577-000100WOPT

[0172] Embodiment 95: The topical formulation of any one of Embodiments 1-94, wherein the formulation comprises a glycoside.

[0173] Embodiment 96: The topical formulation of Embodiment 95, wherein the glycoside is selected from the group consisting of steroidal glycoside, anthraquinones glycosides, cardiac glycosides, saponin glycosides, tetracyclic triterpenoids saponins, pentacyclic Ttriterpenoid saponins, coumarin glycosides, furocoumarin glycosides, cyanophore glycosides, flavonoids glycosides, flavone glycosides, flavanol glycosides, flavanone glycosides, chalone glycosides, isoflavonoid glycoside, anthocyanidin glycosides, isothiocyanate glycosides, phenol glycoside, aldehyde glycosides, bitter glycosides, and combinations thereof.

[0174] Embodiment 97: The topical formulation of any one of Embodiments 95 -96, wherein the formulation comprises the glycoside in an amount from about 0.005% to about 5% (w / w orw / v).

[0175] Embodiment 98: The topical formulation of any one of Embodiments 1-97, wherein the formulation comprises a silicone-based carrier or excipient.

[0176] Embodiment 99: The topical formulation of Embodiment 98, wherein the silicone-based carrier or excipient is a silicone elastomer blend, a silicone organic elastomer blend, a silicone resin, a silicone elastomer, a pressure sensitive adhesive, a silicone gum, a silicone wax, an elastomer base sealant, adhesive or any combination thereof. The silicone-based excipient may be a dimethicone cross polymer, a dimethicone / bis-isobutyl propylene glycol cross polymer, a polyethylene glycol-12 dimethicone / bis-isobutyl propylene glycol-20 cross polymer, or any combination thereof.

[0177] Embodiment 100: The topical formulation of any one of Embodiments 98-99, wherein the formulation comprises the silicone-based carrier or excipient in an amount from about 2% to about 99% (w / w or w / v).

[0178] Embodiment 101: The topical formulation of any one of Embodiments 1-100, wherein the composition comprises a carrier oil.

[0179] Embodiment 102: The topical formulation of Embodiment 101, wherein the carrier oils is coconut oil, jojoba oil, shea butter, primrose oil, arnica oil, argan oil, rosehip seed oil, tamanu oil, avocado oil, grape seed oil, safflower oil, sunflower oil, vegetable oil, canola oil, or any combinations thereof.

[0180] Embodiment 103: The topical formulation of any one of Embodiments 101-102, wherein the formulation comprises the carrier oil in an amount from about 2% to about 99% (w / w or w / v).4922-4270-5705 1 46Attorney Docket No.: 102577-000100WOPT

[0181] Embodiment 104: The topical formulation of any one of Embodiments 1-103, wherein the composition comprises an essential oil,

[0182] Embodiment 105: The topical formulation of Embodiment 104, wherein the essential oil is peppermint, frankincense, menthol, spearmint, wintergreen, copaiba, chamomile, lavender, marjoram, eucalyptus, rosemary, thyme, coconut oil, olive oil, clary sage, sandalwood, juniper, ginger, yarrow, vetiver, helichrysum, black pepper oil, lemongrass, rose geranium, bergamot, clove, jojoba, sweet almond, or any combinations thereof.

[0183] Embodiment 106: The topical formulation of any one of Embodiments 103-14, wherein the formulation comprises the essential oil in an amount from about 2% to about 99% (w / w or w / v).

[0184] Embodiment 107: The topical formulation of any one of Embodiments 1-106, wherein the composition comprises the pharmaceutically acceptable topical carrier or excipient in an amount from about 5% to about 99.9955% (w / w or w / v).

[0185] Embodiment 108: The topical formulation of any one of Embodiments 1-107, wherein the formulation has a pH of from about 4.5 to about 9.5 (e.g., from about 5 to about 9, from about 5.5 to about 8.5, from about 6 to about 8, or from about 6.5 to about 7.5).

[0186] Embodiment 109: The topical formulation of any one of Embodiments 1-108, wherein the formulation is in the form of a lotion, cream, solution, gel, emugel, oil, serum, powder, ointment, suspension, slurry, paste, spray, dispersion, or foam.

[0187] Embodiment 110: The topical formulation of any one of Embodiments 1-109, wherein the formulation is a transdermal patch or a controlled-release patch.

[0188] Embodiment 111: A composition comprising a CDA inhibitor, capecitabine, and a pharmaceutically acceptable carrier or excipient, wherein the composition is formulated for oral administration to a subject.

[0189] Embodiment 112: The composition of Embodiment 111, wherein the CDA inhibitor is tetrahydrouridine (THU); THU analog or derivative; ASTX727 (E7727); 5-methyl-2',3'-dideoxy-3'-azidocytidine (5mAZC); 5-methyl-2',3'-dideoxycytidine; 5-ethyl-2',3'dideoxy-3'-azidocytidine; 5-propyl-2',3'-dideoxycytidine; 5-propyl-2',3'-dideoxy-3'-azidocytidine; 5-propene-2',3'-dideoxy-3'-azidocytidine; 5-propyne-2',3'-dideoxy-3'-azidocytidine; 5-propyne-2',3'-dideoxy-3'-azidocytidine; Zebularine; or any combination thereof.

[0190] Embodiment 113: The composition of Embodiment 111 or 112, wherein the CDA inhibitor is tetrahydrouridine, or a fluorinated derivative thereof.4922-4270-5705 1 47Attorney Docket No.: 102577-000100WOPT

[0191] Embodiment 114: The composition of any one of Embodiments 111-113, wherein the CDA inhibitor is tetrahydrouridine, 2'-fluoro-2’-deoxytetrahydrouridine, or 2’-deoxy-2',2'-difluorotetrahydrouridine.

[0192] Embodiment 115: The composition of any one of Embodiments 111-113, wherein the CDA inhibitor is tetrahydrouridine; 2',2'-difluoro-dihydrouridine (DFDHU); 2',2'-difluoro-tetrahydrouridine (DFTHU); 2'(R)-fluoro-2’-deoxy-tetrahydrouridine; 2'(R)-fluoro-2’-deoxy-dihydrouridine ((R)-FDHU); 2'(S)-fluoro-2’-deoxy-tetrahydrouridine; 2'(S)-fluoro-2’-deoxy-dihydrouridine ((S)-FDHU); 2'(S)-fluoro-2’-deoxy-tetrahydrouridine ((S)-FTHU); 2’-deoxy-2',2'-difluoro-5,6-dihydrouridine; (4R)-2’-deoxy-2',2'-difluoro-3, 4,5,6-tetrahydrouridine; (4S)-2’-deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine; 1-(2-Deoxy-2,2-difluoro-p-D-erythro-pentofuranosyl)-tetrahydro-2(1H)-pyrimidinone; 2’-deoxy-2'-fluoro-5,6-dihydrouridine; (4R)-2’-deoxy-2'-fluoro-3,4,5,6-tetrahydrouridine; (4S)-2’-deoxy-2'-fluoro-3,4,5,6-tetrahydrouridine; 1 -(2-deoxy-2-fluoro-(3-D-ribofuranosyl)tetrahydro-2(1 H)-pyrimidinone; 1-(2-deoxy-2-fluoro-p-D-arabinofuranosyl)dihydro-2,4-(1H,3H)-pyrimidinedione; (4R)-1-(2-deoxy-2-fluoro-(3-D-arabinofuranosyl)tetrahydro-4-hydroxy-2(1 H)-pyrimidinone; (4S)-1 -(2-deoxy-2-fluoro-(3-D-arabinofuranosyl)tetrahydro-4-hydroxy-2(1H)-pyrimidinone; or any combination thereof.

[0193] Embodiment 116: The composition of any one of Embodiments 111-115, wherein the CDA inhibitor is tetrahydrouridine or (4R)-2'-Deoxy-2',2'-difluoro-3, 4,5,6-tetrahydrouridine.

[0194] Embodiment 117: The composition of any one of Embodiments 111-116, wherein the composition is in the form of a tablet, pill, capsule, powder, solution, suspension, or paste.

[0195] Embodiment 118: The composition of any one of Embodiments 111-117, wherein the CDA inhibitor and the capecitabine are differentially located in the composition.

[0196] Embodiment 119: The composition of any one of Embodiments 111-118, wherein the CDA inhibitor is bio-available prior to the capecitabine.

[0197] Embodiment 120: The composition of any one of Embodiments 111-118, wherein the CDA inhibitor is bio-available prior to the capecitabine.

[0198] Embodiment 121: A method for treating, reducing or inhibiting a symptom, complication or side effect caused by capecitabine, the method comprises: administering an effective amount of a CDA inhibitor to a subject in need thereof.4922-4270-5705 1 48Attorney Docket No.: 102577-000100WOPT

[0199] Embodiment 122: The method of Embodiment 121, wherein the subject is undergoing treatment with capecitabine and the method comprises co-administering the CDA inhibitor and the capecitabine.

[0200] Embodiment 123: The method of Embodiment 121 or 122, wherein the subject is undergoing treatment with capecitabine and the method comprises administering the CDA inhibitor prior to administering the capecitabine.

[0201] Embodiment 124: The method of Embodiment 123, wherein the CDA inhibitor is administered at least 15 minutes (e.g., at least 30 minutes, at least 45 minutes, at least an hour, at least 1.25 hours, at least 1.5 hours, at least 1.75 hours, at least 2 hours or more) prior to administering the capecitabine.

[0202] Embodiment 125: The method of Embodiment 121 or 122, wherein the subject is undergoing treatment with capecitabine and the method comprises administering the CDA inhibitor after administering the capecitabine.

[0203] Embodiment 126: The method of Embodiment 125, wherein the CDA inhibitor is administered at least 15 minutes (e.g., at least 30 minutes, at least 45 minutes, at least an hour, at least 1.25 hours, at least 1.5 hours, at least 1.75 hours, at least 2 hours or more) after administering the capecitabine.

[0204] Embodiment 127: The method of Embodiment 121 or 122, wherein the subject is undergoing treatment with capecitabine and the method comprises administering the CDA inhibitor and the capecitabine at the same time.

[0205] Embodiment 128: The method of any one of Embodiments 121-127, wherein the method comprises administering a second dose of the CDA inhibitor to the subject.

[0206] Embodiment 129: The method of Embodiment 128, wherein the second dose is administered at least about an hour (e.g., 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours or more) after the first dose.

[0207] Embodiment 130: The method of Embodiments 128 or 129, wherein the second dose is at a lower amount than the first administration of the CDA inhibitor.

[0208] Embodiment 131: The method of Embodiments 128 or 129, wherein the second dose is at a higher amount than the first administration of the CDA inhibitor.

[0209] Embodiment 132: The method of Embodiments 128 or 129, wherein the second dose is at about the same amount as the first administration of the CDA inhibitor.

[0210] Embodiment 133: The method of any one of Embodiments 121-132, wherein the symptom, complication or side effect caused by capecitabine is inflammation of the hands and feet (hand-foot syndrome, erythrodysesthesia); diarrhea, stomach pain and4922-4270-5705 1 49Attorney Docket No.: 102577-000100WOPTother gastro-intestinal symptom or complication; pain, redness, swelling, sores, or ulcers in mouth or lips; itching in the genital or other skin areas; anemia; and vomiting.

