Compositions, uses, kits, and formulations of a topical estrogen cream

Abstract

The present disclosure includes compositions, uses, kits, and method of formulation for a composition comprising an estrogen and a pharmaceutically acceptable vehicle for delivering the estrogen to a non-vaginal area of a subject in need thereof.

Description

COMPOSITIONS, USES, KITS, AND FORMULATIONS OF A TOPICAL ESTROGENCREAMCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 609,254 filed December 12, 2023 and US Provisional Application 63 / 669,122 filed July 9, 2024, each of which are incorporated herein by reference.BACKGROUND

[0002] Skin aging can be significantly delayed by the administration of estrogen. Estrogens have a profound influence on skin. Estrogen-deficient condition is associated with a dramatic reduction in skin health and wellness. The relative hypoestrogenism that accompanies menopause, perimenopause, or any other period of estrogen deficiency in both men and women exacerbates the deleterious effects of both intrinsic and environmental aging.SUMMARY

[0003] In an aspect of the present disclosure is a composition comprising an estrogen and a pharmaceutically acceptable vehicle for delivering the estrogen to a non- vaginal area of a subject in need thereof. In some embodiments, the non- vaginal area is a face of the subject. In some embodiments, the estrogen is selected from the group consisting of estriol, estradiol, and estrone. In some embodiments, the estrogen is estriol. In some embodiments, the composition comprises about 0.001% to about 1.0 % of the estrogen. In some embodiments, the composition comprises about 0.001% to about 0.5% of the estrogen. In some embodiments, the composition comprises at most about 1.0% of the estrogen. In some embodiments, the composition comprises about 0.3% of the estrogen. In some embodiments, the composition further comprises about 0.2 % to about 0.5% of tretinoin. In some embodiments, the composition further comprises about 4% to about 10% of niacinamide. In some embodiments, the pharmaceutically acceptable vehicle comprises glycerin, oleic acid, or vitamin E or derivatives thereof. In some embodiments, the pharmaceutically acceptable vehicle comprises at least two of glycerin, oleic acid, and vitamin E or derivatives thereof. In some embodiments, the pharmaceutically acceptable vehicle comprises at least glycerin, oleic acid, and vitamin E or derivatives thereof. In some embodiments, the pharmaceutically acceptable vehicle comprises C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxyethyl acrylate / sodium acryloyldimethyl, a taurate copolymer, oleic acid, olive oil, PEG- 100 stearate,phenoxyethanol, polymethylsiloxane, purified water, stearic acid, trolamine NF, vitamin E acetate, or any combination thereof. In some embodiments, the pharmaceutically acceptable vehicle comprises Aloe Barbadensis Leaf Juice, C 12 - 14 Isoparaffin, Caprylic / Capric Triglyceride, Deionized Water, Laureth-7, Phenoxyethanol, Polyacrylamide, Tocopheryl Acetate, Triethylene Glycol, or any combination thereof. In some embodiments, the composition is formulated as a topical cream. In some embodiments, the composition is formulated as a topical face cream. In some embodiments, the topical cream is applied on a subject’s face, neck, hands, legs, knees, shoulders, arms, abdomen, or any combination thereof. In some embodiments, the composition reduces a severity of one or more symptoms selected from skin dryness, decreased skin firmness, decreased skin elasticity, loss of collagen, loss of elastin, loss of fibroblast function, loss of vascularity, and increased matrix metalloproteinase(s) enzymatic activities. In some embodiments, the composition has one of more effects selected from the group consisting of increased collagen production, increased skin moisture, increased skin firmness, decreased pore size, decreased wrinkle depth, increased skin elasticity, and reversal of effects of estrogen-deficiency in skin due to menopause.

[0004] In some embodiments is use of the composition for the treatment of a disease or a condition in a subject in need thereof. In some embodiments, the treatment is formulated as a topical cream. In some embodiments, the treatment is formulated as a topical face cream. In some embodiments, the composition treats a disease or condition in the subject. In some embodiments, the subject has a Fitzpatrick skin type I, II, III, IV, V, or VI. In some embodiments, the subject is ages 13-80. In some embodiments, the subject is ages 35-80. In some embodiments, the disease or condition is perimenopause or menopause. In some embodiments, the disease or condition is skin aging due to perimenopause or menopause. In some embodiments, the treatment is most effective when started around perimenopause. In some embodiments, the composition treats or ameliorates a condition of the subject’s skin. In some embodiments, the condition is derived from menopause and / or perimenopause. In some embodiments, the condition is selected from the group consisting of acne scarring, wound healing, bum healing, skin dryness, epidermal thinning, decreased skin firmness, decreased skin elasticity, loss of collagen, loss of elastin, loss of fibroblast function, loss of vascularity, increased matrix metalloproteinase(s) enzymatic activities, and any combinations thereof. In some embodiments is use of the composition for treating symptoms of menopause and / or perimenopause. In some embodiments, the subject further uses other treatments for menopause hormone therapy. In some embodiments, the other treatments for menopause hormone therapy comprise estrogen vaginal cream, estrogen pills, estrogen vaginal rings, estrogen patch, estrogenspray, estrogen progesterone combination pill, estrogen progesterone combination patch, vaginal dehydroepiandrosterone insert, or a combination thereof. In some embodiments, the composition is applied at least once daily to a face of a subject in need thereof. In some embodiments, the composition is applied at least once daily at nighttime to a face of a subject in need thereof. In some embodiments, the composition is applied at about 0.2 mL to about 0.4 mL at least once daily to face. In some embodiments, the composition is applied at about 0.3 mL at least once daily to face. In some embodiments, the composition is safely used with retinoids, vitamin c, or spot treatments. In some embodiments, the composition is applied safely to under-eye areas.

[0005] In an aspect of the present disclosure is a kit comprising a composition of an estrogen and a pharmaceutically acceptable vehicle for delivering the estrogen to a non-vaginal area of a subject in need thereof and a sealed container for housing the composition. In some embodiments, the kit further comprises instructions for use.

[0006] In some embodiments is a method for the treatment of skin conditions in a subject in need thereof comprising administering to a skin of a subject a composition of an estrogen and a pharmaceutically acceptable vehicle for delivering the estrogen to a non-vaginal area of a subject in need thereof and a sealed container for housing the composition. In some embodiments, the skin conditions are due to menopause and / or perimenopause. In some embodiments, the skin conditions are one or more selected from skin dryness, decreased skin firmness, decreased skin elasticity, loss of collagen, loss of elastin, loss of fibroblast function, and loss of vascularity. In some embodiments, the subject is perimenopausal or menopausal. In some embodiments, the treatment decreases loss of structural architecture of the skin and / or decreases propensity to skin damage. In some embodiments, the treatment mitigates skin aging. In some embodiments, the treatment elevates levels of mucopolysaccharides and hyaluronic acids in a dermis of the subject. In some embodiments, the treatment increases a relative collagen synthesis in the skin of the subject.

[0007] In an aspect of the present disclosure is a method of formulating a composition comprising an estrogen and a pharmaceutically acceptable vehicle for delivering the estrogen to a non-vaginal area of a subject in need thereof wherein the method comprises mixing an estrogen and a portion of the pharmaceutically acceptable vehicle to an unguator, adding the remaining amount of the pharmaceutically acceptable vehicle to the unguator, mixing the estrogen and the pharmaceutically acceptable vehicle in the unguator to create the composition. In some embodiments, the estrogen is a powder.

[0008] In an aspect of the present disclosure is a composition comprising an estrogen for topical application to a skin of a subject in need thereof, wherein the composition furthercomprises C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxyethyl acrylate / sodium acryloyldimethyl, a taurate copolymer, oleic acid, olive oil, PEG- 100 stearate, phenoxyethanol, polymethylsiloxane, purified water, stearic acid, trolamine NF, and vitamin E acetate. In some embodiments, the estrogen is selected from the group consisting of estriol, estradiol, and estrone. In some embodiments, the estrogen is estriol. In some embodiments, the composition comprises about 0.001% to about 1.0 % of the estrogen. In some embodiments, the composition comprises about 0.001% to about 0.5% of the estrogen. In some embodiments, the composition comprises at most about 1.0% of the estrogen. In some embodiments, the composition comprises about 0.3% of the estrogen. In some embodiments, the composition further comprises about 0.2 % to about 0.5% of tretinoin. In some embodiments, the composition further comprises about 4% to about 10% of niacinamide.

[0009] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.INCORPORATION BY REFERENCE

[0010] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.DETAILED DESCRIPTION

[0011] While various embodiments of the disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed.

[0012] Estrogens play major roles in maintaining physiological functions in the human body. Menopause represents an inflection point, after which the skin undergoes conspicuous decline in appearance and function and carries messages of age-related decline. Women with estrogen- deficient skin seek cosmetic and medical treatments to improve dermal health and physical characteristics to enhance their self-perception and inhibit skin aging, particularly in highly visible body areas.

[0013] Studies have shown that estrogen deprivation in postmenopausal conditions accelerates many skin changes, including dryness, atrophy, fine wrinkling, and poor wound healing. Thus, the effects of low estrogen on the skin are an important endogenous cause of aging skin. Despite estrogen supplementation having a positive effect on the skin, topical treatment strategies that target cutaneous symptoms are limited. The lack of topical treatment strategies is further compounded by the misinformation surrounding the use of exogenous estrogens. Thus, there is a need for a safe topical cream that addresses skin aging due to estrogen deficiency.

[0014] DEFINITIONS

[0015] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of any embodiment. As used herein, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and / or “comprising,” when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof. As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items.

[0016] Unless specifically stated or obvious from context, as used herein, the term “about” in reference to a number or range of numbers is understood to mean the stated number and numbers + / - 10% thereof, or 10% below the lower listed limit and 10% above the higher listed limit for the values listed for a range.

[0017] The terms "subject," "individual," and "patient" may be used interchangeably and refer to humans, as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like). In various embodiments, the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as anoutpatient, or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker.

[0018] As used herein, the phrase "a subject in need thereof refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.

[0019] The terms “administer”, “administered”, “administers” and “administering” are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration. In certain embodiments, oral routes of administering a composition can be used. The terms “administer”, “administered”, “administers” and “administering” a compound should be understood to mean providing a compound of the disclosure or a prodrug of a compound of the disclosure to the individual in need.

[0020] The term “vehicle” refers to a substance that serves as a carrier, whether diluent or excipient, for improving the efficiency of delivery and the effectiveness of a pharmaceutical composition. The phrase “pharmaceutically acceptable vehicle” is art recognized and includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering compounds of the present disclosure to mammals. The vehicles include liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body. Each vehicle must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient or to the subject. Some examples of materials which can serve as pharmaceutically acceptable vehicles include: water; aloe vera leaf juice; emulsifiers or thickening agents, such as carbomer, cetearyl alcohol, cetyl alcohol, glyceryl stearate, stearic acid, xanthan gum, and viscous liquids; sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter, myristyl myristate, Shea butter, and suppository waxes; oils, such as acai palm fruit oil, calendula flower oil, com oil, cottonseed oil, jojoba seed oil, olive oil, passion fruit seed oil, peanut oil, rice bran oil, safflower oil, sesame oil, soybean oil, and sweet almond seed oil; glycols, such as propylene glycol; polyols, such as glycerin, vegetable glycerin, sorbitol, mannitol and polyethylene glycol (e.g., ceteareth-20 and PEG- 100 myristate); esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen- free water; isotonicsaline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0021] COMPOSITIONS

[0022] In certain aspects of the present disclosure is a composition comprising an estrogen and a pharmaceutically acceptable vehicle for delivering the estrogen to a non-vaginal area of a subject in need thereof. In some embodiments, the non-vaginal area is an area exclusive of a vagina of a subject. In some embodiments, the non-vaginal area is a face of the subject. In some embodiments, the non-vaginal area is a face, neck, hands, arms, eyelids, undereye, knees, and / or legs of a subject.