[0211] Embodiment 134: The method of any one of Embodiments 121-133, wherein the CDA inhibitor is tetrahydrouridine (THU); THU analog or derivative; ASTX727 (E7727); 5-methyl-2',3'-dideoxy-3'-azidocytidine (5mAZC); 5-methyl-2',3'-dideoxycytidine; 5-ethyl-2',3'dideoxy-3'-azidocytidine; 5-propyl-2',3'-dideoxycytidine; 5-propyl-2',3'-dideoxy-3'-azidocytidine; 5-propene-2',3'-dideoxy-3'-azidocytidine; 5-propyne-2',3'-dideoxy-3'-azidocytidine; 5-propyne-2',3'-dideoxy-3'-azidocytidine; Zebularine; or any combination thereof.

[0212] Embodiment 135: The method of any one of Embodiments 121-134, wherein the CDA inhibitor is tetrahydrouridine, or a fluorinated derivative thereof.

[0213] Embodiment 136: The method of any one of Embodiments 121-135, wherein the CDA inhibitor is tetrahydrouridine, 2'-fluoro-2’-deoxytetrahydrouridine, or 2’-deoxy-2',2'-difluorotetrahydrouridine.

[0214] Embodiment 137: The method of any one of Embodiments 121-135, wherein the CDA inhibitor is tetrahydrouridine; 2',2'-difluoro-dihydrouridine (DFDHU); 2', 2'-difluoro-tetrahydrouridine (DFTHU); 2'(R)-fluoro-2’-deoxy-tetrahydrouridine; 2'(R)-fluoro-2’-deoxy-dihydrouridine ((R)-FDHU); 2'(S)-fluoro-2’-deoxy-tetrahydrouridine; 2'(S)-fluoro-2’-deoxy-dihydrouridine ((S)-FDHU); 2'(S)-fluoro-2’-deoxy-tetrahydrouridine ((S)-FTHU); 2’-deoxy-2',2'-difluoro-5,6-dihydrouridine; (4R)-2’-deoxy-2',2'-difluoro-3, 4,5,6-tetrahydrouridine; (4S)-2’-deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine; 1-(2-Deoxy-2,2-difluoro-p-D-erythro-pentofuranosyl)-tetrahydro-2(1H)-pyrimidinone; 2’-deoxy-2'-fluoro-5,6-dihydrouridine; (4R)-2’-deoxy-2'-fluoro-3,4,5,6-tetrahydrouridine; (4S)-2’-deoxy-2'-fluoro-3,4,5,6-tetrahydrouridine; 1 -(2-deoxy-2-fluoro-(3-D-ribofuranosyl)tetrahydro-2(1 H)-pyrimidinone; 1-(2-deoxy-2-fluoro-p-D-arabinofuranosyl)dihydro-2,4-(1H,3H)-pyrimidinedione; (4R)-1-(2-deoxy-2-fluoro-(3-D-arabinofuranosyl)tetrahydro-4-hydroxy-2(1 H)-pyrimidinone; (4S)-1 -(2-deoxy-2-fluoro-(3-D-arabinofuranosyl)tetrahydro-4-hydroxy-2(1H)-pyrimidinone; or any combination thereof.

[0215] Embodiment 138: The method of any one of Embodiments 121-137, wherein the CDA inhibitor is tetrahydrouridine.

[0216] Embodiment 139: The method of any one of Embodiments 121-138, wherein the method further comprises co-administering a second active agent (other than the CDA inhibitor and the capecitabine) to the subject.4922-4270-5705 1 50Attorney Docket No.: 102577-000100WOPT

[0217] Embodiment 140: The method of Embodiment 139, wherein the second active agent is for treating, reducing or inhibiting a symptom, complication or side effect caused by capecitabine in a subject undergoing treatment with capecitabine.

[0218] Embodiment 141: The method of Embodiment 139 or 140, wherein said second active agent is an anti-inflammatory agent, a phosphodiesterase 5 (PDE5) inhibitor, a corticosteroid, urea, or pyridoxine (vitamin B6).

[0219] Embodiment 142: The method of Embodiment 141, wherein said second active agent is an anti-inflammatory agent.

[0220] Embodiment 143: The method of Embodiment 142, wherein the antiinflammatory agent is selected from the group consisting of steroidal anti-inflammatory agents, non-steroidal anti-inflammatory drugs (NSAIDs, such as COX inhibitors, e.g., COX-1 or COX nonspecific inhibitors, and selective COX-2 inhibitors), corticosteroids (including glucocorticoids, e.g. cortisol, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, and beclometasone), anti-malarial medication (such as hydrochloroquine), methotrexrate, sulfasalazine, leflunomide, anti-TNF medications, cyclophosphamise, pro-resolving drugs, mycophenolate, dexamethasone, rosiglitazone, prednisolone, corticosterone, budesonide, estrogen, estradiol, sulfasalazine, fenfibrate, pravastatin, simvastatin, proglitazone, acetylsalicylic acid, mycophenolic acid, mesalamine, hydroxyurea, opiates (e.g., endorphins, enkephalins, dynorphin, barbiturates, oxycodone, morphine, lidocaine and the like), steroids, sirolimus, everolimus, biolimus (A9), zotarolimus (ABT-578), tacrolimus, pimecrolimus, genistein, and any combinations thereof.

[0221] Embodiment 144: The method of Embodiment 143, wherein the antiinflammatory agent is selected from the group consisting of salicylic acid derivatives such as aspirin, sodium salicylate, choline magnesium trisalicylate, salicylate, diflunisal, sulfasalazine and olsalazine; para-aminophenol derivatives such as acetaminophen; indole and indene acetic acids such as indomethacin and sulindac; heteroaryl acetic acids such as tolmetin, dicofenac and ketorolac; arylpropionic acids such as ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen and oxaprozin; anthranilic acids (fenamates) such as mefenamic acid and meloxicam; enolic acids such as the oxicams (piroxicam, meloxicam); alkanones such as nabumetone; diarylsubstituted furanones such as refecoxib; diaryl-substituted pyrazoles such as celecoxib; indole acetic acids such as etodolac and sulfonanilides such as nimesulide; and analogues and derivatives thereof.4922-4270-5705 1 51Attorney Docket No.: 102577-000100WOPT

[0222] Embodiment 145: The method of Embodiment 141, said second active agent is a PDE5 inhibitor.

[0223] Embodiment 146: The method of Embodiment 145, wherein PDE5 inhibitor is sildenafil, vardenafil, tadalafil, avanafil, mirodenafil, udenafil, gisadenafil, yonkenafil (tunodafil), lodenafil fenspiride, MBCQ, zaprinast, icariin, NS-0200, or any combination thereof.

[0224] Embodiment 147: The method of Embodiment 139, wherein the second active agent is selected from the group consisting of corticosteroids, urea, pyridoxine (vitamin B6), 2-hydroxy-1,4-naphthoquinone, glycosides, antiarrhythmics, glucosamine sulfate, Boswellia, hyaluronic acid, rutin, MSM, trypsin, bromelain, chondroitin sulfate, glucosamine HCL, curcumin, turmeric, resveratrol, polyphenol classes, UC-II Collagen, Black pepper extract, 5-Loxin, Calcium, horsetail leaf extract, omega-3 fatty acids, Vitamin C, cetyl myristoleate, Gelatin, silicon dioxide, titanium dioxide, magnesium stearate, amitriptyline, nortriptyline, duloxetine, venlafaxine, willow bark, clover, prickly ash bark, Corydalis yanhusuo, lobelia, California poppy, metformin, carbamazepine, topiramate, pregabalin, gabapentin, duloxetine, desvenlafaxine, amitriptyline, azathioprine, cyclosporine, melatonin, fish oil, ginseng root, Ginkgo biloba extract, coenzyme Q10, St. John's Wort, S-adenosyl methionine, hypericin, pseudohypericin, xanthones, folic acid, vitamin B6, vitamin B12, Butterbur, cayenne, Zyflamend, acetaminophen, vitamin K, Epsom salt, proline, glycine, glutamine, phosphorus, silicon, Sulphur, Earl Grey, Tanacetum parthenium, Filipendula ulmaria, Boswellia serrata, Harpagophytum procumbens, Alpinia officinarum Uncaria tomentosa, Foeniculum vulgare, Origanum vulgare ssp. Hirtum, Rosmarinus officinalis, Thymus vulgaris, Antelaea azadirachta, Azadirachta indica, Melia azadirachta, Rumex crispus, Crocus sativus, Passiflora incarnata, Pedicularis canadensis, Lactuca virosa, Curcuma longa, Tabebuia avellanedae, Bupleurum spp., Commiphora mukul, Yucca spp., Dioscorea villosa, Salix caprea, flower of water hyacinth, Flower of Henna (fragrance), Bitter Orange, Sweet Orange, Vanilla and combinations thereof.

[0225] Embodiment 148: The method of any one of Embodiments 121-147, wherein the CDA inhibitor is administered locally.

[0226] Embodiment 149: The method of Embodiment 148, wherein the CDA inhibitor is administered topically, e.g., the CDA inhibitor is administered topically to the skin, such as the CDA inhibitor is administered topically to the skin of the hands or feet.

[0227] Embodiment 150: The method of Embodiment 148 or 149, wherein the CDA inhibitor is comprised in a topical formulation of any one of Embodiments 1-110.4922-4270-5705 1 52Attorney Docket No.: 102577-000100WOPT

[0228] Embodiment 151: The method of any one of Embodiments 121-147, wherein the CDA inhibitor is administered systemically.

[0229] Embodiment 152: The method of Embodiment 151, wherein the CDA inhibitor is administered orally.

[0230] Embodiment 153: The method of Embodiment 151 or 152, wherein the CDA inhibitor is comprised in a composition of any one of Embodiments 111 -120.

[0231] Embodiment 154: The method of any one of Embodiment 121-147, wherein the symptom or complication caused by capecitabine is inflammation of the hands and feet (hand-foot syndrome, erythrodysesthesia) and the CDA inhibitor is administered locally.

[0232] Embodiment 155: The method of Embodiment 154, wherein said local administration comprises topically applying the CDA inhibitor, e.g., the CDA inhibitor is administered topically to the skin, such as the CDA inhibitor is administered topically to the skin of the hands or feet.

[0233] Embodiment 156: The method of any one of Embodiments 154-155, wherein the CDA inhibitor is comprised in a topical formulation of any one of Embodiments 1-120 and the formulation comprises the CDA inhibitor in amount from about 0.2mg / g to about 5 mg / g, based on the total weight of the formulation.

[0234] Embodiment 157: The method of any one of Embodiments 121-147, wherein the symptom or complication caused by capecitabine is diarrhea, stomach pain, or other gastro-intestinal symptom or complication, and the CDA inhibitor is administered systemically.

[0235] Embodiment 158: The method of Embodiment 157, wherein said systemic administration comprises oral administration.

[0236] Embodiment 159: The method of any one of Embodiments 121-158, wherein the subject has a higher level of CDA relative to an average level in humans.

[0237] Embodiment 160: The method of any one of Embodiments 121-159, further comprising measuring or determining a CDA level in the subject prior to administering the CDA inhibitor.

[0238] Embodiment 161: A method for treating cancer, the method comprising coadministering an effective amount of capecitabine and an effective amount of a CDA inhibitor to a subject in need thereof.

[0239] Embodiment 162: The method of Embodiment 161, wherein the cancer is colorectal cancer, gastric cancer, breast cancer, pancreatic cancer, bladder cancer, cervix cancer, endometrium cancer, esophagus cancer, head and neck cancer, islet cell4922-4270-5705 1 53Attorney Docket No.: 102577-000100WOPTcancer, liver cancer, lung cancer, ovary cancer or prostate cancer, optionally, the cancer is colorectal cancer, gastric cancer or breast cancer.

[0240] Embodiment 163: The method of Embodiment 161 or 162, wherein the CDA inhibitor is administered prior to administering the capecitabine.

[0241] Embodiment 164: The method of Embodiment 163, wherein the CDA inhibitor is administered at least 15 minutes (e.g., at least 30 minutes, at least 45 minutes, at least an hour, at least 1.25 hours, at least 1.5 hours, at least 1.75 hours, at least 2 hours or more) prior to administering the capecitabine.

[0242] Embodiment 165: The method of Embodiment 161 or 162, wherein the CDA inhibitor is administered after administering the capecitabine.

[0243] Embodiment 166: The method of Embodiment 165, wherein the CDA inhibitor is administered at least 15 minutes (e.g., at least 30 minutes, at least 45 minutes, at least an hour, at least 1.25 hours, at least 1.5 hours, at least 1.75 hours, at least 2 hours or more) after administering the capecitabine.

[0244] Embodiment 167: The method of Embodiment 161 or 162, wherein the subject is undergoing treatment with capecitabine and the method comprises administering the CDA inhibitor and the capecitabine at the same time.

[0245] Embodiment 168: The method of any one of Embodiments 161 or 167, wherein the method comprises administering a second dose of the CDA inhibitor to the subject.

[0246] Embodiment 169: The method of Embodiment 168, wherein the second dose is administered at least about an hour (e.g., 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours or more) after the first dose.

[0247] Embodiment 170: The method of Embodiments 168 or 169, wherein the second dose is at a lower amount than the first administration of the CDA inhibitor.

[0248] Embodiment 171: The method of Embodiments 168 or 169, wherein the second dose is at a higher amount than the first administration of the CDA inhibitor.

[0249] Embodiment 172: The method of Embodiments 168 or 169, wherein the second dose is at about the same about as the first administration of the CDA inhibitor.

[0250] Embodiment 173: The method of any one of Embodiments 161-172, wherein the subject has a symptom, complication or side effect caused by capecitabine.

[0251] Embodiment 174: The method of any one of Embodiments 161-174, wherein the CDA inhibitor is tetrahydrouridine (THU); THU analog or derivative; ASTX727 (E7727); 5-methyl-2',3'-dideoxy-3'-azidocytidine (5mAZC); 5-methyl-2',3'-dideoxycytidine; 5-ethyl-2',3'dideoxy-3'-azidocytidine; 5-propyl-2',3'-dideoxycytidine; 5-4922-4270-5705 1 54Attorney Docket No.: 102577-000100WOPTpropyl-2',3'-dideoxy-3'-azidocytidine; 5-propene-2',3'-dideoxy-3'-azidocytidine; 5-propyne-2',3'-dideoxy-3'-azidocytidine; 5-propyne-2',3'-dideoxy-3'-azidocytidine; Zebularine; or any combination thereof.

[0252] Embodiment 175: The method of any one of Embodiments 161-174, wherein the CDA inhibitor is tetrahydrouridine, or a fluorinated derivative thereof.

[0253] Embodiment 176: The method of any one of Embodiments 161-175, wherein the CDA inhibitor is tetrahydrouridine, 2'-fluoro-2’-deoxytetrahydrouridine, or 2’-deoxy-2',2'-difluorotetrahydrouridine.

[0254] Embodiment 177: The method of any one of Embodiments 161-175, wherein the CDA inhibitor is tetrahydrouridine; 2',2'-difluoro-dihydrouridine (DFDHU); 2', 2'-difluoro-tetrahydrouridine (DFTHU); 2'(R)-fluoro-2’-deoxy-tetrahydrouridine; 2'(R)-fluoro-2’-deoxy-dihydrouridine ((R)-FDHU); 2'(S)-fluoro-2’-deoxy-tetrahydrouridine; 2'(S)-fluoro-2’-deoxy-dihydrouridine ((S)-FDHU); 2'(S)-fluoro-2’-deoxy-tetrahydrouridine ((S)-FTHU); 2’-deoxy-2',2'-difluoro-5,6-dihydrouridine; (4R)-2’-deoxy-2',2'-difluoro-3, 4,5,6-tetrahydrouridine; (4S)-2’-deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine; 1-(2-Deoxy-2,2-difluoro-p-D-erythro-pentofuranosyl)-tetrahydro-2(1H)-pyrimidinone; 2’-deoxy-2'-fluoro-5,6-dihydrouridine; (4R)-2’-deoxy-2'-fluoro-3,4,5,6-tetrahydrouridine; (4S)-2’-deoxy-2'-fluoro-3,4,5,6-tetrahydrouridine; 1 -(2-deoxy-2-fluoro-(3-D-ribofuranosyl)tetrahydro-2(1 H)-pyrimidinone; 1-(2-deoxy-2-fluoro-p-D-arabinofuranosyl)dihydro-2,4-(1H,3H)-pyrimidinedione; (4R)-1-(2-deoxy-2-fluoro-(3-D-arabinofuranosyl)tetrahydro-4-hydroxy-2(1 H)-pyrimidinone; (4S)-1 -(2-deoxy-2-fluoro-(3-D-arabinofuranosyl)tetrahydro-4-hydroxy-2(1H)-pyrimidinone; or any combination thereof.

[0255] Embodiment 178: The method of any one of Embodiments 161-177, wherein the CDA inhibitor is tetrahydrouridine or (4R)-2'-Deoxy-2',2'-difluoro-3, 4,5,6-tetrahydrouridine.

[0256] Embodiment 179: The method of any one of Embodiments 161-178, wherein the method further comprises co-administering a second active agent (other than the CDA inhibitor and the capecitabine) or therapy to the subject.

[0257] Embodiment 180: The method of Embodiment 179, wherein the second active agent or therapy is an anti-cancer therapy.

[0258] Embodiment 181: The method of Embodiment 180, wherein the second active agent is an anti-cancer agent.

[0259] Embodiment 182: The method of Embodiment 181, wherein the anti-cancer agent is selected from the group consisting of inhibitors of topoisomerase I and II, alkylating agents, microtubule inhibitors (e.g., taxol), and angiogenesis inhibitor,4922-4270-5705 1 55Attorney Docket No.: 102577-000100WOPToptionally, the anti-cancer agent is. paclitaxel (taxol); docetaxel; gemicitabine; Aldesleukin; Alemtuzumab; alitretinoin; allopurinol; altretamine; amifostine; anastrozole; arsenic trioxide; Asparaginase; BCG Live; bexarotene capsules; bexarotene gel; bleomycin; busulfan intravenous; busulfanoral; calusterone; capecitabine; carboplatin; carmustine; carmustine with Polifeprosan Implant; celecoxib; chlorambucil; cisplatin; cladribine; cyclophosphamide; cytarabine; cytarabine liposomal; dacarbazine; dactinomycin; actinomycin D; Darbepoetin alfa; daunorubicin liposomal; daunorubicin, daunomycin; Denileukin diftitox, dexrazoxane; docetaxel; doxorubicin; doxorubicin liposomal; Dromostanolone propionate; Elliott's B Solution; epirubicin; Epoetin alfa estramustine; etoposide phosphate; etoposide (VP-16); exemestane; Filgrastim; floxuridine (intraarterial); fludarabine; fluorouracil (5-FU); fulvestrant; gemtuzumab ozogamicin; goserelin acetate; hydroxyurea; Ibritumomab Tiuxetan; idarubicin; ifosfamide; imatinib mesylate; Interferon alfa-2a; Interferon alfa-2b; irinotecan; letrozole; leucovorin; levamisole; lomustine (CCNU); mechlorethamine (nitrogenmustard); megestrol acetate; melphalan (L-PAM); mercaptopurine (6-MP); mesna; methotrexate; methoxsalen; mitomycin C; mitotane; mitoxantrone; nandrolone phenpropionate; Nofetumomab; LOddC; Oprelvekin; oxaliplatin; pamidronate; pegademase; Pegaspargase; Pegfilgrastim; pentostatin; pipobroman; plicamycin; mithramycin; porfimer sodium; procarbazine; quinacrine; Rasburicase; Rituximab; Sargramostim; streptozocin; talbuvidine (LDT); talc; tamoxifen; temozolomide; teniposide (VM-26); testolactone; thioguanine (6-TG); thiotepa; topotecan; toremifene; Tositumomab; Trastuzumab; tretinoin (ATRA); Uracil Mustard; valrubicin; valtorcitabine (monoval LDC); vinblastine; vinorelbine; zoledronate; gemcitabine, cisplatin, paclitaxel, carboplatin, bortezomib, AMG479, vorinostat, rituximab, temozolomide, rapamycin, ABT-737, PI-103; alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine,4922-4270-5705 1 56Attorney Docket No.: 102577-000100WOPTifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (see, e.g., Angew, Chem. Inti. Ed. Engl., 33: 183-186 (1994)); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® doxorubicin (including morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, N. J.), ABRAXANE® Cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg,4922-4270-5705 1 57Attorney Docket No.: 102577-000100WOPTIII.), and TAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil; GEMZAR® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE.RTM. vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (Camptosar, CPT-11) (including the treatment regimen of irinotecan with 5-FU and leucovorin); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; combretastatin; leucovorin (LV); oxaliplatin; lapatinib (Tykerb. RTM.); inhibitors of PKC-alpha, Raf, H-Ras, EGFR (e.g., erlotinib (Tarceva®)) and VEGF-A.

[0260] Embodiment 183: The method of Embodiment 179, wherein the second active agent is for treating, reducing or inhibiting a symptom, complication or side effect caused by capecitabine in a subject undergoing treatment with capecitabine.

[0261] Embodiment 184: The method of Embodiment 179, wherein said second active agent is an anti-inflammatory agent, a phosphodiesterase 5 (PDE5) inhibitor, a corticosteroid, urea, or pyridoxine (vitamin B6).

[0262] Embodiment 185: The method of Embodiment 184, wherein said second active agent is an anti-inflammatory agent.

[0263] Embodiment 186: The method of Embodiment 185, wherein the antiinflammatory agent is selected from the group consisting of steroidal anti-inflammatory agents, non-steroidal anti-inflammatory drugs (NSAIDs, such as COX inhibitors, e.g., COX-1 or COX nonspecific inhibitors, and selective COX-2 inhibitors), corticosteroids (including glucocorticoids, e.g. cortisol, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, and beclometasone), anti-malarial medication (such as hydrochloroquine), methotrexrate, sulfasalazine, leflunomide, anti-TNF medications, cyclophosphamise, pro-resolving drugs, mycophenolate, dexamethasone, rosiglitazone, prednisolone, corticosterone, budesonide, estrogen, estradiol, sulfasalazine, fenfibrate, pravastatin, simvastatin, proglitazone, acetylsalicylic acid, mycophenolic acid, mesalamine, hydroxyurea, opiates (e.g., endorphins, enkephalins, dynorphin, barbiturates, oxycodone, morphine, lidocaine and the like), steroids, sirolimus, everolimus, biolimus (A9), zotarolimus (ABT-578), tacrolimus, pimecrolimus, genistein, and any combinations thereof.