[0023] In some embodiments, the estrogen is selected from the group consisting of estriol estradiol, and estrone. In some embodiments, the estrogen is selected from the group consisting of estriol and estradiol. In some embodiments, the estrogen is estriol. In some embodiments, the estrogen is estradiol. In some embodiments, the estrogen is a synthetic derivative thereof. In some embodiments, the composition comprises about 0.001% to about 1.0 % of the estrogen. In some embodiments, the composition comprises at most about 1.0% of the estrogen. In some embodiments, the composition comprises about 0.3% of the estrogen. In some embodiments, the composition comprises about 0.001 % to about 1.5 % of the estrogen. In some embodiments, the composition comprises about 0.001 % to about 0.01 %, about 0.001 % to about 0.05 %, about 0.001 % to about 0.1 %, about 0.001 % to about 0.2 %, about 0.001 % to about 0.3 %, about 0.001 % to about 0.4 %, about 0.001 % to about 0.5 %, about 0.001 % to about 0.75 %, about 0.001 % to about 1 %, about 0.001 % to about 1.25 %, about 0.001 % to about 1.5 %, about 0.01 % to about 0.05 %, about 0.01 % to about 0.1 %, about 0.01 % to about 0.2 %, about 0.01 % to about 0.3 %, about 0.01 % to about 0.4 %, about 0.01 % to about 0.5 %, about 0.01 % to about 0.75 %, about 0.01 % to about 1 %, about 0.01 % to about 1.25 %, about 0.01 % to about 1.5 %, about 0.05 % to about 0.1 %, about 0.05 % to about 0.2 %, about 0.05 % to about 0.3 %, about 0.05 % to about 0.4 %, about 0.05 % to about 0.5 %, about 0.05 % to about 0.75 %, about 0.05 % to about 1 %, about 0.05 % to about 1.25 %, about 0.05 % to about 1.5 %, about 0.1 % to about 0.2 %, about 0.1 % to about 0.3 %, about 0.1 % to about 0.4 %, about 0.1 % to about 0.5 %, about 0.1 % to about 0.75 %, about 0.1 % to about 1 %, about 0.1 % to about 1.25 %, about 0.1 % to about 1.5 %, about 0.2 % to about 0.3 %, about 0.2 % to about 0.4 %, about 0.2 % to about 0.5 %, about 0.2 % to about 0.75 %, about 0.2 % to about 1 %, about 0.2 % to about 1.25 %, about 0.2 % to about 1.5 %, about 0.3 % to about 0.4 %, about 0.3 % to about 0.5 %, about 0.3 % to about 0.75 %, about 0.3 % to about 1 %, about 0.3 % to about 1.25 %, about 0.3 % to about 1.5 %, about 0.4 % to about 0.5 %, about 0.4 % to about 0.75 %, about 0.4 % to about 1 %,about 0.4 % to about 1.25 %, about 0.4 % to about 1.5 %, about 0.5 % to about 0.75 %, about 0.5 % to about 1 %, about 0.5 % to about 1.25 %, about 0.5 % to about 1.5 %, about 0.75 % to about 1 %, about 0.75 % to about 1.25 %, about 0.75 % to about 1.5 %, about 1 % to about 1.25 %, about 1 % to about 1.5 %, or about 1.25 % to about 1.5 % of the estrogen. In some embodiments, the composition comprises about 0.001 %, about 0.01 %, about 0.05 %, about 0.1 %, about 0.2 %, about 0.3 %, about 0.4 %, about 0.5 %, about 0.75 %, about 1 %, about 1.25 %, or about 1.5 % of the estrogen. In some embodiments, the composition comprises at least about 0.001 %, at least about 0.01 %, at least about 0.05 %, at least about 0.1 %, at least about 0.2 %, at least about 0.3 %, at least about 0.4 %, at least about 0.5 %, at least about 0.75 %, at least about 1 %, or at least about 1.25 % of the estrogen. In some embodiments, the composition comprises at most about 0.01 %, at most about 0.05 %, at most about 0.1 %, at most about 0.2 %, at most about 0.3 %, at most about 0.4 %, at most about 0.5 %, at most about 0.75 %, at most about 1 %, at most about 1.25 %, or at most about 1.5 % of the estrogen. In some embodiments, the composition comprises about 0.001 %, about 0.01 %, about 0.05 %, about 0.1 %, about 0.2 %, about 0.3 %, about 0.4 %, about 0.5 %, about 0.75 %, about 1 %, about 1.25 %, or about 1.5 % of the estradiol. In some embodiments, the composition comprises at least about 0.001 %, at least about 0.01 %, at least about 0.05 %, at least about 0.1 %, at least about 0.2 %, at least about 0.3 %, at least about 0.4 %, at least about 0.5 %, at least about 0.75 %, at least about 1 %, or at least about 1.25 % of the estradiol. In some embodiments, the composition comprises at most about 0.01 %, at most about 0.05 %, at most about 0.1 %, at most about 0.2 %, at most about 0.3 %, at most about 0.4 %, at most about 0.5 %, at most about 0.75 %, at most about 1 %, at most about 1.25 %, or at most about 1.5 % of the estradiol.

[0024] In some embodiments, the composition comprises about 0.3 % to about 6 % of the estrogen. In some embodiments, the composition comprises about 0.3 % to about 1 %, about 0.3 % to about 1.5 %, about 0.3 % to about 2 %, about 0.3 % to about 2.5 %, about 0.3 % to about 3 %, about 0.3 % to about 3.5 %, about 0.3 % to about 4 %, about 0.3 % to about 4.5 %, about 0.3 % to about 5 %, about 0.3 % to about 5.5 %, about 0.3 % to about 6 %, about 1 % to about 1.5 %, about 1 % to about 2 %, about 1 % to about 2.5 %, about 1 % to about 3 %, about 1 % to about 3.5 %, about 1 % to about 4 %, about 1 % to about 4.5 %, about 1 % to about 5 %, about 1 % to about 5.5 %, about 1 % to about 6 %, about 1.5 % to about 2 %, about 1.5 % to about 2.5 %, about 1.5 % to about 3 %, about 1.5 % to about 3.5 %, about 1.5 % to about 4 %, about 1.5 % to about 4.5 %, about 1.5 % to about 5 %, about 1.5 % to about 5.5 %, about 1.5 % to about 6 %, about 2 % to about 2.5 %, about 2 % to about 3 %, about 2 % to about 3.5 %, about 2 % to about 4 %, about 2 % to about 4.5 %, about 2 % to about 5 %, about 2 % to about 5.5 %, about 2 % toabout 6 %, about 2.5 % to about 3 %, about 2.5 % to about 3.5 %, about 2.5 % to about 4 %, about 2.5 % to about 4.5 %, about 2.5 % to about 5 %, about 2.5 % to about 5.5 %, about 2.5 % to about 6 %, about 3 % to about 3.5 %, about 3 % to about 4 %, about 3 % to about 4.5 %, about3 % to about 5 %, about 3 % to about 5.5 %, about 3 % to about 6 %, about 3.5 % to about 4 %, about 3.5 % to about 4.5 %, about 3.5 % to about 5 %, about 3.5 % to about 5.5 %, about 3.5 % to about 6 %, about 4 % to about 4.5 %, about 4 % to about 5 %, about 4 % to about 5.5 %, about4 % to about 6 %, about 4.5 % to about 5 %, about 4.5 % to about 5.5 %, about 4.5 % to about 6 %, about 5 % to about 5.5 %, about 5 % to about 6 %, or about 5.5 % to about 6 % of the estrogen. In some embodiments, the composition comprises about 0.3 %, about 1 %, about 1.5 %, about 2 %, about 2.5 %, about 3 %, about 3.5 %, about 4 %, about 4.5 %, about 5 %, about5.5 %, or about 6 % of the estrogen. In some embodiments, the composition comprises at least about 0.3 %, about 1 %, about 1.5 %, about 2 %, about 2.5 %, about 3 %, about 3.5 %, about 4 %, about 4.5 %, about 5 %, or about 5.5 % of the estrogen. In some embodiments, the composition comprises at most about 1 %, about 1.5 %, about 2 %, about 2.5 %, about 3 %, about 3.5 %, about 4 %, about 4.5 %, about 5 %, about 5.5 %, or about 6 % of the estrogen. In some embodiments, the composition comprises about 0.3 %, about 1 %, about 1.5 %, about 2 %, about 2.5 %, about 3 %, about 3.5 %, about 4 %, about 4.5 %, about 5 %, about 5.5 %, or about 6 % of the estradiol. In some embodiments, the composition comprises at least about 0.3 %, about1 %, about 1.5 %, about 2 %, about 2.5 %, about 3 %, about 3.5 %, about 4 %, about 4.5 %, about 5 %, or about 5.5 % of the estradiol. In some embodiments, the composition comprises at most about 1 %, about 1.5 %, about 2 %, about 2.5 %, about 3 %, about 3.5 %, about 4 %, about4.5 %, about 5 %, about 5.5 %, or about 6 % of the estradiol.

[0025] In some embodiments, the composition comprises about 2 % to about 10 % of the estrogen. In some embodiments, the composition comprises about 2 % to about 3 %, about 2 % to about 4 %, about 2 % to about 5 %, about 2 % to about 6 %, about 2 % to about 7 %, about 2 % to about 8 %, about 2 % to about 9 %, about 2 % to about 10 %, about 3 % to about 4 %, about 3 % to about 5 %, about 3 % to about 6 %, about 3 % to about 7 %, about 3 % to about 8 %, about 3 % to about 9 %, about 3 % to about 10 %, about 4 % to about 5 %, about 4 % to about 6 %, about 4 % to about 7 %, about 4 % to about 8 %, about 4 % to about 9 %, about 4 % to about 10 %, about 5 % to about 6 %, about 5 % to about 7 %, about 5 % to about 8 %, about 5 % to about 9 %, about 5 % to about 10 %, about 6 % to about 7 %, about 6 % to about 8 %, about 6 % to about 9 %, about 6 % to about 10 %, about 7 % to about 8 %, about 7 % to about 9 %, about 7 % to about 10 %, about 8 % to about 9 %, about 8 % to about 10 %, or about 9 % to about 10 % of the estrogen. In some embodiments, the composition comprises about 2 %, about3 %, about 4 %, about 5 %, about 6 %, about 7 %, about 8 %, about 9 %, or about 10 % of the estrogen. In some embodiments, the composition comprises at least about 2 %, about 3 %, about4 %, about 5 %, about 6 %, about 7 %, about 8 %, or about 9 % of the estrogen. In some embodiments, the composition comprises at most about 3 %, about 4 %, about 5 %, about 6 %, about 7 %, about 8 %, about 9 %, or about 10 % of the estrogen. In some embodiments, the composition comprises about 2 %, about 3 %, about 4 %, about 5 %, about 6 %, about 7 %, about 8 %, about 9 %, or about 10 % of the estradiol. In some embodiments, the composition comprises at least about 2 %, about 3 %, about 4 %, about 5 %, about 6 %, about 7 %, about 8 %, or about 9 % of the estradiol. In some embodiments, the composition comprises at most about 3 %, about 4 %, about 5 %, about 6 %, about 7 %, about 8 %, about 9 %, or about 10 % of the estradiol.