[0264] Embodiment 187: The method of Embodiment 186, wherein the antiinflammatory agent is selected from the group consisting of salicylic acid derivatives such as aspirin, sodium salicylate, choline magnesium trisalicylate, salicylate, diflunisal,4922-4270-5705 1 58Attorney Docket No.: 102577-000100WOPTsulfasalazine and olsalazine; para-aminophenol derivatives such as acetaminophen; indole and indene acetic acids such as indomethacin and sulindac; heteroaryl acetic acids such as tolmetin, dicofenac and ketorolac; arylpropionic acids such as ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen and oxaprozin; anthranilic acids (fenamates) such as mefenamic acid and meloxicam; enolic acids such as the oxicams (piroxicam, meloxicam); alkanones such as nabumetone; diarylsubstituted furanones such as refecoxib; diaryl-substituted pyrazoles such as celecoxib; indole acetic acids such as etodolac and sulfonanilides such as nimesulide; and analogues and derivatives thereof.

[0265] Embodiment 188: The method of Embodiment 184, said second active agent is a PDE5 inhibitor.

[0266] Embodiment 189: The method of Embodiment 189, wherein PDE5 inhibitor is sildenafil, vardenafil, tadalafil, avanafil, mirodenafil, udenafil, gisadenafil, yonkenafil (tunodafil), lodenafil fenspiride, MBCQ, zaprinast, icariin, NS-0200, or any combination thereof.

[0267] Embodiment 190: The method of Embodiment 179, wherein the second active agent is selected from the group consisting of 2-hydroxy-1,4-naphthoquinone, glycosides, antiarrhythmics, glucosamine sulfate, Boswellia, hyaluronic acid, rutin, MSM, trypsin, bromelain, chondroitin sulfate, glucosamine HCL, curcumin, turmeric, resveratrol, polyphenol classes, UC-II Collagen, Black pepper extract, 5-Loxin, Calcium, horsetail leaf extract, omega-3 fatty acids, Vitamin C, cetyl myristoleate, Gelatin, silicon dioxide, titanium dioxide, magnesium stearate, amitriptyline, nortriptyline, duloxetine, venlafaxine, willow bark, clover, prickly ash bark, Corydalis yanhusuo, lobelia, California poppy, metformin, carbamazepine, topiramate, pregabalin, gabapentin, duloxetine, desvenlafaxine, amitriptyline, azathioprine, cyclosporine, melatonin, fish oil, ginseng root, Ginkgo biloba extract, coenzyme Q10, St. John's Wort, S-adenosyl methionine, hypericin, pseudohypericin, xanthones, folic acid, vitamin B6, vitamin B12, Butterbur, cayenne, Zyflamend, acetaminophen, vitamin K, Epsom salt, proline, glycine, glutamine, phosphorus, silicon, Sulphur, Earl Grey, Tanacetum parthenium, Filipendula ulmaria, Boswellia serrata, Harpagophytum procumbens, Alpinia officinarum Uncaria tomentosa, Foeniculum vulgare, Origanum vulgare ssp. Hirtum, Rosmarinus officinalis, Thymus vulgaris, Antelaea azadirachta, Azadirachta indica, Melia azadirachta, Rumex crispus, Crocus sativus, Passiflora incarnata, Pedicularis canadensis, Lactuca virosa, Curcuma longa, Tabebuia avellanedae, Bupleurum spp., Commiphora mukul,4922-4270-5705 1 59Attorney Docket No.: 102577-000100WOPTYucca spp., Dioscorea villosa, Salix caprea, flower of water hyacinth, Flower of Henna (fragrance), Bitter Orange, Sweet Orange, Vanilla and combinations thereof.

[0268] Embodiment 191: The method of any one of Embodiments 161-190, wherein the CDA inhibitor is administered locally.

[0269] Embodiment 192: The method of Embodiment 191, wherein the CDA inhibitor is administered topically, e.g., the CDA inhibitor is administered topically to the skin, such as the CDA inhibitor is administered topically to the skin of the hands or feet.

[0270] Embodiment 193: The method of Embodiment 191 or 192, wherein the CDA inhibitor is comprised in a topical formulation of any one of Embodiments 1-110.

[0271] Embodiment 194: The method of any one of Embodiments 161-190, wherein the CDA inhibitor is administered systemically.

[0272] Embodiment 195: The method of Embodiment 194, wherein the CDA inhibitor is administered orally.

[0273] Embodiment 196: The method of Embodiment 194 or 195, wherein the CDA inhibitor is comprised in a composition of any one of Embodiments 111 -120.

[0274] Embodiment 197: The method of any one of Embodiment 161-190, wherein the symptom or complication caused by capecitabine is inflammation of the hands and feet (hand-foot syndrome, erythrodysesthesia) and the CDA inhibitor is administered locally.

[0275] Embodiment 198: The method of Embodiment 197, wherein said local administration comprises topically applying the CDA inhibitor, e.g., the CDA inhibitor is administered topically to the skin, such as the CDA inhibitor is administered topically to the skin of the hands or feet.

[0276] Embodiment 199: The method of any one of Embodiments 197-198, wherein the CDA inhibitor is comprised in a topical formulation of any one of Embodiments 1-120 and the formulation comprises the CDA inhibitor in amount from about 0.2mg / g to about 5 mg / g, based on the total weight of the formulation.

[0277] Embodiment 200: The method of any one of Embodiments 161-190, wherein the symptom or complication caused by capecitabine is diarrhea, stomach pain, or other gastro-intestinal symptom or complication, and the CDA inhibitor is administered systemically.

[0278] Embodiment 201: The method of Embodiment 200, wherein said systemic administration comprises oral administration.

[0279] Embodiment 202: The method of any one of Embodiments 161-201, wherein the subject has a higher level of CDA relative to an average level in humans.4922-4270-5705 1 60Attorney Docket No.: 102577-000100WOPT

[0280] Embodiment 203: The method of any one of Embodiments 161-202, further comprising measuring or determining a CDA level in the subject prior to administering the CDA inhibitor or capecitabine.

[0281] Embodiment 204: The method of any one of Embodiments 161-203, wherein a symptom, complication or side effect caused by capecitabine, when without the CDA inhibitor, is reduced or inhibited.

[0282] Embodiment 205: The method of Embodiment 204, wherein the symptom, complication or side effect caused by capecitabine is inflammation of the hands and feet (hand-foot syndrome, erythrodysesthesia); diarrhea, stomach pain and other gastrointestinal symptom or complication; pain, redness, swelling, sores, or ulcers in mouth or lips; itching in the genital or other skin areas; and vomiting.

[0283] Embodiment 206: The method of Embodiment 205, wherein the symptom, complication or side effect caused by capecitabine is inflammation of the hands and feet.

[0284] Embodiment 207: The method of Embodiment 205, wherein the symptom, complication or side effect caused by capecitabine is diarrhea, stomach pain, or other gastro-intestinal symptom or complication.

[0285] Embodiment 208: A method for treating palmar-plantar erythrodysesthesia comprising administering an effective amount of a CDA inhibitor to a subject in need thereof.

[0286] Embodiment 209: The method of Embodiment 208, wherein the palmar-plantar erythrodysesthesia is chemotherapy induced palmar-plantar erythrodysesthesia.

[0287] Embodiment 210: The method of Embodiment 208 or 209, wherein the palmar-plantar erythrodysesthesia is 5-fluorouracil chemotherapy induced palmar-plantar erythrodysesthesia.

[0288] Embodiment 211: The method of any one of Embodiments 208-210, wherein the palmar-plantar erythrodysesthesia is capecitabine chemotherapy induced palmar-plantar erythrodysesthesia.

[0289] Embodiment 212: The method of any one of Embodiments 208-211 wherein the CDA inhibitor is administered locally.

[0290] Embodiment 213: The method of any one of Embodiments 208-212, wherein the CDA inhibitor is administered topically to the skin.

[0291] Embodiment 214: The method of any one of Embodiments 208-213, wherein the CDA inhibitor is administered topically to the skin of the hands or feet.

[0292] Embodiment 215: The method of any one of Embodiments 208-214, wherein the CDA inhibitor is tetrahydrouridine (THU); THU analog or derivative; ASTX7274922-4270-5705 1 61Attorney Docket No.: 102577-000100WOPT(E7727); 5-methyl-2',3'-dideoxy-3'-azidocytidine (5mAZC); 5-methyl-2',3'-dideoxycytidine; 5-ethyl-2',3'dideoxy-3'-azidocytidine; 5-propyl-2',3'-dideoxycytidine; 5-propyl-2',3'-dideoxy-3'-azidocytidine; 5-propene-2',3'-dideoxy-3'-azidocytidine; 5-propyne-2',3'-dideoxy-3'-azidocytidine; 5-propyne-2',3'-dideoxy-3'-azidocytidine; Zebularine; or any combination thereof.

[0293] Embodiment 216: The method of any one of Embodiments 208-215, wherein the CDA inhibitor is tetrahydrouridine, or a fluorinated derivative thereof.

[0294] Embodiment 217: The method of any one of Embodiments 208-216, wherein the CDA inhibitor is tetrahydrouridine, 2'-fluoro-2’-deoxytetrahydrouridine, or 2’-deoxy-2',2'-difluorotetrahydrouridine.

[0295] Embodiment 218: The method of any one of Embodiments 208-215, wherein the CDA inhibitor is tetrahydrouridine; 2',2'-difluoro-dihydrouridine (DFDHU); 2', 2'-difluoro-tetrahydrouridine (DFTHU); 2'(R)-fluoro-2’-deoxy-tetrahydrouridine; 2'(R)-fluoro-2’-deoxy-dihydrouridine ((R)-FDHU); 2'(S)-fluoro-2’-deoxy-tetrahydrouridine; 2'(S)-fluoro-2’-deoxy-dihydrouridine ((S)-FDHU); 2'(S)-fluoro-2’-deoxy-tetrahydrouridine ((S)-FTHU); 2’-deoxy-2',2'-difluoro-5,6-dihydrouridine; (4R)-2’-deoxy-2',2'-difluoro-3, 4,5,6-tetrahydrouridine; (4S)-2’-deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine; 1-(2-Deoxy-2,2-difluoro-p-D-erythro-pentofuranosyl)-tetrahydro-2(1H)-pyrimidinone; 2’-deoxy-2'-fluoro-5,6-dihydrouridine; (4R)-2’-deoxy-2'-fluoro-3,4,5,6-tetrahydrouridine; (4S)-2’-deoxy-2'-fluoro-3,4,5,6-tetrahydrouridine; 1 -(2-deoxy-2-fluoro-(3-D-ribofuranosyl)tetrahydro-2(1 H)-pyrimidinone; 1-(2-deoxy-2-fluoro-p-D-arabinofuranosyl)dihydro-2,4-(1H,3H)-pyrimidinedione; (4R)-1-(2-deoxy-2-fluoro-(3-D-arabinofuranosyl)tetrahydro-4-hydroxy-2(1 H)-pyrimidinone; (4S)-1 -(2-deoxy-2-fluoro-(3-D-arabinofuranosyl)tetrahydro-4-hydroxy-2(1H)-pyrimidinone; or any combination thereof.

[0296] Embodiment 219: The method of any one of Embodiments 208-218, wherein the CDA inhibitor is tetrahydrouridine or (4R)-2'-Deoxy-2',2'-difluoro-3, 4,5,6-tetrahydrouridine.

[0297] Embodiment 220: The method of any one of Embodiments 208-219, wherein the method further comprises co-administering a second active agent (other than the CDA inhibitor) to the subject.

[0298] Embodiment 221: The method of Embodiment 220, wherein said second active agent is an anti-inflammatory agent, a phosphodiesterase 5 (PDE5) inhibitor, a corticosteroid, urea, or pyridoxine (vitamin B6).