[0026] In some embodiments, the composition further comprises tretinoin. In some embodiments, the composition further comprises about 0.2 % to about 0.5% of tretinoin. In some embodiments, the composition further comprises about 0.001 % to about 1 % of tretinoin. In some embodiments, the composition further comprises about 0.001 % to about 0.01 %, about 0.001 % to about 0.1 %, about 0.001 % to about 0.2 %, about 0.001 % to about 0.3 %, about0.001 % to about 0.4 %, about 0.001 % to about 0.5 %, about 0.001 % to about 0.6 %, about0.001 % to about 0.7 %, about 0.001 % to about 0.8 %, about 0.001 % to about 0.9 %, about0.001 % to about 1 %, about 0.01 % to about 0.1 %, about 0.01 % to about 0.2 %, about 0.01 % to about 0.3 %, about 0.01 % to about 0.4 %, about 0.01 % to about 0.5 %, about 0.01 % to about 0.6 %, about 0.01 % to about 0.7 %, about 0.01 % to about 0.8 %, about 0.01 % to about 0.9 %, about 0.01 % to about 1 %, about 0.1 % to about 0.2 %, about 0.1 % to about 0.3 %, about 0.1 % to about 0.4 %, about 0.1 % to about 0.5 %, about 0.1 % to about 0.6 %, about 0.1 % to about 0.7 %, about 0.1 % to about 0.8 %, about 0.1 % to about 0.9 %, about 0.1 % to about 1 %, about 0.2 % to about 0.3 %, about 0.2 % to about 0.4 %, about 0.2 % to about 0.5 %, about 0.2 % to about 0.6 %, about 0.2 % to about 0.7 %, about 0.2 % to about 0.8 %, about 0.2 % to about 0.9 %, about 0.2 % to about 1 %, about 0.3 % to about 0.4 %, about 0.3 % to about 0.5 %, about 0.3 % to about 0.6 %, about 0.3 % to about 0.7 %, about 0.3 % to about 0.8 %, about 0.3 % to about 0.9 %, about 0.3 % to about 1 %, about 0.4 % to about 0.5 %, about 0.4 % to about 0.6 %, about 0.4 % to about 0.7 %, about 0.4 % to about 0.8 %, about 0.4 % to about 0.9 %, about 0.4 % to about 1 %, about 0.5 % to about 0.6 %, about 0.5 % to about 0.7 %, about 0.5 % to about 0.8 %, about 0.5 % to about 0.9 %, about 0.5 % to about 1 %, about 0.6 % to about 0.7 %, about 0.6 % to about 0.8 %, about 0.6 % to about 0.9 %, about 0.6 % to about 1 %, about 0.7 % to about 0.8 %, about 0.7 % to about 0.9 %, about 0.7 % to about 1 %, about 0.8 % to about 0.9 %, about 0.8 %to about 1 %, or about 0.9 % to about 1 % of tretinoin. In some embodiments, the composition further comprises about 0.001 %, about 0.01 %, about 0.1 %, about 0.2 %, about 0.3 %, about 0.4 %, about 0.5 %, about 0.6 %, about 0.7 %, about 0.8 %, about 0.9 %, or about 1 % of tretinoin. In some embodiments, the composition further comprises at least about 0.001 %, about 0.01 %, about 0.1 %, about 0.2 %, about 0.3 %, about 0.4 %, about 0.5 %, about 0.6 %, about 0.7 %, about 0.8 %, or about 0.9 % of tretinoin. In some embodiments, the composition further comprises at most about 0.01 %, at most about 0.1 %, at most about 0.2 %, at most about 0.3 %, at most about 0.4 %, at most about 0.5 %, at most about 0.6 %, at most about 0.7 %, at most about 0.8 %, at most about 0.9 %, or at most about 1 % of tretinoin. In some embodiments, the composition further comprises niacinamide.

[0027] In some embodiments, the composition further comprises niacinamide. In some embodiments, the composition further comprises about 0.1 % to about 10 % of niacinamide. In some embodiments, the composition further comprises about 0.1 % to about 0.5 %, about 0.1 % to about 1 %, about 0.1 % to about 2 %, about 0.1 % to about 3 %, about 0.1 % to about 4 %, about 0.1 % to about 5 %, about 0.1 % to about 6 %, about 0.1 % to about 7 %, about 0.1 % to about 8 %, about 0.1 % to about 9 %, about 0.1 % to about 10 %, about 0.5 % to about 1 %, about 0.5 % to about 2 %, about 0.5 % to about 3 %, about 0.5 % to about 4 %, about 0.5 % to about 5 %, about 0.5 % to about 6 %, about 0.5 % to about 7 %, about 0.5 % to about 8 %, about 0.5 % to about 9 %, about 0.5 % to about 10 %, about 1 % to about 2 %, about 1 % to about 3 %, about 1 % to about 4 %, about 1 % to about 5 %, about 1 % to about 6 %, about 1 % to about 7 %, about 1 % to about 8 %, about 1 % to about 9 %, about 1 % to about 10 %, about 2 % to about 3 %, about 2 % to about 4 %, about 2 % to about 5 %, about 2 % to about 6 %, about 2 % to about 7 %, about 2 % to about 8 %, about 2 % to about 9 %, about 2 % to about 10 %, about 3 % to about 4 %, about 3 % to about 5 %, about 3 % to about 6 %, about 3 % to about 7 %, about 3 % to about 8 %, about 3 % to about 9 %, about 3 % to about 10 %, about 4 % to about 5 %, about 4 % to about 6 %, about 4 % to about 7 %, about 4 % to about 8 %, about 4 % to about 9 %, about 4 % to about 10 %, about 5 % to about 6 %, about 5 % to about 7 %, about 5 % to about 8 %, about 5 % to about 9 %, about 5 % to about 10 %, about 6 % to about 7 %, about 6 % to about 8 %, about 6 % to about 9 %, about 6 % to about 10 %, about 7 % to about 8 %, about 7 % to about 9 %, about 7 % to about 10 %, about 8 % to about 9 %, about 8 % to about 10 %, or about 9 % to about 10 % of niacinamide. In some embodiments, the composition further comprises about 0.1 %, about 0.5 %, about 1 %, about 2 %, about 3 %, about 4 %, about 5 %, about 6 %, about 7 %, about 8 %, about 9 %, or about 10 % of niacinamide. In some embodiments, the composition further comprises at least about 0.1 %, at least about 0.5 %, atleast about 1 %, at least about 2 %, at least about 3 %, at least about 4 %, at least about 5 %, at least about 6 %, at least about 7 %, at least about 8 %, or at least about 9 % of niacinamide. In some embodiments, the composition further comprises at most about 0.5 %, at most about 1 %, at most about 2 %, at most about 3 %, at most about 4 %, at most about 5 %, at most about 6 %, at most about 7 %, at most about 8 %, at most about 9 %, or at most about 10 % of niacinamide.

[0028] In some embodiments, the composition further comprises azelaic acid. In some embodiments, the composition further comprises about 0.1 % to about 10 % of azelaic acid. In some embodiments, the composition further comprises about 0.1 % to about 0.5 %, about 0.1 % to about 1 %, about 0.1 % to about 2 %, about 0.1 % to about 3 %, about 0.1 % to about 4 %, about 0.1 % to about 5 %, about 0.1 % to about 6 %, about 0.1 % to about 7 %, about 0.1 % to about 8 %, about 0.1 % to about 9 %, about 0.1 % to about 10 %, about 0.5 % to about 1 %, about 0.5 % to about 2 %, about 0.5 % to about 3 %, about 0.5 % to about 4 %, about 0.5 % to about 5 %, about 0.5 % to about 6 %, about 0.5 % to about 7 %, about 0.5 % to about 8 %, about 0.5 % to about 9 %, about 0.5 % to about 10 %, about 1 % to about 2 %, about 1 % to about 3 %, about 1 % to about 4 %, about 1 % to about 5 %, about 1 % to about 6 %, about 1 % to about 7 %, about 1 % to about 8 %, about 1 % to about 9 %, about 1 % to about 10 %, about 2 % to about 3 %, about 2 % to about 4 %, about 2 % to about 5 %, about 2 % to about 6 %, about 2 % to about 7 %, about 2 % to about 8 %, about 2 % to about 9 %, about 2 % to about 10 %, about 3 % to about 4 %, about 3 % to about 5 %, about 3 % to about 6 %, about 3 % to about 7 %, about 3 % to about 8 %, about 3 % to about 9 %, about 3 % to about 10 %, about 4 % to about 5 %, about 4 % to about 6 %, about 4 % to about 7 %, about 4 % to about 8 %, about 4 % to about 9 %, about 4 % to about 10 %, about 5 % to about 6 %, about 5 % to about 7 %, about 5 % to about 8 %, about 5 % to about 9 %, about 5 % to about 10 %, about 6 % to about 7 %, about 6 % to about 8 %, about 6 % to about 9 %, about 6 % to about 10 %, about 7 % to about 8 %, about 7 % to about 9 %, about 7 % to about 10 %, about 8 % to about 9 %, about 8 % to about 10 %, or about 9 % to about 10 % of azelaic acid. In some embodiments, the composition further comprises about 0.1 %, about 0.5 %, about 1 %, about 2 %, about 3 %, about 4 %, about 5 %, about 6 %, about 7 %, about 8 %, about 9 %, or about 10 % of azelaic acid. In some embodiments, the composition further comprises at least about 0.1 %, at least about 0.5 %, at least about 1 %, at least about 2 %, at least about 3 %, at least about 4 %, at least about 5 %, at least about 6 %, at least about 7 %, at least about 8 %, or at least about 9 % of niacinamide. In some embodiments, the composition further comprises at most about 0.5 %, at most about 1 %, at most about 2 %, at most about 3 %, at most about 4 %, at most about 5 %, at most about 6 %, at most about 7 %, at most about 8 %, at most about 9 %, or at most about 10 % of azelaic acid.

[0029] In some embodiments, the pharmaceutically acceptable vehicle comprises glycerin, oleic acid, or vitamin E. In some embodiments, the pharmaceutically acceptable vehicle comprises at least two of glycerin, oleic acid, and vitamin E. In some embodiments, the pharmaceutically acceptable vehicle comprises at least glycerin, oleic acid, and vitamin E. In some embodiments, the pharmaceutically acceptable vehicle comprises glycerin or a derivative thereof and vitamin E or a derivative thereof. In some embodiments, the glycerin may be a derivative thereof. In some embodiments, the oleic acid may be a derivative thereof. In some embodiments, the vitamin E may be a derivative thereof. In some embodiments, the vitamin E may be a tocopherol and / or a tocotrienol. In some embodiments, the vitamin E may be alphatocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol, tocopheryl acetate, alpha- tocotrienol, beta-tocotrienol, gamma tocotrienol, or delta tocotrienol. In some embodiments, the glycerin derivative is acetol, acrolein, polyglycerol, glycerin acid, dihydroxyacetone, monoglycerides, mono-acyl glyceride, di-acyl glyceride, mono ether glycerol, 1 ,2-propanediol, or 1,3-propanediol. In some embodiments, the oleic acid derivative is oleic betaine or monoolein.

[0030] In some embodiments, the pharmaceutically acceptable vehicle comprises C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxyethyl acrylate / sodium acryloyldimethyl, a taurate copolymer, oleic acid, olive oil, PEG- 100 stearate, phenoxyethanol, polymethylsiloxane, purified water, stearic acid, trolamine NF, vitamin E acetate, or any combination thereof.