[0299] Embodiment 222: The method of Embodiment 221, wherein said second active agent is an anti-inflammatory agent.4922-4270-5705 1 62Attorney Docket No.: 102577-000100WOPT

[0300] Embodiment 223: The method of Embodiment 222, wherein the antiinflammatory agent is selected from the group consisting of steroidal anti-inflammatory agents, non-steroidal anti-inflammatory drugs (NSAIDs, such as COX inhibitors, e.g., COX-1 or COX nonspecific inhibitors, and selective COX-2 inhibitors), corticosteroids (including glucocorticoids, e.g. cortisol, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, and beclometasone), anti-malarial medication (such as hydrochloroquine), methotrexrate, sulfasalazine, leflunomide, anti-TNF medications, cyclophosphamise, pro-resolving drugs, mycophenolate, dexamethasone, rosiglitazone, prednisolone, corticosterone, budesonide, estrogen, estradiol, sulfasalazine, fenfibrate, pravastatin, simvastatin, proglitazone, acetylsalicylic acid, mycophenolic acid, mesalamine, hydroxyurea, opiates (e.g., endorphins, enkephalins, dynorphin, barbiturates, oxycodone, morphine, lidocaine and the like), steroids, sirolimus, everolimus, biolimus (A9), zotarolimus (ABT-578), tacrolimus, pimecrolimus, genistein, and any combinations thereof.

[0301] Embodiment 224: The method of Embodiment 223, wherein the antiinflammatory agent is selected from the group consisting of salicylic acid derivatives such as aspirin, sodium salicylate, choline magnesium trisalicylate, salicylate, diflunisal, sulfasalazine and olsalazine; para-aminophenol derivatives such as acetaminophen; indole and indene acetic acids such as indomethacin and sulindac; heteroaryl acetic acids such as tolmetin, dicofenac and ketorolac; arylpropionic acids such as ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen and oxaprozin; anthranilic acids (fenamates) such as mefenamic acid and meloxicam; enolic acids such as the oxicams (piroxicam, meloxicam); alkanones such as nabumetone; diarylsubstituted furanones such as refecoxib; diaryl-substituted pyrazoles such as celecoxib; indole acetic acids such as etodolac and sulfonanilides such as nimesulide; and analogues and derivatives thereof.

[0302] Embodiment 225: The method of Embodiment 221, said second active agent is a PDE5 inhibitor.

[0303] Embodiment 226: The method of Embodiment 226, wherein PDE5 inhibitor is sildenafil, vardenafil, tadalafil, avanafil, mirodenafil, udenafil, gisadenafil, yonkenafil (tunodafil), lodenafil fenspiride, MBCQ, zaprinast, icariin, NS-0200, or any combination thereof.

[0304] Embodiment 227: The method of Embodiment 220, wherein the second active agent is selected from the group consisting of 2-hydroxy-1,4-naphthoquinone, glycosides, antiarrhythmics, glucosamine sulfate, Boswellia, hyaluronic acid, rutin, MSM,4922-4270-5705 1 63Attorney Docket No.: 102577-000100WOPTtrypsin, bromelain, chondroitin sulfate, glucosamine HCL, curcumin, turmeric, resveratrol, polyphenol classes, UC-II Collagen, Black pepper extract, 5-Loxin, Calcium, horsetail leaf extract, omega-3 fatty acids, Vitamin C, cetyl myristoleate, Gelatin, silicon dioxide, titanium dioxide, magnesium stearate, amitriptyline, nortriptyline, duloxetine, venlafaxine, willow bark, clover, prickly ash bark, Corydalis yanhusuo, lobelia, California poppy, metformin, carbamazepine, topiramate, pregabalin, gabapentin, duloxetine, desvenlafaxine, amitriptyline, azathioprine, cyclosporine, melatonin, fish oil, ginseng root, Ginkgo biloba extract, coenzyme Q10, St. John's Wort, S-adenosyl methionine, hypericin, pseudohypericin, xanthones, folic acid, vitamin B6, vitamin B12, Butterbur, cayenne, Zyflamend, acetaminophen, vitamin K, Epsom salt, proline, glycine, glutamine, phosphorus, silicon, Sulphur, Earl Grey, Tanacetum parthenium, Filipendula ulmaria, Boswellia serrata, Harpagophytum procumbens, Alpinia officinarum Uncaria tomentosa, Foeniculum vulgare, Origanum vulgare ssp. Hirtum, Rosmarinus officinalis, Thymus vulgaris, Antelaea azadirachta, Azadirachta indica, Melia azadirachta, Rumex crispus, Crocus sativus, Passiflora incarnata, Pedicularis canadensis, Lactuca virosa, Curcuma longa, Tabebuia avellanedae, Bupleurum spp., Commiphora mukul, Yucca spp., Dioscorea villosa, Salix caprea, flower of water hyacinth, Flower of Henna (fragrance), Bitter Orange, Sweet Orange, Vanilla and combinations thereof.

[0305] Embodiment 228: The method of Embodiment 227, wherein the second active agent is 2-hydroxy-1,4-naphthoquinone, a glycoside, or an antiarrhythmic, optionally, the glycoside is selected from the group consisting of steroidal glycoside, anthraquinones glycosides, cardiac glycosides, saponin glycosides, tetracyclic triterpenoids saponins, pentacyclic Ttriterpenoid saponins, coumarin glycosides, furocoumarin glycosides, cyanophore glycosides, flavonoids glycosides, flavone glycosides, flavanol glycosides, flavanone glycosides, chalone glycosides, isoflavonoid glycoside, anthocyanidin glycosides, isothiocyanate glycosides, phenol glycoside, aldehyde glycosides, bitter glycosides, and combinations thereof, optionally, the antiarrhythmic is selected from the group consisting of lidocaine, quinidine, procainamide, phenytoin, flecainide, disopyramide, tocainide, acebutolol, propranolol, propranolol, esmolol, amiodarone, dofetilide, sotalol, dronedarone, ibutilide, diltiazem, verapamil, adenosine and combinations thereof.

[0306] Embodiment 229: The method of any one of Embodiments 220-228, wherein the second active agent is administered locally.

[0307] Embodiment 230: The method of any one of Embodiments 220-228, wherein the second active agent is administered topically to the skin.4922-4270-5705 1 64Attorney Docket No.: 102577-000100WOPT

[0308] Embodiment 231: The method of any one of Embodiments 220-228, wherein the second active agent is administered topically to the skin of the hands or feet.

[0309] Embodiment 232: The method of any one of Embodiments 220-231, wherein the second active agent is administered prior to administering the CDA inhibitor.

[0310] Embodiment 233: The method of any one of Embodiments 220-231, wherein the second active agent is administered after administering the CDA inhibitor.

[0311] Embodiment 234: The method of any one of Embodiments 220-231, wherein the second active agent is administered simultaneously with the CDA inhibitor.

[0312] Embodiment 235: The method of any one of Embodiments 208-234, wherein the method comprises administering a second dose of the CDA inhibitor to the subject.

[0313] Embodiment 236: The method of Embodiment 235, wherein the second dose is administered at least about an hour (e.g., 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours or more) after the first dose.

[0314] Embodiment 237: The method of Embodiments 235 or 236, wherein the second dose is at a lower amount than the first administration of the CDA inhibitor.

[0315] Embodiment 238: The method of Embodiments 235 or 236, wherein the second dose is at a higher amount than the first administration of the CDA inhibitor.

[0316] Embodiment 239: The method of Embodiments 235 or 236, wherein the second dose is at about the same about as the first administration of the CDA inhibitor.

[0317] Embodiment 240: The method of any one of Embodiments 208-239, wherein the CDA inhibitor is comprised in a topical formulation of any one of Embodiments 1-110, optionally, the topical formulation comprises the CDA inhibitor in an amount from about 0.1 mg / g to about 5 mg / g (w / w).

[0318] Embodiment 241: The method of any one of Embodiments 208-240, wherein the subject is undergoing chemotherapy treatment.

[0319] Embodiment 242: The method of any one of Embodiments 208-241, wherein the subject is undergoing 5-fluorouracil chemotherapy.

[0320] Embodiment 243: The method of any one of Embodiments 208-242, wherein the subject is undergoing capecitabine chemotherapy.

[0321] Embodiment 244: The method of any one of Embodiments 241-243, wherein the CDA inhibitor is administered prior to administering the chemotherapy.

[0322] Embodiment 245: The method of Embodiment 244, wherein the CDA inhibitor is administered at least 15 minutes (e.g., at least 30 minutes, at least 45 minutes, at least an hour, at least 1.25 hours, at least 1.5 hours, at least 1.75 hours, at least 2 hours or more) prior to administering the chemotherapy.4922-4270-5705 1 65Attorney Docket No.: 102577-000100WOPT

[0323] Embodiment 246: The method of any one of Embodiments 241-243, wherein the CDA inhibitor is administered after administering the chemotherapy.

[0324] Embodiment 247: The method of Embodiment 246, wherein the CDA inhibitor is administered at least 15 minutes (e.g., at least 30 minutes, at least 45 minutes, at least an hour, at least 1.25 hours, at least 1.5 hours, at least 1.75 hours, at least 2 hours or more) after administering the chemotherapy.

[0325] Embodiment 248: The method of any one of Embodiments 241-243, wherein the CDA inhibitor is administered simultaneously with the chemotherapy.

[0326] Embodiment 249: The method of any one of Embodiments 208-248, wherein the subject has a higher level of CDA relative to an average level in humans.

[0327] Embodiment 250: The method of any one of Embodiments 249, further comprising measuring or determining a CDA level in the subject prior to administering the CDA inhibitor.

[0328] Embodiment 251: A kit comprising: (i) CDA inhibitor; and (ii) at least one of capecitabine, an anti-inflammatory agent, or an agent for treating a side effect of capecitabine.

[0329] Embodiment 252: The kit of Embodiment 251, wherein the CDA inhibitor is comprised in a topical formulation of any one of Embodiments 1-110 or a composition of any one of Embodiments 111-120.

[0330] Embodiment 253: The kit of any one Embodiment 251-252, wherein the kit further comprises instructions for use.Some selected definitions

[0331] For convenience, certain terms employed herein, in the specification, examples and appended claims are collected herein. Unless stated otherwise, or implicit from context, the following terms and phrases include the meanings provided below. Unless explicitly stated otherwise, or apparent from context, the terms and phrases below do not exclude the meaning that the term or phrase has acquired in the art to which it pertains. The definitions are provided to aid in describing particular embodiments, and are not intended to limit the claimed invention, because the scope of the invention is limited only by the claims. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0332] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as those commonly understood to one of ordinary skill in the art to which this invention pertains. Although any known methods, devices, and materials may4922-4270-5705 1 66Attorney Docket No.: 102577-000100WOPTbe used in the practice or testing of the invention, the methods, devices, and materials in this regard are described herein.

[0333] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0334] Certain ranges are presented herein with numerical values being preceded by the term “about.” The term “about” is used herein to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In determining whether a number is near to or approximately a specifically recited number, the near or approximating unrecited number may be a number which, in the context in which it is presented, provides the substantial equivalent of the specifically recited number.

[0335] As used herein the term “comprising” or “comprises” is used in reference to compositions, methods, and respective component(s) thereof, that are essential to the invention, yet open to the inclusion of unspecified elements, whether essential or not. In other words, except where the context requires otherwise, the term “comprise” and variations of the term, such as “comprising”, “comprises” and “comprised”, are not intended to exclude further additives, components, integers or steps.

[0336] The term “consisting of” refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the implementation.

[0337] The singular terms “a,” “an,” and “the” include plural referents unless context clearly indicates otherwise. Similarly, the word “or” is intended to include “and” unless the context clearly indicates otherwise. It is further noted that the claims can be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

[0001] The terms “lower”, “reduced”, “reduction” or “decrease”, “down-regulate” or “inhibit” are all used herein generally to mean a decrease by a statistically significant4922-4270-5705 1 67Attorney Docket No.: 102577-000100WOPTamount. However, for avoidance of doubt, “lower”, “reduced”, “reduction” or “decrease” or “inhibit” means a decrease by at least 10% as compared to a reference level, for example a decrease by at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% decrease (i.e. absent level as compared to a reference sample), or any decrease between 10-100% as compared to a reference level.

[0002] The terms “significantly different than,”, “statistically significant,” and similar phrases refer to comparisons between data or other measurements, wherein the differences between two compared individuals or groups are evidently or reasonably different to the trained observer, or statistically significant (if the phrase includes the term “statistically” or if there is some indication of statistical test, such as a p-value, or if the data, when analyzed, produce a statistical difference by standard statistical tests known in the art).

[0003] The phrase “effective amount” as used herein means that amount of a compound (e.g., CDA inhibitor) or a formulation or composition comprising a compound (e.g., a CDA inhibitor) described herein which is effective for producing some desired therapeutic effect in at least a sub-population of cells at a reasonable benefit / risk ratio applicable to any medical treatment. Thus, “effective amount” means that amount which, when administered to a subject for treating a chemotherapy induced symptom, complication or side effect, is sufficient to affect such treatment for the symptom, complication or side effect. In one non-limiting example, an effective amount using the methods as disclosed herein would be considered as the amount sufficient to reduce at least one chemotherapy induced symptom, complication or side effect by at least 10%. An effective amount as used herein would also include an amount sufficient to prevent or delay the development of at least one chemotherapy induced symptom, complication or side effect, alter the course of at least one chemotherapy induced symptom, complication or side effect (for example but not limited to, slow the progression), or reverse at least one chemotherapy induced symptom, complication or side effect. Accordingly, the term “effective amount” or “therapeutically effective amount” as used herein refers to the amount of a therapeutic agent (e.g., CDA inhibitor) as disclosed herein or a formulation or composition comprising same to alleviate at least one chemotherapy induced symptom, complication or side effect.

[0004] Depending on the route of administration, effective doses can be calculated according to the body weight, body surface area, or organ size of the subject to be4922-4270-5705 1 68Attorney Docket No.: 102577-000100WOPTtreated. Optimization of the appropriate dosages can readily be made by one skilled in the art in light of pharmacokinetic data observed in human clinical trials. Alternatively, or additionally, the dosage to be administered can be determined from studies using animal models for the particular type of condition to be treated, and / or from animal or human data obtained from agents which are known to exhibit similar pharmacological activities. The final dosage regimen will be determined by the attending surgeon or physician, considering various factors which modify the action of active agent (e.g. CDA inhibitor) such as the agent’s specific activity, the agent’s specific half-life in vivo, the severity of the condition and the responsiveness of the patient, the age, condition, body weight, sex and diet of the patient, the severity of any present infection, time of administration, the use (or not) of other concomitant therapies, and other clinical factors. Accordingly, an effective dose described herein is an amount sufficient to produce at least some desired therapeutic effect in a subject.

[0005] The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of use or administration utilized.

[0006] The effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the therapeutic which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Levels in plasma can be measured, for example, by high performance liquid chromatography. The effects of any particular dosage can be monitored by a suitable bioassay. The effective plasma concentration for a compound as disclosed herein can be about 0.01 pM to about 10 pM, about 0.2 pM to about 5 pM, or about 0.8 to about 3 pM in a subject, such as a rat, dog, or human.

[0007] Generally, the formulations and compositions are administered so that the active agent (e.g., CDA inhibitor) is used or given at a dose from 1 pg / kg to 1000 mg / kg; 1 pg / kg to 500 mg / kg; 1 pg / kg to 150 mg / kg, 1 pg / kg to 100 mg / kg, 1 pg / kg to 50 mg / kg, 1 pg / kg to 20 mg / kg, 1 pg / kg to 10 mg / kg, 1 pg / kg to 1 mg / kg, 100 pg / kg to 100 mg / kg, 100 pg / kg to 50 mg / kg, 100 pg / kg to 20 mg / kg, 100 pg / kg to 10 mg / kg, 100pg / kg to 1 mg / kg, 1 mg / kg to 100 mg / kg, 1 mg / kg to 50 mg / kg, 1 mg / kg to 20 mg / kg, 1 mg / kg to 10 mg / kg, 10 mg / kg to 100 mg / kg, 10 mg / kg to 50 mg / kg, or 10 mg / kg to 20 mg / kg. It is to be understood that ranges given here include all intermediate ranges, for example,4922-4270-5705 1 69Attorney Docket No.: 102577-000100WOPTthe range 1 mg / kg to 10 mg / kg includes 1mg / kg to 2 mg / kg, 1mg / kg to 3 mg / kg, 1mg / kg to 4 mg / kg, 1 mg / kg to 5 mg / kg, 1 mg / kg to 6 mg / kg, 1 mg / kg to 7 mg / kg, 1 mg / kg to 8 mg / kg, 1 mg / kg to 9 mg / kg, 2mg / kg to 10mg / kg, 3mg / kg to 10mg / kg, 4mg / kg to 10mg / kg, 5mg / kg to 10mg / kg, 6mg / kg to 10mg / kg, 7mg / kg to 10mg / kg, 8mg / kg to 10mg / kg, 9mg / kg to 10mg / kg, and the like. Further contemplated is a dose (either as a bolus or continuous infusion) of about 0.1 mg / kg to about 10 mg / kg, about 0.3 mg / kg to about 5 mg / kg, or 0.5 mg / kg to about 3 mg / kg. It is to be further understood that the ranges intermediate to those given above are also within the scope of this disclosure, for example, in the range 1 mg / kg to 10 mg / kg, for example use or dose ranges such as 2mg / kg to 8 mg / kg, 3mg / kg to 7 mg / kg, 4mg / kg to 6mg / kg, and the like.

[0008] As used herein, a “subject” is an animal, such as a mammal, including a primate (e.g., a human), a non-human primate, (e.g., a monkey and a chimpanzee), a non-primate (e.g., a cow, a pig, a camel, a llama, a horse, a goat, a rabbit, a sheep, a hamster, a guinea pig, a cat, a dog, a rat, a mouse, a horse, and a whale), or a bird (e.g., a duck or a goose). In an embodiment, the subject is a human, such as a human being assessed for a stiffened joint, a human at risk for developing a stiffened joint, a human having a stiffened joint, and / or a human being treated for a disease or disorder.

[0009] Preferably, the subject is a mammal. The mammal can be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but is not limited to these examples. Mammals other than humans can be advantageously used as subjects that represent animal models of disease e.g., a chemotherapy induced symptom, complication or side effect. A subject can be male or female.

[0010] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0011] The phrase “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agents from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, for example the carrier does not decrease the impact of the agent on the treatment. In other words, a carrier is pharmaceutically inert. The terms “physiologically4922-4270-5705 1 70Attorney Docket No.: 102577-000100WOPTtolerable carriers” and “biocompatible delivery vehicles” are used interchangeably. Suitable pharmaceutical camers / excipients and their formulations are described for example, in Remington: The Science and Practice of Pharmacy (23rded., Academic Press, Cambridge, MA, 2020), contents of which are incorporated herein by reference in their entireties.

[0012] The phrase “pharmaceutically acceptable topical carrier” or “pharmaceutically acceptable topical carrier” as used herein refers to a “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” that can be applied to skin surfaces without undue toxicity, irritation, or allergic reaction. In some embodiments, the pharmaceutically acceptable topical carrier or excipient is unsuitable for oral administration.

[0013] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the CDA inhibiotr, the liquid dosage forms can contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0014] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active agent, e.g., CDA inhibiotr are mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcelhdose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monosteamte, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene4922-4270-5705 1 71Attorney Docket No.: 102577-000100WOPTglycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form can also comprise buffering agents.

[0015] Solid compositions of a similar type can also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols, and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They can optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols, and the like.

[0016] The active agent, e.g., the CDA inhibitor can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active agent, e.g., the CDA inhibitor can be admixed with at least one inert diluent such as sucrose, lactose and starch. Such dosage forms can also comprise, as in normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms can also comprise buffering agents. They can optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.

[0017] As used herein, the term “administer” refers to the placement of an active agent (e.g., CDA inhibitor) or a composition comprising same into a subject by a method or route which results in at least partial localization of the active agent at a desired site such that desired effect is produced. A compound or composition described herein can be administered by any appropriate route known in the art including, but not limited to, topical, oral or parenteral routes, including intravenous, intramuscular, subcutaneous,4922-4270-5705 1 72Attorney Docket No.: 102577-000100WOPTtransdermal, airway (aerosol), pulmonary, nasal, rectal, and topical (including buccal and sublingual) administration.

[0018] Exemplary modes of administration include, but are not limited to, topical application to skin, ingestion, injection, infusion, instillation, or inhalation.

[0019] In some embodiments, the administration is local administration. For example,As used herein the term “local administration” means administering or applying the active agent (e.g., CDA inhibitor) or a composition comprising same to a specified area of the body. Local administration can be administration to an area of skin. Local administration can be topical or percutaneous, such as applying to or on the surface of the skin. Local administration can include the deposition of a drug depot for or slow- or controlled release of the active agent under the skin.

[0020] In some embodiments, administration is topical administration. As used herein, “topical administration” refers to the application of an active agent (e.g., CDA inhibitor) or a composition comprising same to any skin surface. “Skin surface” refers to the protective outer covering of the body of a vertebrate, generally comprising a layer of epidermal cells and a layer of dermal cells.

[0021] In some embodiments, administration is systemic or peripheral administration. The phrases “systemic administration,” “administered systemically”, “peripheral administration” and “administered peripherally” as used herein mean the administration of a composition comprising at least a CDA inhibitor such that it enters the subject’s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.

[0022] In some embodiments, the administration is oral administration. Without limitations, oral administration can be in the form of solutions, suspensions, tablets, pills, capsules, sustained-release formulations, oral rinses, powders and the like.

[0023] In some embodiments, the administration can be parenteral administration. As used herein, the term “parenteral administration,” refers modes of administration other than enteral and topical administration, and usually through injection or infusion. Parenteral administration includes, but is not limited to, subcutaneous administration, intravenous administration, or intramuscular administration. As used herein, the term “subcutaneous administration” refers to administration just below the skin. “Intravenous administration” means administration into a vein. “Injection” includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous,4922-4270-5705 1 73Attorney Docket No.: 102577-000100WOPTsubcuticular, intraarticular, sub capsular, subarachnoid, intraspinal, intracerebro spinal, and intrasternal injection and infusion.

[0024] In jurisdictions that forbid the patenting of methods that are practiced on the human body, the meaning of “administering” of a composition to a human subject shall be restricted to prescribing a controlled substance that a human subject will selfadminister by any technique (e.g., orally, inhalation, topical application, injection, insertion, etc.). The broadest reasonable interpretation that is consistent with laws or regulations defining patentable subject matter is intended. In jurisdictions that do not forbid the patenting of methods that are practiced on the human body, the “administering” includes both methods practiced on the human body and also the foregoing activities.