[0031] In some embodiments, the composition comprises an estrogen, C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxyethyl acrylate / sodium acryloyldimethyl, a taurate copolymer, oleic acid, olive oil, PEG- 100 stearate, phenoxyethanol, polymethylsiloxane, purified water, stearic acid, trolamine NF, and vitamin E acetate. In some embodiments, the composition comprises an estrogen, tretinoin, C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxyethyl acrylate / sodium acryloyldimethyl, a taurate copolymer, oleic acid, olive oil, PEG- 100 stearate, phenoxyethanol, polymethylsiloxane, purified water, stearic acid, trolamine NF, and vitamin E acetate. In some embodiments, the composition comprises an estrogen, niacinamide, C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxyethyl acrylate / sodium acryloyldimethyl, a taurate copolymer, oleic acid, olive oil, PEG- 100 stearate, phenoxyethanol, polymethylsiloxane, purified water, stearic acid, trolamine NF, and vitamin E acetate. In some embodiments, the composition comprises an estrogen, tretinoin, niacinamide, C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol,ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxyethyl acrylate / sodium acryloyldimethyl, a taurate copolymer, oleic acid, olive oil, PEG- 100 stearate, phenoxyethanol, polymethylsiloxane, purified water, stearic acid, trolamine NF, and vitamin E acetate.

[0032] In some embodiments, the pharmaceutically acceptable vehicle comprises Aloe Barbadensis Leaf Juice, C 12 - 14 Isoparaffin, Caprylic / Capric Triglyceride, Deionized Water, Laureth-7, Phenoxyethanol, Polyacrylamide, Tocopheryl Acetate, Triethylene Glycol, or any combination thereof.

[0033] In some embodiments, the composition comprises an estrogen, Aloe Barbadensis Leaf Juice, C 12 - 14 Isoparaffin, Caprylic / Capric Triglyceride, Deionized Water, Laureth-7, Phenoxyethanol, Polyacrylamide, Tocopheryl Acetate, and Triethylene Glycol. In some embodiments, the composition comprises an estrogen, tretinoin, Aloe Barbadensis Leaf Juice, C 12 - 14 Isoparaffin, Caprylic / Capric Triglyceride, Deionized Water, Laureth-7, Phenoxyethanol, Polyacrylamide, Tocopheryl Acetate, and Triethylene Glycol. In some embodiments, the composition comprises an estrogen, tretinoin, niacinamide, Aloe Barbadensis Leaf Juice, C 12 - 14 Isoparaffin, Caprylic / Capric Triglyceride, Deionized Water, Laureth-7, Phenoxyethanol, Polyacrylamide, Tocopheryl Acetate, and Triethylene Glycol. In some embodiments, the composition comprises an estrogen, niacinamide, Aloe Barbadensis Leaf Juice, C 12 - 14 Isoparaffin, Caprylic / Capric Triglyceride, Deionized Water, Laureth-7, Phenoxyethanol, Polyacrylamide, Tocopheryl Acetate, and Triethylene Glycol.

[0034] In some embodiments, the pharmaceutically acceptable vehicles comprises a humectant, an emulsifier, a thickening agent, an oil, a preservative, a polyol, or any combination thereof.

[0035] In an aspect of the present disclosure is a composition comprising an estrogen for topical application to a skin of a subject in need thereof, wherein the composition further comprises C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxyethyl acrylate / sodium acryloyldimethyl, a taurate copolymer, oleic acid, olive oil, PEG- 100 stearate, phenoxyethanol, polymethylsiloxane, purified water, stearic acid, trolamine NF, and vitamin E acetate.

[0036] In an aspect of the present disclosure is a composition comprising an estrogen for topical application to a skin of a subject in need thereof, wherein the composition further comprises Aloe Barbadensis Leaf Juice , C 12 - 14 Isoparaffin, Caprylic / Capric Triglyceride, Deionized Water, Laureth-7, Phenoxyethanol, Polyacrylamide, Tocopheryl Acetate, and Triethylene Glycol.

[0037] AREAS FOR APPLICATION

[0038] In some embodiments, the composition is formulated as a topical cream. In some embodiments, the composition is formulated as a topical face cream. In some embodiments, the topical cream is applied on a subject’s face and / or neck. In some embodiments, the composition is applied on a subject’s face, neck, eyelid, undereye, hands, knees, arms, and / or legs. In some embodiments, the composition is applied on a subject’s face, neck, eyelid, and / or undereye. In some embodiments, the composition is applied on a subject’s eyelid and / or undereye.

[0039] In some embodiments, the composition is applied daily to the non-vaginal area. In some embodiments, the composition is applied once, twice, or thrice per day to the non-vaginal area. In some embodiments, the non-vaginal area is a face, neck, hands, knees, legs, arms, torso, or undereye of the subject. In some embodiments, the composition is applied daily to a face. In some embodiments, the composition is applied once, twice, or thrice daily to a face. In some embodiments, the composition is applied at least once daily to a face. In some embodiments, the composition is applied at least once daily to a non-vaginal area. In some embodiments, the composition is applied at least once daily to a non-vaginal area comprising a face, neck, hands, knees, legs, arms, torso, undereye, or any combination thereof. In some embodiments, the composition is applied once daily to face at nighttime. In some embodiments, the composition is applied once daily to face at daytime. In some embodiments, the composition is applied daily both at nighttime and daytime. In some embodiments, the composition is applied as needed. In some embodiments, the composition is applied at about 0.2 mL to about 0.4 mL daily to the non- vaginal area. In some embodiments, the composition is applied at about 0.2 mL to about 0.4 mL daily to the face. In some embodiments, the composition is applied at about 0.3 mL daily to the face. In some embodiments, the composition is applied at about 0.1 mL to about 2 mL to the non-vaginal area. In some embodiments, the composition is applied at about 0.1 mL to about 0.2 mL, about 0.1 mL to about 0.3 mL, about 0.1 mL to about 0.4 mL, about 0.1 mL to about 0.5 mL, about 0.1 mL to about 0.6 mL, about 0.1 mL to about 0.7 mL, about 0.1 mL to about 0.8 mL, about 0.1 mL to about 0.9 mL, about 0.1 mL to about 1 mL, about 0.1 mL to about 1.5 mL, about 0.1 mL to about 2 mL, about 0.2 mL to about 0.3 mL, about 0.2 mL to about 0.4 mL, about 0.2 mL to about 0.5 mL, about 0.2 mL to about 0.6 mL, about 0.2 mL to about 0.7 mL, about 0.2 mL to about 0.8 mL, about 0.2 mL to about 0.9 mL, about 0.2 mL to about 1 mL, about 0.2 mL to about 1.5 mL, about 0.2 mL to about 2 mL, about 0.3 mL to about 0.4 mL, about 0.3 mL to about 0.5 mL, about 0.3 mL to about 0.6 mL, about 0.3 mL to about 0.7 mL, about 0.3 mL to about 0.8 mL, about 0.3 mL to about 0.9 mL, about 0.3 mL to about 1 mL, about 0.3 mL to about 1.5 mL, about 0.3 mL to about 2 mL, about 0.4 mL to about 0.5 mL, about 0.4 mL to about 0.6mL, about 0.4 mL to about 0.7 mL, about 0.4 mL to about 0.8 mL, about 0.4 mL to about 0.9 mL, about 0.4 mL to about 1 mL, about 0.4 mL to about 1.5 mL, about 0.4 mL to about 2 mL, about 0.5 mL to about 0.6 mL, about 0.5 mL to about 0.7 mL, about 0.5 mL to about 0.8 mL, about 0.5 mL to about 0.9 mL, about 0.5 mL to about 1 mL, about 0.5 mL to about 1.5 mL, about 0.5 mL to about 2 mL, about 0.6 mL to about 0.7 mL, about 0.6 mL to about 0.8 mL, about 0.6 mL to about 0.9 mL, about 0.6 mL to about 1 mL, about 0.6 mL to about 1.5 mL, about 0.6 mL to about 2 mL, about 0.7 mL to about 0.8 mL, about 0.7 mL to about 0.9 mL, about 0.7 mL to about 1 mL, about 0.7 mL to about 1.5 mL, about 0.7 mL to about 2 mL, about 0.8 mL to about 0.9 mL, about 0.8 mL to about 1 mL, about 0.8 mL to about 1.5 mL, about 0.8 mL to about 2 mL, about 0.9 mL to about 1 mL, about 0.9 mL to about 1.5 mL, about 0.9 mL to about 2 mL, about 1 mL to about 1.5 mL, about 1 mL to about 2 mL, or about 1.5 mL to about 2 mL to the non-vaginal area. In some embodiments, the composition is applied at about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1 mL, about 1.5 mL, or about 2 mL to the non-vaginal area. In some embodiments, the composition is applied at least about 0.1 mL, at least about 0.2 mL, at least about 0.3 mL, at least about 0.4 mL, at least about 0.5 mL, at least about 0.6 mL, at least about 0.7 mL, at least about 0.8 mL, at least about 0.9 mL, at least about 1 mL, or at least about 1.5 mL to the non-vaginal area. In some embodiments, the composition is applied at most about 0.2 mL, at most about 0.3 mL, at most about 0.4 mL, at most about 0.5 mL, at most about 0.6 mL, at most about 0.7 mL, at most about 0.8 mL, at most about 0.9 mL, at most about 1 mL, at most about 1.5 mL, or at most about 2 mL to the non-vaginal area.

[0040] In some embodiments, the composition is applied at about 1 mL to about 50 mL to the non-vaginal area. In some embodiments, the composition is applied at about 1 mL to about 2 mL, about 1 mL to about 3 mL, about 1 mL to about 4 mL, about 1 mL to about 5 mL, about 1 mL to about 10 mL, about 1 mL to about 15 mL, about 1 mL to about 20 mL, about 1 mL to about 25 mL, about 1 mL to about 30 mL, about 1 mL to about 40 mL, about 1 mL to about 50 mL, about 2 mL to about 3 mL, about 2 mL to about 4 mL, about 2 mL to about 5 mL, about 2 mL to about 10 mL, about 2 mL to about 15 mL, about 2 mL to about 20 mL, about 2 mL to about 25 mL, about 2 mL to about 30 mL, about 2 mL to about 40 mL, about 2 mL to about 50 mL, about 3 mL to about 4 mL, about 3 mL to about 5 mL, about 3 mL to about 10 mL, about 3 mL to about 15 mL, about 3 mL to about 20 mL, about 3 mL to about 25 mL, about 3 mL to about 30 mL, about 3 mL to about 40 mL, about 3 mL to about 50 mL, about 4 mL to about 5 mL, about 4 mL to about 10 mL, about 4 mL to about 15 mL, about 4 mL to about 20 mL, about 4 mL to about 25 mL, about 4 mL to about 30 mL, about 4 mL to about 40 mL, about 4 mL toabout 50 mL, about 5 mL to about 10 mL, about 5 mL to about 15 mL, about 5 mL to about 20 mL, about 5 mL to about 25 mL, about 5 mL to about 30 mL, about 5 mL to about 40 mL, about 5 mL to about 50 mL, about 10 mL to about 15 mL, about 10 mL to about 20 mL, about 10 mL to about 25 mL, about 10 mL to about 30 mL, about 10 mL to about 40 mL, about 10 mL to about 50 mL, about 15 mL to about 20 mL, about 15 mL to about 25 mL, about 15 mL to about 30 mL, about 15 mL to about 40 mL, about 15 mL to about 50 mL, about 20 mL to about 25 mL, about 20 mL to about 30 mL, about 20 mL to about 40 mL, about 20 mL to about 50 mL, about 25 mL to about 30 mL, about 25 mL to about 40 mL, about 25 mL to about 50 mL, about 30 mL to about 40 mL, about 30 mL to about 50 mL, or about 40 mL to about 50 mL to the non-vaginal area. In some embodiments, the composition is applied at about 1 mL, about 2 mL, about 3 mL, about 4 mL, about 5 mL, about 10 mL, about 15 mL, about 20 mL, about 25 mL, about 30 mL, about 40 mL, or about 50 mL to the non-vaginal area. In some embodiments, the composition is applied at least about 1 mL, about 2 mL, about 3 mL, about 4 mL, about 5 mL, about 10 mL, about 15 mL, about 20 mL, about 25 mL, about 30 mL, or about 40 mL to the non-vaginal area. In some embodiments, the composition is applied at most about 2 mL, about 3 mL, about 4 mL, about 5 mL, about 10 mL, about 15 mL, about 20 mL, about 25 mL, about 30 mL, about 40 mL, about 50 mL, about 60 mL, about 70 mL, about 80 mL, about 90 mL, or about 100 mL to the non-vaginal area.