[0025] The terms “co-administration”, “co-administering” and the like, as used herein are meant to encompass administration of the selected treatments (e.g., the CDA inhibitor and the chemotherapy, such as 5-fluorouracil or capecitabine, or the CDA inhibitor and the second active agent) to a single patient and are intended to include treatment regimens in which the selected treatments (e.g., the CDA inhibitor and the chemotherapy, such as 5-fluorouracil or capecitabine, or the CDA inhibitor and the second active agent) are administered by the same or different route of administration or at the same or different time. The particular combination of therapies (therapeutics or procedures) to employ in such a combination regimen will take into account compatibility of the desired therapeutics and / or procedures and the desired therapeutic effect to be achieved.

[0026] It is noted that CDA inhibitor administration may occur prior to, consecutively with, concurrently with or following the administration of the chemotherapy (e.g., 5-fluorouracil or capecitabine) or the second active agent. Accordingly, in some embodiments, the CDA inhibitor is administered prior to administering the chemotherapy (e.g., 5-fluorouracil or capecitabine) or the second active agent. For example, the CDA inhibitor is administered at least 15 minutes (e.g., at least 30 minutes, at least 45 minutes, at least an hour, at least 1.25 hours, at least 1.5 hours, at least 1.75 hours, at least 2 hours or more) prior to administering the chemotherapy.

[0027] In some other embodiments, the CDA inhibitor is administered after administering the chemotherapy (e.g., 5-fluorouracil or capecitabine) or the second active agent. For example, the CDA inhibitor is administered at least 15 minutes (e.g., at least 30 minutes, at least 45 minutes, at least an hour, at least 1.25 hours, at least 1.54922-4270-5705 1 74Attorney Docket No.: 102577-000100WOPThours, at least 1.75 hours, at least 2 hours or more) after administering the chemotherapy (e.g., 5-fluorouracil or capecitabine) or the second active agent.

[0028] In yet some embodiments, the CDA inhibitor is administered simultaneously with the chemotherapy (e.g., 5-fluorouracil or capecitabine) or the second active agent. For example, the CDA inhibitor is administered simultaneously with the chemotherapy (e.g., 5-fluorouracil or capecitabine) or the second active agent are comprised in the same composition or formulation.

[0029] In some embodiments, the CDA inhibitor and the chemotherapy (e.g., 5-fluorouracil or capecitabine) or the second active agent are administered alternatingly.

[0030] As used herein, the terms "treat,” "treatment," "treating,” or “amelioration” refer to therapeutic treatments, wherein the object is to reverse, alleviate, ameliorate, inhibit, slow down or stop the progression or severity of a disease or disorder, e.g., at least one chemotherapy induced symptom, complication or side effect. Treatment is generally “effective" if one or more symptoms or clinical markers are reduced. Alternatively, treatment is “effective" if the progression of a disease or disorder is reduced or halted. That is, “treatment" includes not just the improvement of symptoms or markers, but also a cessation of, or at least slowing of, progress or worsening of symptoms compared to what would be expected in the absence of treatment. Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptom(s), diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, remission (whether partial or total), and / or decreased mortality, whether detectable or undetectable. The term "treatment" of a disease also includes providing relief from the symptoms or side-effects of the disease (including palliative treatment).

[0031] As used herein, “prevention” or “preventing,” when used in reference to a disease or disorder, e.g., at least one chemotherapy induced symptom, complication or side effect, refers to a reduction in the likelihood that a subject, e.g., a human subject, will develop a symptom associated with such disease or disorder, or a reduction in the frequency and / or duration of a symptom associated with a disease or disorder. The likelihood of developing a given disease or disorder is reduced, for example, when a subject having one or more risk factors for the disease or disorder either fails to develop or develops with less severity relative to a population having the same risk factors and not receiving treatment as described herein. The failure to develop a disease or disorder, or the reduction in the development of a symptom associated with disease or4922-4270-5705 1 75Attorney Docket No.: 102577-000100WOPTdisorder (e.g., by at least about 10%), or the exhibition of delayed symptoms (e.g., delayed by days, weeks, months or years) is considered effective prevention.

[0338] Specific elements of any of the disclosed embodiments can be combined or substituted for elements in other embodiments. Furthermore, while advantages associated with certain embodiments of the disclosure have been described in the context of these embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fail within the scope of the disclosure.EXAMPLES

[0339] The following examples illustrate some embodiments and aspects of the invention. It will be apparent to those skilled in the relevant art that various modifications, additions, substitutions, and the like can be performed without altering the spirit or scope of the invention, and such modifications and variations are encompassed within the scope of the invention as defined in the claims which follow. The following examples do not in any way limit the invention.Example 1: Improving capecitabine safety and sustainability by local inhibition of cytidine deaminase

[0340] We disclose topical and oral medicinal compositions containing small molecule inhibitors of cytidine deaminase, and related methods, to prevent and treat inflammation of the hands and feet (hand-foot syndrome, erythrodysesthesia), and to prevent and treat diarrhea and other gastro-intestinal symptoms and complications, caused by capecitabine, an orally administered chemotherapeutic used to treat cancer. Capecitabine is a pro-drug that requires the pyrimidine metabolism enzyme cytidine deaminase (CDA) for conversion into the active molecule 5-fluorouracil that treats cancer and causes side-effects. Therefore, to prevent and treat side-effects caused by CDA-mediated activation of capecitabine in the palms of the hands and soles of the feet, we apply a small molecule inhibitor of CDA, e.g., tetrahydrouridine (THU), locally via topical application. The topical medicinal composition can be administered as an ointment, cream, gel, lotion, liquid or suspension. The patient applies the topical medicinal composition to the palms of their hands and soles of their feet around the same time that they ingest their oral capecitabine. The patient can repeat the topical application 1 hour later if symptoms, e.g., pain, do occur. To prevent capecitabine-induced gastrointestinal toxicities, the small molecule CDA-inhibitor is ingested as an4922-4270-5705 1 76Attorney Docket No.: 102577-000100WOPToral medicinal composition. The oral medicinal composition can be administered as a tablet, mini-tablets, capsule, powder or solution. The oral medicinal composition is ingested around the same time that the patient ingests oral capecitabine to treat their cancer. Alternatively, the oral medicinal composition may contain coformulated CDA-inhibitor and capecitabin, with both agents contained in a capsule or tablet. The amount of the CDA-inhibitor in the topical and oral medicinal compositions is selected to produce sufficient local inhibition of cytidine deaminase to prevent and treat the local side-effects of erythrodysesthesia, pain, diarrhea, etc., but avoid systemic cytidine deaminase inhibition, to thereby ensure continued activation of capecitabine by cytidine deaminase in cancer cells in the body. Decreasing side-effects of capecitabine using these medicinal compositions and methods can also increase capecitabine anti-cancer activity, because the present way of managing these capecitabine side-effects is by interrupting, decreasing or discontinuing the anti-cancer therapy.BACKGROUND

[0341] 5-fluorouracil (5FU) is an antimetabolite chemotherapeutic that is routinely used to treat gastrointestinal and other cancers. These actions of 5FU in normal cells cause major systemic toxicities, e.g., lowering of blood counts, abdominal pain, mucositis and diarrhea. Furthermore, 5FU is a parenteral drug administered via intravenous infusion, that adds to complications, costs-of-care and further compromises quality-of-life. Therefore, capecitabine was developed as an oral pro-drug of 5FU to reduce side-effects and improve accessibility. The pro-drug capecitabine is preferentially converted into active 5FU in some types of cancer cells because of their higher expression of the pyrimidine metabolism enzymes that convert capecitabine toward 5FU, or their lower expression of enzymes that catabolize or destroy 5FU. In this way, capecitabine reduces some side-effects compared to 5FU, e.g., mucositis. Moreover, capecitabine is orally bioavailable, and is thus more accessible and practical for patients, with less impact on quality-of-life from travel and time in the clinic or hospital, and with lower costs for health care systems. With these advantages, capecitabine has for several decades been a key, standard treatment for patients with gastrointestinal and breast cancers. Capecitabine nevertheless does still cause major side-effects, such that -50% or more of patients require capecitabine dose-reductions and interruptions to decrease these side-effects (1-3). Such treatment interruptions and dose reductions are expected to compromise treatment efficacy (1-3). Hence, these side-effects negatively impact both quality- and quantity-of-life.4922-4270-5705 1 77Attorney Docket No.: 102577-000100WOPT

[0342] The most frequent of these capecitabine induced side-effects or adverse events, occurring in >50% of treated patients, are erythrodysesthesia (‘hand-foot syndrome’) and diarrhea (4). These side-effects of capecitabine are caused by activation and accumulation of capecitabine in the palms of the hand, soles of the feet, and in the cells lining the gastro-intestinal tract (5). Activation of capecitabine towards the active chemotherapeutic 5FU requires the pyrimidine metabolism enzyme cytidine deaminase (CDA), which is naturally highly expressed in gastro-intestinal tract epithelial cells (6, 7) (Figure 1). Thus, capecitabine is not cytotoxic to cells if they do not express CDA (6). In fact, humans which demonstrate higher amounts or activity of CDA in their tissues demonstrate higher risks for capecitabine-induced toxicities (8-11). CDA can be reversibly inhibited by the small molecule drug tetrahydrouridine (THU) and analogs of THU, e.g., cedazuridine.

[0343] To convey the severity of the capecitabine-induced side-effects, here is more description: (a) -50% of patients treated with capecitabine experience symptoms and signs of erythrodysesthesia, which include pain, swelling, and blistering of the palms of the hands and soles of the feet such that routine daily activities, such as using a fork and spoon, or walking, become excruciating or impossible. The erythrodysesthesia is severe, with peeling, blisters, bleeding, fissures, edema and / or pain to the extent that routine activities of daily living are limited, in 10-17% of treated patients; (b) -50% of patients treated with capecitabine experience diarrhea within 30-40 days of starting treatment. The diarrhea is severe (>7X / day, or with incontinence, bloody and requiring intravenous fluid support) in 10-14% of treated patients.

[0344] Presently, hand, foot and gastro-intestinal side-effects of capecitabine are managed by interrupting treatment until their resolution, then resuming therapy with a dose-reduction of the capecitabine. Since treatment of the cancer requires exposure to capecitabine, the dose reductions and interruptions are expected to be detrimental not just to quality- but also quantity-of-life (1-3). That is, there are no approved, specific, mechanism-based treatments to prevent or treat capecitabine-induced side-effects: other than treatment interruptions and dose-reductions, management of the side-effects is symptomatic only (12). These symptomatic treatments include: (a) ingestion of oral non-steroidal anti-inflammatory drugs, e.g., celecoxib 200-400 mg 2X / day; (b) ingestion of oral pyridoxine (vitamin B6), e.g., pyridoxine 50-100 mg 2-3X / day; (c) application of topical urea cream, e.g., topical urea 10-12% 3X / day. In most placebo-controlled studies of these interventions, no significant benefit of these interventions were found, e.g., of 2 placebo or no celecoxib versus celecoxib studies in capecitabine-treated cancer4922-4270-5705 1 78Attorney Docket No.: 102577-000100WOPTpatients, 1 did not find a benefit, and 1 showed a reduction in all-grades of erythrodysesthesia to 57.4% with celecoxib versus 74.6% with no celecoxib (12); in 7 placebo or no pyridoxine versus pyridoxine studies in capecitabine-treated cancer patients, none found significant benefit of the pyridoxine (12); in 2 studies of placebo versus urea cream in capecitabine-treated cancer patients, 1 did not find a benefit, and 1 showed a reduction in all grades of erythrodysesthesia to 22.4% with urea cream versus 39.5% with placebo (12).