[0041] In some embodiments, the composition is applied safely to eye areas. In some embodiments, the composition is applied safely to eyelid areas. In some embodiments, the composition is applied safely to under-eye areas. In some embodiments, the composition is safely used with retinoids, vitamin C, or spot treatments. In some embodiments, the composition is safely used with retinoids or derivatives thereof, vitamin C or derivatives thereof, or spot treatments. In some embodiments, the composition is used in tandem with retinoids, vitamin C, or spot treatments. In some embodiments, the composition is used in tandem with retinoids or derivatives thereof, vitamin C or derivatives thereof, or spot treatments. In some embodiments, a spot treatment is a cream, gel, serum, or patch used to treat and reduce active acne blemishes, post-acne scars, and / or dark spots.

[0042] In some embodiments, the composition is a cream. In some embodiments, the composition is a lotion. In some embodiments, the composition is a gel. In some embodiments, the composition is a serum, balm, ointment, or butter.

[0043] EFFECTS

[0044] In some embodiments, the composition reduces a severity of one or more symptoms comprising skin dryness, decreased skin firmness, decreased skin elasticity, loss of collagen, lossof elastin, loss of fibroblast function, loss of vascularity, or increased matrix metalloproteinase(s) enzymatic activities. In some embodiments, the composition has one of more effects comprising reduced acne scarring, increased collagen production, increased skin moisture, increased skin firmness, decreased pore size, decreased wrinkle depth, increased skin elasticity, or reversal of effects of estrogen-deficiency in skin due to menopause. In some embodiments, the composition improves wound healing and / or bum healing of the skin.

[0045] SUBJECT POPULATION

[0046] In some embodiments, the composition treats a disease or condition in the subject. In some embodiments, the subject has a Fitzpatrick skin type I, II, III, IV, V, or VI. In some embodiments, the subject is of ages 13 to 80. In some embodiments, the subject is of ages 35 to 80. In some embodiments, the subject is about 13 to about 90 in age. In some embodiments, the subject is about 13 to about 40, about 13 to about 45, about 13 to about 50, about 13 to about 60, about 13 to about 70, about 13 to about 80, about 13 to about 90, about 18 to about 30, about 18 to about 35, about 18 to about 40, about 18 to about 45, about 18 to about 50, about 18 to about 60, about 18 to about 70, about 18 to about 80, about 18 to about 90, about 30 to about 35, about 30 to about 40, about 30 to about 45, about 30 to about 50, about 30 to about 60, about 30 to about 70, about 30 to about 80, about 30 to about 90, about 35 to about 40, about 35 to about 45, about 35 to about 50, about 35 to about 60, about 35 to about 70, about 35 to about 80, about 35 to about 90, about 40 to about 45, about 40 to about 50, about 40 to about 60, about 40 to about 70, about 40 to about 80, about 40 to about 90, about 45 to about 50, about 45 to about 60, about 45 to about 70, about 45 to about 80, about 45 to about 90, about 50 to about 60, about 50 to about 70, about 50 to about 80, about 50 to about 90, about 60 to about 70, about 60 to about 80, about 60 to about 90, about 70 to about 80, about 70 to about 90, or about 80 to about 90 in age. In some embodiments, the subject is about 13, about 18, about 30, about 35, about 40, about 45, about 50, about 60, about 70, about 80, or about 90 in age. In some embodiments, the subject is at least about 13, at least about 18, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 60, at least about 70, or at least about 80 in age. In some embodiments, the subject is at most about 18, at most about 30, at most about 35, at most about 40, at most about 45, at most about 50, at most about 60, at most about 70, at most about 80, or at most about 90 in age. In some embodiments, the subject is female. In some embodiments, the subject is male. In some embodiments, the subject is perimenopausal. In some embodiments, the subject is menopausal. In some embodiments, the subject is not perimenopausal nor menopausal. In some embodiments, the subject is not perimenopausal normenopausal but is experiencing symptoms of aging. In some embodiments, the subject is not perimenopausal nor menopausal but is experiencing symptoms of estrogen deficiency.

[0047] In some embodiments, the subject produces estrogen and has estrogen receptors on their skin. In some embodiments, the subject is male. All genders produce estrogen and have estrogen receptors on their skin therefore, the compositions and uses disclosed herein are not gender specific and / or restricted. In some embodiments, the composition is a non-systemic composition. In some embodiments, the composition does not enter the bloodstream.

[0048] In some embodiments, the disease or condition is perimenopause or menopause. In some embodiments, the disease or condition is skin aging due to perimenopause or menopause. In some embodiments, the disease or condition is skin aging. In some embodiments, the disease or condition is dermatological issues due to perimenopause or menopause. In some embodiments, the disease or condition is skin dryness, decreased skin firmness, decreased skin elasticity, loss of collagen, loss of elastin, loss of fibroblast function, loss of vascularity, increased matrix metalloproteinase(s) enzymatic activities, or a combination thereof.

[0049] In some embodiments, the treatment is most effective when started around perimenopause. In some embodiments, the treatment is most effective when started before perimenopause. In some embodiments, the treatment is most effective when started within 6 months of onset of perimenopause. In some embodiments, the treatment is most effective when started within about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 12 months of onset of perimenopause. In some embodiments, the composition treats or ameliorates a condition of the subject’s skin. In some embodiments, the condition is derived from menopause and / or perimenopause. In some embodiments, the condition is acne scarring, wound healing, bum healing, skin dryness, epidermal thinning, decreased skin firmness, decreased skin elasticity, loss of collagen, loss of elastin, loss of fibroblast function, loss of vascularity, increased matrix metalloproteinase(s) enzymatic activities, or any combination thereof. In some embodiments, the condition is one or more symptoms of menopause and / or perimenopause.

[0050] In some embodiments, the subject further uses other treatments for menopause hormone therapy. In some embodiments, the other treatments for menopause hormone therapy comprises estradiol vaginal cream, estrogen pills, estrogen creams, estrogen vaginal rings, estrogen vaginal tablets, estrogen patch, estrogen spray, estrogen progesterone combination pill, estrogen progesterone combination patch, or vaginal dehydroepiandrosterone insert.

[0051] METHODS OF TREATMENT

[0052] In an aspect of the present disclosure is a method for the treatment of skin conditions in a subject in need thereof comprising administering to a skin of a subject a composition comprising an estrogen and a pharmaceutically acceptable vehicle for delivering the estrogen to a non- vaginal area of the subject in need thereof.

[0053] In some embodiments, the skin conditions are due to menopause and / or perimenopause. In some embodiments, the skin conditions are one or more selected from skin dryness, decreased skin firmness, decreased skin elasticity, loss of collagen, loss of elastin, loss of fibroblast function, and loss of vascularity.

[0054] In some embodiments, the subject is perimenopausal or menopausal.

[0055] In some embodiments, the treatment decreases loss of structural architecture of the skin and / or decreases propensity to skin damage. In some embodiments, the treatment mitigates skin aging. In some embodiments, the treatment elevates levels of mucopolysaccharides and hyaluronic acids in a dermis of the subject. In some embodiments, the treatment increases a relative collagen synthesis in the skin of the subject.

[0056] In an aspect of the present disclosure is a method of improving skin elasticity comprising administering to a skin of a subject a composition comprising an estrogen and a pharmaceutically acceptable vehicle for delivering the estrogen to a non-vaginal area of the subject in need thereof, wherein the administration of the composition results in an about 88 % improvement in skin elasticity compared to an administration of a placebo composition. In some embodiments, the placebo composition does not comprise an estrogen. In some embodiments, the placebo composition does not comprise estriol. In some embodiments, the placebo composition does not comprise estradiol. In some embodiments, the method improves skin elasticity by at least about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 120%, or more. In some embodiments, the method improves skin elasticity by at most about 200%, about 180%, about 160%, about 140%, about 120%, about 100%, about 90%, or less.

[0057] In an aspect of the present disclosure is a method of improving skin hydration comprising administering to a skin of a subject a composition comprising an estrogen and a pharmaceutically acceptable vehicle for delivering the estrogen to a non-vaginal area of the subject in need thereof, wherein the administration of the composition results in an about 70 % improvement in skin hydration compared to an administration of a placebo composition. In some embodiments, the placebo composition does not comprise an estrogen. In some embodiments, the placebo composition does not comprise estriol. In some embodiments, the placebocomposition does not comprise estradiol. In some embodiments, the method improves skin hydration by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 120%, or more. In some embodiments, the method improves skin hydration by at most about 200%, about 180%, about 160%, about 140%, about 120%, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, or less.

[0058] In an aspect of the present disclosure is a method of improving skin texture comprising administering to a skin of a subject a composition comprising an estrogen and a pharmaceutically acceptable vehicle for delivering the estrogen to a non-vaginal area of the subject in need thereof, wherein the administration of the composition results in an about 57 % improvement in skin texture compared to an administration of a placebo composition. In some embodiments, the placebo composition does not comprise an estrogen. In some embodiments, the placebo composition does not comprise estriol. In some embodiments, the placebo composition does not comprise estradiol. In some embodiments, the method improves skin texture by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 120%, or more. In some embodiments, the method improves skin texture by at most about 200%, about 180%, about 160%, about 140%, about 120%, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, or less.

[0059] In an aspect of the present disclosure is a method of improving skin radiance comprising administering to a skin of a subject a composition comprising an estrogen and a pharmaceutically acceptable vehicle for delivering the estrogen to a non-vaginal area of the subject in need thereof, wherein the administration of the composition results in an about 48 % improvement in skin radiance compared to an administration of a placebo composition. In some embodiments, the placebo composition does not comprise an estrogen. In some embodiments, the placebo composition does not comprise estriol. In some embodiments, the placebo composition does not comprise estradiol. In some embodiments, the method improves skin radiance by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 120%, or more. In some embodiments, the method improves skin radiance by at most about 200%, about 180%, about 160%, about 140%, about 120%, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, or less.

[0060] In an aspect of the present disclosure is a method of improving skin health comprising administering to a skin of a subject a composition comprising an estrogen and a pharmaceutically acceptable vehicle for delivering the estrogen to a non-vaginal area of the subject in need thereof, wherein the administration of the composition results in an about 68 % improvement in skin health compared to an administration of a placebo composition. In someembodiments, the placebo composition does not comprise an estrogen. In some embodiments, the placebo composition does not comprise estriol. In some embodiments, the placebo composition does not comprise estradiol. In some embodiments, the method improves skin health by at least about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 120%, or more. In some embodiments, the method improves skin health by at most about 200%, about 180%, about 160%, about 140%, about 120%, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, or less.