[0345] We developed, scalable, good medical practice methods for the synthesis of THU active pharmaceutical ingredient / drug substance. Importantly, we and others have found that THU has an excellent safety profile, with no significant side-effects identified by us or others in formal toxicology studies in various other species and in numerous clinical trials of orally or parenterally administered THU. We have also identified doses of THU to safely and effectively use in humans, and the timing of these doses in relationship to co-administered pro-drugs whose metabolism we wish to influence (13-15). That is, our pre-clinical and clinical studies, which have included detailed pharmacokinetic and pharmacodynamic measurements of THU, allow us to identify the doses and timings of THU to use in topical and oral medicinal compositions that have the goal preventing and treating serious side-effects of capecitabine (Figure 2).Specifically, we have identified doses and timings of the medicinal compositions for the goal of inhibiting CDA-mediated conversion of capecitabine into active 5FU in healthy hands, feet and gastro-intestinal tract, while not inhibiting capecitabine conversion into active 5FU in cancer cells. Importantly, decreasing side-effects of capecitabine using these medicinal compositions can increase capecitabine anti-cancer activity, by decreasing or eliminating otherwise frequent (>50% of patients) dose-reductions, interruptions and discontinuations that are caused by these side-effects (1-3). In this way, we intend to increase both quality- and quantity-of-life for cancer patients that require treatment with capecitabine.MEDICINAL COMPOSITION and METHOD SPECIFICS:

[0346] 1. THU concentration of 1 pM is sufficient to inhibit conversion of capecitabine into 5FU by >90% (6, 7, 16). Based on our pharmacokinetic studies, the medicinal composition of the cream, ointment, lotion or liquid should contain 0.2% by weight of THU (2 mg of THU content in 1 g of cream, ointment, lotion or liquid). As little as 0.2 mg of THU content in 1 g of cream, ointment, lotion or liquid may be sufficient (0.2-5 mg / g of medium). The goal is to produce sufficient local inhibition of CDA to prevent and treat4922-4270-5705 1 79Attorney Docket No.: 102577-000100WOPTside-effects in palms, soles and other areas of skin but without systemic inhibition of CDA.

[0347] 2. Based on the pharmacokinetics of capecitabine, with peak plasma concentration occurring up to 2 hours after ingestion, with half-life of <1 hour (17-19), and our characterization of the pharmacokinetics and pharmacodynamics of CDA-inhibition by THU, which peaks 1-2 hours after application (15), we recommend topical application simultaneous with capecitabine ingestion and repeated 1 hour later if any symptoms occur.

[0348] 3. Based on similar PK, PD considerations, taken together with oral bioavailability of THU of -20% (20), and the goal of inhibiting CDA locally in healthy cells in the gastro-intestinal tract without significant systemic inhibition of CDA, the oral medicinal composition should contain THU at a dose of approximately 0.5 mg / kg (0.1-2 mg / k), to be ingested around the same time as capecitabine is ingested, and repeated 1 hour later if any symptoms occur.REFERENCES1. Timmers L, Boons CC, Mangnus D, Van de Ven PM, Van den Berg PH, Beeker A, et al. Adherence and Patients' Experiences with the Use of Capecitabine in Daily Practice. Frontiers in pharmacology. 2016;7:310.2. Timmers L, Swart EL, Boons CC, Mangnus D, van de Ven PM, Peters GJ, et al. The use of capecitabine in daily practice: a study on adherence and patients' experiences. Patient Prefer Adherence. 2012;6:741-8.3. Auber ML, Wen S, Hobbs G, and Higa GM. Capecitabine as Maintenance Therapy for High-Risk, Resected Colorectal Cancer. Gastrointest Tumors.2021;8(2):81-6.4. Walko CM, and Lindley C. Capecitabine: a review. Clin Ther. 2005;27(1):23- 44.5. Milano G, Etienne-Grimaldi MC, Mari M, Lassalle S, Formento JL, Francoual M, et al. Candidate mechanisms for capecitabine-related handfoot syndrome. BrJ Clin Pharmacol. 2008;66(1):88-95.6. Shindoh H, Nakano K, Yoshida T, and Ishigai M. Comparison of in vitro metabolic conversion of capecitabine to 5-FU in rats, mice, monkeys and humans-toxicological implications. J Toxicol Sci. 2011;36(4):411-22.7. Morita T, Matsuzaki A, Kurokawa S, and Tokue A. Forced expression of cytidine deaminase confers sensitivity to capecitabine. Oncology.2003;65(3):267-74.8. Caronia D, Martin M, Sastre J, de la Torre J, Garcia-Saenz JA, Alonso MR, et al. A polymorphism in the cytidine deaminase promoter predicts severe capecitabine-induced hand-foot syndrome. Clin Cancer Res.2011;17(7):2006-13.4922-4270-5705 1 80Attorney Docket No.: 102577-000100WOPT9. Ciccolini J, Evrard A, and Lacarelle B. A CDD polymorphism as predictor of capecitabine-induced hand-foot syndrome-letter. Clin Cancer Res.2012;18(1):317.10. Garcia-Gonzalez X, Cortejoso L, Garcia Ml, Garcia-Alfonso P, Robles L, Gravalos C, et al. Variants in CDA and ABCB1 are predictors of capecitabine-related adverse reactions in colorectal cancer. Oncotarget.2015;6(8):6422-30.11. Loganayagam A, Arenas Hernandez M, Corrigan A, Fairbanks L, Lewis CM, Harper P, et al. Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity. Br J Cancer. 2013;108(12):2505-15.12. Pandy JGP, Franco PIG, and Li RK. Prophylactic strategies for hand-foot syndrome / skin reaction associated with systemic cancer treatment: a metaanalysis of randomized controlled trials. Supportive care in cancer: official journal of the Multinational Association of Supportive Care in Cancer.2022;30(11):8655-66.13. Lavelle D, Vaitkus K, Ling Y, Ruiz MA, Mahfouz R, Ng KP, et al. Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine. Blood. 2012; 119(5): 1240-7.14. Molokie R, Lavelle D, Gowhari M, Pacini M, Krauz L, Hassan J, et al. Oral tetrahydrouridine and decitabine for non-cytotoxic epigenetic gene regulation in sickle cell disease: A randomized phase 1 study. PLoS medicine. 2017; 14(9):e1002382.15. Lau H, Woost PG, Friedrich U, Clausen WHO, Jacobberger JW, and Saunthararajah Y. Pharmacokinetics and pharmacodynamics of an oral formulation of decitabine and tetrahydrouridine. European journal of haematology. 2023;111(3):345-55.16. Besnard T, Renee N, Etienne-Grimaldi MC, Francois E, and Milano G.Optimized blood sampling with cytidine deaminase inhibitor for improved analysis of capecitabine metabolites. Journal of chromatography B, Analytical technologies in the biomedical and life sciences.2008;870(1):117-20.17. Reigner B, Blesch K, and Weidekamm E. Clinical pharmacokinetics of capecitabine. Clinical pharmacokinetics. 2001;40(2):85-104.18. Reigner B, Verweij J, Dirix L, Cassidy J, Twelves C, Allman D, et al. Effect of food on the pharmacokinetics of capecitabine and its metabolites following oral administration in cancer patients. Clin Cancer Res. 1998;4(4):941-8. 19. Reigner B, Watanabe T, Schuller J, Lucraft H, Sasaki Y, Bridgewater J, et al.Pharmacokinetics of capecitabine (Xeloda) in Japanese and Caucasian patients with breast cancer. Cancer chemotherapy and pharmacology.2003;52(3): 193-201.20. Beumer JH, Eiseman JL, Parise RA, Florian JA, Jr., Joseph E, D'Argenio DZ, et al. Plasma pharmacokinetics and oral bioavailability of 3, 4,5,6- tetrahydrouridine, a cytidine deaminase inhibitor, in mice. Cancer ChemotherPharmacol. 2008;62(3):457-64.4922-4270-5705 1 81Attorney Docket No.: 102577-000100WOPT

[0349] All patents and other publications identified are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies described in such publications that might be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.4922-4270-5705 1 82

Claims

Attorney Docket No.: 102577-000100WOPTCLAIMSWhat is claimed is:

1. A method for treating palmar-plantar erythrodysesthesia comprising administering an effective amount of a CDA inhibitor to a subject in need thereof.

2. The method of claim 1, wherein the palmar-plantar erythrodysesthesia is chemotherapy induced palmar-plantar erythrodysesthesia.

3. The method of claim 2, wherein the palmar-plantar erythrodysesthesia is 5- fluorouracil or capecitabine chemotherapy induced palmar-plantar erythrodysesthesia.

4. The method of claim 1, wherein the CDA inhibitor is administered locally, optionally, the CDA inhibitor applied topically to the skin.

5. The method of claim 1, wherein the CDA inhibitor is administered systemically.

6. The method of claim 1, wherein the method further comprises co-administering a second active agent (other than the CDA inhibitor) to the subject.

7. The method of claim 6, wherein said second active agent is an anti-inflammatory agent, a phosphodiesterase 5 (PDE5) inhibitor, a corticosteroid, urea, or pyridoxine (vitamin B6).

8. The method of claim 1, wherein the subject has a higher level of CDA relative to an average level in humans.

9. The method of claim 1, further comprising measuring or determining a CDA level in the subject prior to administering the CDA inhibitor.

10. The method of claim 1, wherein the subject is undergoing wherein the subject is undergoing chemotherapy treatment, and the method comprises co-administering the CDA inhibitor and the chemotherapy.

11. The method of claim 10, wherein the subject is undergoing treatment with capecitabine 5-fluorouracil, and the method comprises co-administering the CDA inhibitor and the capecitabine or 5-fluorouracil.

12. The method of claim 1, wherein the method comprises administering a second dose of the CDA inhibitor to the subject.

13. A method for treating, reducing or inhibiting a symptom, complication or side effect caused by capecitabine or 5-fluorouracil, the method comprises: administering an effective amount of a CDA inhibitor to a subject in need thereof.4922-4270-5705 1 83Attorney Docket No.: 102577-000100WOPT14. The method of claim 11, wherein the subject is undergoing treatment with capecitabine 5-fluorouracil, and the method comprises co-administering the CDA inhibitor and the capecitabine or 5-fluorouracil.

15. The method of claim 11, wherein the symptom, complication or side effect caused by capecitabine or 5-fluorouracil is inflammation of the hands and feet (hand-foot syndrome, erythrodysesthesia); diarrhea, stomach pain and other gastro-intestinal symptom or complication; pain, redness, swelling, sores, or ulcers in mouth or lips; itching in the genital or other skin areas; anemia; or vomiting.

16. A method for treating cancer, the method comprising co-administering an effective amount of capecitabine or 5-fluorouracil and an effective amount of a CDA inhibitor to a subject in need thereof17. A topical formulation comprising a cytidine deaminase inhibitor (CDA) inhibitor and a pharmaceutically acceptable topical carrier or excipient.

18. The topical formulation of claim 17, wherein the formulation further comprises a second active agent, optionally the second active agent is for treating, reducing or inhibiting a symptom, complication or side effect caused by capecitabine or 5- fluorouracil in a subject undergoing treatment with capecitabine or 5-fluorouracil.

19. The topical formulation of claim 18, wherein said second active agent is an antiinflammatory agent, a phosphodiesterase 5 (PDE5) inhibitor, a corticosteroid, urea, or pyridoxine (vitamin B6).

20. A composition comprising a CDA inhibitor, capecitabine or 5-fluorouracil, and a pharmaceutically acceptable carrier or excipient, wherein the composition is formulated for oral administration to a subject.4922-4270-5705 1 84

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