[0061] In an aspect of the present disclosure is a method of reducing inflammation or damage to a skin barrier comprising administering to a skin of a subject a composition comprising an estrogen and a pharmaceutically acceptable vehicle for delivering the estrogen to a non- vaginal area of the subject in need thereof, wherein the administration of the composition reduces inflammation or damage to the skin barrier compared to an administration of a placebo composition. In some embodiments, the placebo composition does not comprise an estrogen. In some embodiments, the placebo composition does not comprise estriol. In some embodiments, the placebo composition does not comprise estradiol.

[0062] USES

[0063] In an aspect of the present disclosure is use of the composition comprising an estrogen and a pharmaceutically acceptable vehicle for delivering the estrogen to a non-vaginal area for the treatment of a disease or a condition in a subject in need thereof.

[0064] In some embodiments, the estrogen is selected from the group consisting of estriol estradiol, and estrone. In some embodiments, the estrogen is selected from the group consisting of estriol and estradiol. In some embodiments, the estrogen is estriol. In some embodiments, the estrogen is estradiol. In some embodiments, the estrogen is a synthetic derivative thereof. In some embodiments, the composition comprises about 0.001% to about 1.0 % of the estrogen. In some embodiments, the composition comprises at most about 1.0% of the estrogen. In some embodiments, the composition comprises about 0.3% of the estrogen. In some embodiments, the composition comprises about 0.001 % to about 1.5 % of the estrogen. In some embodiments, the composition comprises about 1 % to about 5 % of the estrogen. In some embodiments, the composition comprises about 0.3 % to about 6 % of the estrogen. In some embodiments, the composition comprises about 2 % to about 10 % of the estrogen.

[0065] In some embodiments, the non-vaginal area is an area exclusive of a vagina of a subject. In some embodiments, the non-vaginal area is a face of the subject. In some embodiments, the non-vaginal area is a face, neck, hands, arms, eyelid, undereye, knees, and / or legs of a subject. In some embodiments, the non-vaginal area is a face, neck, hands, arms, eyelid,and / or undereye of a subject. In some embodiments, the non-vaginal area is a face, neck, eyelid, and / or undereye of a subject.

[0066] In some embodiments, the composition further comprises tretinoin. In some embodiments, the composition further comprises about 0.2 % to about 0.5% of tretinoin. In some embodiments, the composition further comprises about 0.001 % to about 1 % of tretinoin. In some embodiments, the composition further comprises niacinamide. In some embodiments, the composition further comprises azelaic acid.

[0067] In some embodiments, the composition further comprises niacinamide. In some embodiments, the composition further comprises about 0.1 % to about 10 % of niacinamide.

[0068] In some embodiments, the composition further comprises azelaic acid. In some embodiments, the composition further comprises about 0.1 % to about 10 % of azelaic acid.

[0069] In some embodiments, the pharmaceutically acceptable vehicle comprises glycerin, oleic acid, or vitamin E. In some embodiments, the pharmaceutically acceptable vehicle comprises at least two of glycerin, oleic acid, and vitamin E. In some embodiments, the pharmaceutically acceptable vehicle comprises at least glycerin, oleic acid, and vitamin E. In some embodiments, the pharmaceutically acceptable vehicle comprises glycerin or a derivative thereof and vitamin E or a derivative thereof. In some embodiments, the glycerin may be a derivative thereof. In some embodiments, the oleic acid may be a derivative thereof. In some embodiments, the vitamin E may be a derivative thereof. In some embodiments, the vitamin E may be a tocopherol and / or a tocotrienol. In some embodiments, the vitamin E may be alphatocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol, tocopheryl acetate, alpha- tocotrienol, beta-tocotrienol, gamma tocotrienol, or delta tocotrienol. In some embodiments, the glycerin derivative is acetol, acrolein, polyglycerol, glycerin acid, dihydroxyacetone, monoglycerides, mono-acyl glyceride, di-acyl glyceride, mono ether glycerol, 1 ,2-propanediol, or 1,3-propanediol. In some embodiments, the oleic acid derivative is oleic betaine or monoolein.

[0070] In some embodiments, the pharmaceutically acceptable vehicle comprises C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxyethyl acrylate / sodium acryloyldimethyl, a taurate copolymer, oleic acid, olive oil, PEG- 100 stearate, phenoxyethanol, polymethylsiloxane, purified water, stearic acid, trolamine NF, vitamin E acetate, or any combination thereof.

[0071] In some embodiments, the composition comprises an estrogen, C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxyethyl acrylate / sodium acryloyldimethyl, a taurate copolymer, oleic acid, olive oil, PEG- 100 stearate, phenoxyethanol, polymethylsiloxane, purified water, stearic acid,trolamine NF, and vitamin E acetate. In some embodiments, the composition comprises an estrogen, tretinoin, C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxyethyl acrylate / sodium acryloyldimethyl, a taurate copolymer, oleic acid, olive oil, PEG- 100 stearate, phenoxyethanol, polymethylsiloxane, purified water, stearic acid, trolamine NF, and vitamin E acetate. In some embodiments, the composition comprises an estrogen, niacinamide, C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxyethyl acrylate / sodium acryloyldimethyl, a taurate copolymer, oleic acid, olive oil, PEG- 100 stearate, phenoxyethanol, polymethylsiloxane, purified water, stearic acid, trolamine NF, and vitamin E acetate. In some embodiments, the composition comprises an estrogen, tretinoin, niacinamide, C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxyethyl acrylate / sodium acryloyldimethyl, a taurate copolymer, oleic acid, olive oil, PEG- 100 stearate, phenoxyethanol, polymethylsiloxane, purified water, stearic acid, trolamine NF, and vitamin E acetate.

[0072] In some embodiments, the composition is used for the treatment of skin conditions due to menopause and / or perimenopause. In some embodiments, the skin conditions are one or more selected from skin dryness, decreased skin firmness, decreased skin elasticity, loss of collagen, loss of elastin, loss of fibroblast function, and loss of vascularity. In some embodiments, the treatment decreases loss of structural architecture of the skin and / or decreases propensity to skin damage. In some embodiments, the treatment mitigates skin aging. In some embodiments, the treatment elevates levels of mucopolysaccharides and hyaluronic acids in a dermis of the subject. In some embodiments, the treatment increases a relative collagen synthesis in the skin of the subject. In some embodiments, the treatment improves wound healing and / or bum healing. In some embodiments, the treatment reduces acne, acne scarring, and / or dark spots of the skin.

[0073] KITS

[0074] In an aspect of the present disclosure is a kit comprising a composition comprising an estrogen, a pharmaceutically acceptable vehicle for delivering the estrogen to a non- vaginal area of a subject in need thereof, and a sealed container for housing the composition. In some embodiments, the kit further comprises instructions for use. In some embodiments, the sealed container is a tube, jar, or pump bottle.

[0075] METHODS OF FORMULATING

[0076] In an aspect of the present disclosure is a method of formulating a composition comprising an estrogen and a pharmaceutically acceptable vehicle for delivering the estrogen toa non- vaginal area of a subject in need thereof. In some embodiments, the method comprises adding flake and powder ingredient to an oil to prepare an oil phase, adding an estrogen to the oil phase, preparing a water phase comprising the pharmaceutically acceptable vehicle, and mixing the oil phase and the water phase to form an emulsion. In some embodiments, the mixing of the oil phase and the water phase is performed at an elevated temperature. In some embodiments, the elevated temperature is from about 30 °C to about 90 °C.

[0077] In an aspect of the present disclosure is a method of formulation a composition comprising an estrogen and a pharmaceutically acceptable vehicle for delivering the estrogen to a non- vaginal area of a subject in need thereof wherein the method comprises mixing the estrogen and a portion of the pharmaceutically acceptable vehicle in an unguator, adding the remaining amount of the pharmaceutically acceptable vehicle to the unguator, further mixing the estrogen and pharmaceutically vehicle in the unguator. In some embodiments, the estrogen is a solid. In some embodiments, the estrogen is a powder. In some embodiments, the pharmaceutically acceptable vehicle comprises solid or liquid ingredients. In some embodiments, the pharmaceutically acceptable vehicle comprises solid and liquid ingredients. In some embodiments, the pharmaceutically acceptable vehicle is mixed as a homogenous mixture prior to adding into the unguator. In some embodiments, the pharmaceutically acceptable vehicle is a homogenous mixture prior to adding into the unguator.

[0078] EVALUATION OF TREATMENT

[0079] In some embodiments, the skin of a subject is evaluated before and after use of the composition. In some embodiments, the skin of a subject is evaluated using tactile assessments. In some embodiments, the skin of a subject is evaluated using visual assessments. In some embodiments, the skin of a subject is evaluated using non- invasive biomeasurements or invasive biomeasurements. In some embodiments, non-invasive biomeasurements comprise corneometry, transepidermal water loss (TEWL), dermaspectrophotometer (DSP), or photography. In some embodiments, the skin is evaluated for parameters including fine lines, wrinkles, skin tone, dark spots, melanin color, radiance / brightness, roughness (tactile), skin roughness (visual), firmness, pores, hydration, and / or overall appearance issues. In some embodiments, the non-invasive biomeasurements are tactile or visual. In some embodiments, the invasive biomeasurements are tactile or visual.EXAMPLESExample 1: A Clinical Study to Assess Efficacy of an Estrogen Composition

[0080] Objective: Investigate the efficacy of an estrogen topical cream (e.g. 0.3% estriol topical facial cream, 0.01% estradiol topical facial cream) as compared to placebo on the signs of skin health after a specified period (e.g. 12 weeks) of use (e.g. at bedtime).

[0081] Test Products:1. Placebo (base, no actives) - 30 subjects2. Estrogen Formulation 1 (e.g., 0.3% Estriol in a pharmaceutically acceptable vehicle) - 30 subjects3. Estrogen Formulation 2 (e.g., 0.01% Estradiol in a pharmaceutically acceptable vehicle) - 30 subjects.

[0082] Study Population: Healthy subjects (e.g., female of 50-60 years of age) of Fitzpatrick skin types I- VI with mild to moderate photoaging.

[0083] Inclusion Criteria1. Subjects with mild to moderate facial photoaging.2. Subjects who are in menopause (no period for at least 12 months).3. Female subjects aged 50-60 years.4. Subjects with Fitzpatrick skin types I- VI, with at least 10-15% of subjects being African American. Each study arm must contain 5 African Americans.5. Subjects who have never taken systemic hormone replacement therapy (HRT).6. Subject agrees not to introduce any new colored cosmetics (lipsticks, eye shadows, facial foundations, blush, powder) or skin care products, such as cleansers or sunscreens, during the study.7. Subject agrees to use no other facial skin care products, except for the facial moisturizer, cleanser, and sunscreen provided during the study.8. Subject has signed an Informed Consent Form in compliance with 21CFR Part 50: "Protection of Human Subjects."9. Subject is dependable and able to follow directions and is willing to comply with the schedule of visits.10. Subject is in generally good physical and mental health.

[0084] Exclusion Criteria1. A subject who is currently receiving Hormone Replacement Therapy (HRT).2. A subject who has regular menstrual cycles.3. A subject with any uncontrolled systemic disease. A potential subject in whom therapy for a systemic disease is not yet stabilized will not be considered for entry into the study.4. A subject with a significant history or current evidence of a medical, psychological or other disorder that, in the investigator’s opinion, would preclude enrollment into the study.5. A subject with a known hypersensitivity to any of the components of the study medications.6. A subject using any topical product containing a retinoid, retinol, or other vitamin A derivative within 3 months prior to or during the study period, other than the study medication.7. A subject using any systemic steroid therapy within 6 months prior to or during the study period.8. A patient that has been treated with Botox / Dysport or filler / biostimulatory molecule injections to his / her face, facial dermabrasion (deep skin peel), laser treatments, microdermabrasion or chemical peels within the past six months; patients must also refrain from these treatments throughout the entire course of the study.9. A subject using any topical medicated creams, lotions, powders, etc. on the treatment areas during the study period, other than the study treatment regimen.10. A subject using any topical sunless tanning products containing dihydroxyacetone (DHA) on the treatment areas for at least 7 days prior to the start of the study as well as throughout the entire course of the study.11. A subject that has previously been treated with systemic retinoids within the past year (e.g., isotretinoin).12. A subject that undergoes facial waxing, bleaching, or depilatory cream use within 30 days prior to entering the study as well as throughout the entire course of the study.13. A subject has used any topical products containing alpha-hydroxy acids, salicylic acid, or vitamin C on the face for at least 7 days prior to the start of the study, as well as throughout the entire course of the study.14. A subject with recently excessive facial exposure to sunlight or artificial UV light (e.g.: use of tanning beds / booths and / or sunbathing). During the study, when excessive sun exposure is unavoidable, subjects must wear appropriate protective clothing (e.g. hat) and comply with the study dosing regimen of daily application of the dispensed sunblock.15. A subject with a recent history or active presence of any facial skin condition / disease that might interfere with the diagnosis or evaluation of study parameters (e.g. moderate to severe acne vulgaris, atopic dermatitis, psoriasis, rosacea, seborrheic dermatitis, excessive facial hair or coloration).16. Cannot have a hormonal IUD (e.g. Mirena).

[0085] Study Design

[0086] Subjects (e.g. female) were enrolled in this single site double blind placebo controlled 3-arm study on facial appearance and signs of photoaging. Subjects who sign consent and meet all inclusion criteria and none of the exclusion criteria were enrolled at the baseline visit.Subjects presented to the research center with a clean washed face. Subjects who do not present with a clean washed face were asked to clean with a simple wipe.

[0087] Subjects were randomized to receive one of three study arm products: Estrogen Formulation 1 facial moisturizer, Estrogen Formulation 2 facial moisturizer, or a placebo facial moisturizer. The assigned product was applied (e.g. at bedtime) following facial washing. 30 subjects were randomly assigned to each arm, however the arms will be balanced for age, skin color, and severity of photoaging to the best degree possible. Subjects were provided by the sponsor with a facial cleanser, bland facial moisturizer (e.g. without estrogen), and a sunscreen. No other skin care products can be used on the face. Subjects may use color cosmetics unchanged during the study that they have used without problem for the past 30 days. Subjects received a compliance diary to record the bedtime applications.

[0088] Blood was taken at baseline to determine serum levels of estradiol for safety considerations. The dermatologist investigator and subjects assessed efficacy and tolerability on a 5-point ordinal scale. Photographs were taken of all subjects (e.g. with the Visia CR 4.3 using standard lighting 1 of the central, right, and left face). The subjects underwent noninvasive assessments of the face after acclimating to the research center for a specified period of time (e.g. at least 30 minutes). The noninvasive assessments comprised facial comeometry, elasticity, DSP for melanin at a target site, and TEWL at baseline.

[0089] Subjects returned to the research center with a clean washed face at specified timepoints (e.g. week 4, week 8, and week 12). A reminder text was sent out before the visits to encourage compliance. Diaries and study product were checked for compliance. Additional product was dispensed as needed. The dermatologist investigator and subjects assessed efficacy and tolerability on a 5-point ordinal scale. Photographs were taken of all subjects (e.g. with the Visia CR 4.3 using standard lighting 1 of the central, right, and left face). The subjects underwent noninvasive assessments of the face after acclimating to the research center for at least 30 minutes. The noninvasive assessments comprised facial comeometry, elasticity, DSP for melanin at a target site, and TEWL at baseline.

[0090] Subjects returned to the research center at the end of study (e.g. week 12). Study product and diaries were checked for compliance and collected. The dermatologist investigator and subjects assessed efficacy and tolerability on a 5-point ordinal scale. Photographs were takenof all subjects (e.g. with the Visia CR 4.3 using standard lighting 1 of the central, right, and left face). The subjects underwent noninvasive assessments of the face after acclimating to the research center for a specified time (e.g. at least 30 minutes). The noninvasive assessments comprised facial comeometry, elasticity, DSP for melanin at a target site, and TEWL at baseline. Blood was drawn for a study completion estradiol and estriol level. Subjects completed their study participation.

[0091] Endpoints

[0092] Tolerability Endpoint: The tolerability endpoint is the investigator-assessed absence of skin irritation from the study products at any time during the 12-week study.

[0093] Primary Safety Endpoint: The primary safety endpoint is the overall incidence of all adverse events reported during the study.

[0094] Secondary Safety Endpoint: The secondary safety endpoint is the absence of elevated serum estradiol levels in all subjects, improvement in the dermatologist investigator’s assessment of overall facial appearance in subjects using the study products for 12 weeks comparing the 0.3% estriol, 0.01% estradiol, and placebo groups to each other, as well as to baseline.

[0095] Efficacy Endpoint: The primary efficacy endpoint is the statistically significant improvement in the dermatologist investigator’s assessment of overall facial appearance in subjects using the study products for the duration of the study (e.g. 12 weeks) comparing the Estrogen Formulation 1, Estrogen Formulation 2, and placebo groups to each other, as well as to baseline.

[0096] Measures

[0097] Dermatologist Investigator assessed efficacy parameters: Fine lines, wrinkles, lack of even skin tone / dark spots, lack of radiance / brightness, skin roughness (tactile), skin roughness (visual), lack of firmness, pores, hydration, and overall appearance issues. All assessments were made on a 5-point ordinal scale (0=none, l=minimal, 2=mild, 3=moderate, 4=severe) at baseline and specified timepoints (e.g. week 4, week 8, and week 12).

[0098] Dermatologist Investigator assessed tolerability parameters: dryness, peeling, erythema, edema. All assessments were made on a 5-point ordinal scale (0=none, l=minimal, 2=mild, 3=moderate, 4=severe) at baseline and specified timepoints (e.g. week 4, week 8, and week 12).

[0099] Subject assessed efficacy parameters: Fine lines, wrinkles, lack of even skin tone / dark spots, lack of radiance / brightness, skin roughness (tactile), skin roughness (visual), lack of firmness, pores, hydration, and overall appearance issues. All assessments were made on a 5-point ordinal scale (0=none, l=minimal, 2=mild, 3=moderate, 4=severe) at baseline and specified timepoints (e.g. week 4, week 8, and week 12).

[0100] Subject assessed tolerability parameters: dryness, peeling, stinging, and itching. All assessments were made on a 5-point ordinal scale (0=none, l=minimal, 2=mild, 3=moderate, 4=severe) at baseline and specified timepoints (e.g., week 4, week 8, and week 12).

[0101] Noninvasive Biomeasurements: Corneometry, TEWL, DSP for melanin at a target site, and elasticity measurements on the face were conducted at baseline, week 4, week 8, and week 12.

[0102] Photography: Color photographs were taken at each time point with standard 1 lighting of the central, right, and left face with a Visia CR4.3. Photographs were performed at the following time points: baseline and specified timepoints (e.g., week 4, week 8, and week 12).

[0103] Statistical Methods

[0104] Along with descriptive statistics (e.g., means, standard deviations and percentages), investigator ordinal nonparametric data was analyzed using Wilcoxon signed rank test and sign test for paired comparison at different time points. The noninvasive parametric data was analyzed using paired t-test. Change is considered significant at the alpha level of 0.05.

[0105] Subject Compliance

[0106] The diary sheets were used to determine compliance. Subjects recorded product application and any comments on the provided weekly diary. Diary sheets remained at the study center as part of the source documentation records.

[0107] Noncompliant Subjects

[0108] No subjects were found to be noncompliant. All collected data was used in the final analysis.

[0109] Final Subject Status

[0110] 86 / 90 subjects successfully completed the study. The subjects who discontinued were unable to return to the research facility to complete the study. The study enrolled all Fitzpatrick skin types. The study enrolled 3 Asians, 24 African Americans, and 60 Caucasians.

[0111] Study Products & Administration

[0112] Formulations

[0113] The study formulation was attached as a separate document.

[0114] Precautions

[0115] Study products were used in their intended fashion and not orally consumed or placed in the eyes.

[0116] Study product Administration

[0117] The subjects applied the study product at bedtime to the entire face after washing.

[0118] Packaging, Labeling, Distribution

[0119] Study products were dispensed in the packaging provided by the sponsor.

[0120] Storage and accountability of Study product

[0121] The study products were stored at room temperature in a locked, limited access area at the study site. Only the investigator and staff members designated to dispense study medication was allowed access to the study products. Study product logs were used to record the dispensation and return of all study products. The subject number / initials, and the initials and date of the person dispensing and receiving the returned study products were documented on this form.

[0122] Code disclosure

[0123] A randomization code was maintained indicating the 30 subjects who were using vehicle and the 30 subjects who were using the 0.3% estriol cream and the 30subjects who were using the 0.01% estradiol cream. An independent dispenser maintained the blind and perform dispensing such that both the investigator and the subjects were blinded providing for a doubleblind study design. The randomization code is presented below.

[0124] Randomization Key: P=Placebo; ET=Estradiol; ES=Estriol

[0125] Adverse events

[0126] Adverse reactions previously reported

[0127] The study products had been reported to rarely produce skin irritation.

[0128] Statistical methods

[0129] Along with descriptive statistics (means, standard deviations and percentages), investigator ordinal nonparametric data were analyzed using Wilcoxon signed rank test and sign test for paired comparison at different time points. The noninvasive parametric data were analyzed using paired t-test. Change was considered significant at the alpha level of 0.05.

[0130] Sample size rationale

[0131] A sample size of 90 study subjects was chosen by the study sponsor.

[0132] Significance level

[0133] Significance was defined at the p<0.05 level based on a two-sided test.

[0134] Discussion

[0135] The results are discussed separately for each of the data sets.

[0136] Comeometry

[0137] Comeometry measurements were taken from the cheek to evaluate the amount water in the skin. A higher number is indicative of increase skin water content. The summary is presented below in Tables 1A-1C.

[0138] Table 1A: Corneometry of Estradiol Group

[0139] Table IB: Comeometry of Estriol Group

[0140] Table 1C: Comeometry of Placebo Group

[0141] Both the estradiol and the estriol produced statistically significant increases in skin water content after 12 weeks of product use. The placebo did not improve skin hydration. There was a statistically significant 20% increase in skin hydration (p=0.007) after 12 weeks of use with the estradiol and a statistically significant 26% increase in skin hydration (p=0.001) after 12 weeks of use with the estriol.

[0142] Elasticity

[0143] Skin elasticity measurements were taken from the cheek. The summary is presented below in Tables 2A-2C.

[0144] Table 2A: Elasticity of Estradiol Group

[0145] Table 2B: Elasticity of Estriol Group

[0146] Table 2C: Elasticity of Placebo Group

[0147] There were no consistent changes in skin elasticity induced by the estradiol, estriol, or placebo facial products.

[0148] Investigator Efficacy

[0149] The investigator assessed fine lines, wrinkles, lack of even skin tone / dark spots, lack of radiance / brightness, skin roughness (tactile), skin roughness (visual), lack of firmness, pores, hydration, elasticity, and overall appearance issues. All assessments were made on a 5 -point ordinal scale (0=none, l=minimal, 2=mild, 3=moderate, 4=severe) at baseline, week 4, week 8, and week 12. The summary is presented below in Tables 3A-3C. This table is an intragroup analysis comparing each product to itself at baseline. There were statistically significant (p<0.001) increases in the estradiol group in terms of radiance with a 19% increase at week 8 and a 29% increase at week 12. Additional statistically significant (p<0.001) improvement was seen at week 12 in terms of visual roughness (31% improvement), tactile roughness (33% improvement), firmness (15% improvement), hydration (26% improvement), and overall skin health (18% improvement). Similar improvements were seen in the estriol group at week 12. There was a statistically significant (p<0.001) 29% improvement in radiance, 31% improvement in tactile roughness, 31% improvement in visual roughness, 15% improvement in firmness, 2% improvement in hydration, 12% improvement in elasticity, and a 19% improvement in overall skin health.

[0150] Table 3 A: Investigator Efficacy of Estradiol Group

[0151] Table 3B: Investigator Efficacy of Estriol Group

[0152] Table 3C: Investigator Efficacy of Placebo Group

[0153] The estriol and estradiol results were also compared to each other and to placebo.The intergroup summary is presented below in Table 3D.

[0154] Table 3D: Investigator Efficacy - Intergroup Summary

[0155] There were no statistically significant differences between the study products at week 4 or week 8. The most dramatic improvement and differentiation from placebo occurred at week 12. There was no difference between the estriol and estradiol in the eyes of the investigator, however both products were demonstrated to be superior to placebo in several qualities. The estradiol demonstrated a statistically significant 50% improvement in radiance, 62% improvement in tactile roughness, 58% improvement in visual roughness, 67% improvement in firmness, 76% improvement in hydration, and 67% improvement in overall skin health as compared to placebo. The estriol demonstrated a statistically significant 48% improvement in radiance, 57% improvement in tactile roughness, 57% improvement in visual roughness, 70% improvement in hydration, 88% improvement in skin elasticity, and 68% improvement in overall skin health as compared to placebo.

[0156] Investigator Tolerability

[0157] The dermatologist evaluated tolerability in terms of dryness, peeling, erythema, edema. Assessments were made on a 5 -point ordinal scale (0=none, l=minimal, 2=mild, 3=moderate, 4=severe) at baseline, week 4, week 8, and week 12. The summary is presented below in Tables 4A-4C.

[0158] Table 4 A: Investigator Tolerability of Estradiol Group

[0159] Table 4B: Investigator Tolerability of Estriol Group

[0160] Table 4C: Investigator Tolerability of Placebo Group

[0161] No tolerability issues were identified by the investigator.

[0162] Laboratory Results

[0163] Estradiol and estriol levels were drawn on all subjects to evaluate possible systemic absorption of the study creams. The summary is presented below in Table 5.

[0164] Table 5: Laboratory Results

[0165] There was no statistically significant change in estriol levels in the blood from baseline to week 12. There was a slight increase in estradiol levels from baseline to week 12, but this change is within laboratory error going from 12.92 to 16.60.

[0166] Melanin Readings

[0167] Melanin readings were taken with a dermaspectrophotometer from the cheek. The summary is presented below in Tables 6A-6C.

[0168] Table 6A: Melanin Readings of Estradiol Group

[0169] Table 6B: Melanin Readings of Estriol Group

[0170] Table 6C: Melanin Readings of Placebo Group

[0171] Estrogens have been thought to possibly induce skin pigmentation as an unwanted side effect. No increase in pigmentation was noted with the estriol or estradiol products. There was a slight 1-2% decrease in facial pigmentation.

[0172] Subject Efficacy

[0173] The subjects assessed efficacy in terms of fine lines, wrinkles, lack of even skin tone / dark spots, lack of radiance / brightness, skin roughness (tactile), skin roughness (visual), lack of firmness, pores, hydration, elasticity, and overall appearance issues. Assessments were made on a 5-point ordinal scale (0=none, l=minimal, 2=mild, 3=moderate, 4=severe) at baseline, week 4, week 8, and week 12. The subjects were unable to distinguish between the estriol, estradiol, and placebo as they only had exposure to one product. Excellent ratings were given to all products. The summary is presented below in Tables 7A-7C.

[0174] Table 7 A: Subject Efficacy for Estradiol Group

[0175] Table 7B: Subject Efficacy for Estriol Group

[0176] Table 7C: Subject Efficacy for Placebo Group

[0177] Subject Tolerability

[0178] The subjects assessed tolerability in terms of dryness, peeling, stinging, and itching.All assessments were made on a 5-point ordinal scale (0=none, l=minimal, 2=mild, 3=moderate, 4=severe) at baseline, week 4, week 8, and week 12. The summary is are presented below in Tables 8A-8C. The subjects did not identify any tolerability issues.

[0179] Table 8 A: Subject Tolerability for Estradiol Group

[0180] Table 8B: Subject Tolerability for Estriol Group

[0181] Table 8C: Subject Tolerability for Placebo Group

[0182] Transepidermal Water Loss (TEWL)

[0183] Transepidermal Water Loss (TEWL) measurements were taken from the cheek.TEWL is a measure of the water leaving the skin and a lower number indicates superior skin barrier function. The summary is presented below in Tables 9A-9C.

[0184] Table 9 A: Transepidermal Water Loss (TEWL) measurements for Estradiol Group

[0185] Table 9B: Transepidermal Water Loss (TEWL) measurements for Estriol Group

[0186] Table 9C: Transepidermal Water Loss (TEWL) measurements for Placebo Group

[0187] The estriol produced a statistically significant increase in water leaving the skin of 13% at week 12 (p=0.027). The placebo and estradiol demonstrated barrier neutrality. None of the products were shown to induce irritation as evidenced by the subject tolerability ratings.

[0188] Summary

[0189] Primary Efficacy Endpoint

[0190] The primary efficacy endpoint was the statistically significant improvement in the dermatologist investigator’s assessment of overall facial appearance in subjects using the study products for 12 weeks comparing the 0.3% estriol, 0.01% estradiol, and placebo groups to each other, as well as to baseline. The estriol and estradiol formulations produced a statistically significant improvement in facial appearance as compared to placebo. The primary efficacy endpoint was met.

[0191] Tolerability Endpoint

[0192] The tolerability endpoint was the investigator-assessed absence of skin irritation from the study products at any time during the 12-week study. No skin irritation occurred. The tolerability endpoint was met.

[0193] Primary Safety Endpoint

[0194] The safety endpoint was the overall incidence of all adverse events reported during the study. No adverse events occurred during the conduct of the study. The primary safety endpoint was met.

[0195] Secondary Safety Endpoint

[0196] The secondary safety endpoint was the absence of elevated serum estradiol and estriol levels in all subjects. The secondary safety endpoint was met.Example 2: Formulation of An Estrogen Cream

[0197] An estrogen composition as disclosed herein is formulated with a pharmaceutically acceptable vehicle.

[0198] To an unguator, the estrogen and a first amount of the pharmaceutically acceptable vehicle (e.g. one-third) is added and mixed. After the estrogen and the first amount of the pharmaceutically acceptable vehicle are mixed, the remainder (e.g. two-thirds) of the pharmaceutically acceptable vehicle is added to the unguator and mixed further. The composition is removed from the unguator and placed into a container.

[0199] The composition is batch tested for accuracy of strength of the estrogen. The composition may be batch tested for accuracy of strength of the pharmaceutically acceptable vehicle.

[0200] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. It is not intended that the disclosure be limited by the specific examples provided within the specification. While the disclosure has been described with reference to the aforementioned specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. Furthermore, it shall be understood that all aspects of the disclosure are not limited to the specific depictions, configurations or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure. It is therefore contemplated that the disclosure shall also cover any such alternatives, modifications, variations or equivalents. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A composition comprising: a. an estrogen; and b. a pharmaceutically acceptable vehicle for delivering the estrogen to a non- vaginal area of a subject in need thereof.

2. The composition of claim 1, wherein the non-vaginal area is a face of the subject.

3. The composition of claim 1 or 2, wherein the estrogen is selected from the group consisting of estriol, estradiol, and estrone.

4. The composition of claim 3, wherein the estrogen is estriol.

5. The composition of claim any one of claims 1-4, wherein the composition comprises about 0.001% to about 1.0 % of the estrogen.

6. The composition of claim 5, wherein the composition comprises about 0.001% to about 0.5% of the estrogen.

7. The composition of claim 1, wherein the composition comprises at most about 1.0% of the estrogen.

8. The composition of any one of claims 1-7, wherein the composition comprises about 0.3% of the estrogen.

9. The composition of any one of claim 1-8, wherein the composition further comprises about 0.2 % to about 0.5% of tretinoin.

10. The composition of any one of claim 1-9, wherein the composition further comprises about 4% to about 10% of niacinamide.

11. The composition of any one of claims 1-10, wherein the pharmaceutically acceptable vehicle comprises glycerin, oleic acid, or vitamin E or derivatives thereof.

12. The composition of claim 11, wherein the pharmaceutically acceptable vehicle comprises at least two of glycerin, oleic acid, and vitamin E or derivatives thereof.

13. The composition of claim 12, wherein the pharmaceutically acceptable vehicle comprises at least glycerin, oleic acid, and vitamin E or derivatives thereof.

14. The composition of any one of claims 1-13, wherein the pharmaceutically acceptable vehicle comprises C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxyethyl acrylate / sodium acryloyldimethyl, a taurate copolymer, oleic acid, olive oil, PEG- 100 stearate, phenoxyethanol, polymethylsiloxane, purified water, stearic acid, trolamine NF, vitamin E acetate, or any combination thereof.

15. The composition of any one of claims 1-13, wherein the pharmaceutically acceptable vehicle comprises Aloe Barbadensis Leaf Juice, C 12 - 14 Isoparaffin, Caprylic / Capric Triglyceride, Deionized Water, Laureth-7, Phenoxyethanol, Polyacrylamide, Tocopheryl Acetate, Triethylene Glycol, or any combination thereof.

16. The composition of any one of claims 1-14, wherein the composition is formulated as a topical cream.

17. The composition of any one of claims 1-16, wherein the composition is formulated as a topical face cream.

18. The composition of claim 16, wherein the topical cream is applied on a subject’s face, neck, hands, legs, knees, shoulders, arms, abdomen, or any combination thereof.

19. The composition of any one of claims 1-18, wherein the composition reduces a severity of one or more symptoms selected from skin dryness, decreased skin firmness, decreased skin elasticity, loss of collagen, loss of elastin, loss of fibroblast function, loss of vascularity, and increased matrix metalloproteinase(s) enzymatic activities.

20. The composition of any one of claim 19, wherein the composition has one of more effects selected from the group consisting of increased collagen production, increased skin moisture, increased skin firmness, decreased pore size, decreased wrinkle depth, increased skin elasticity, and reversal of effects of estrogen-deficiency in skin due to menopause.

21. Use of a composition of any one of claims 1-20, for the treatment of a disease or a condition in a subject in need thereof.

22. Use of claim 21, wherein the treatment is formulated as a topical cream.

23. Use of claim 22, wherein the treatment is formulated as a topical face cream.

24. Use of any one of claims 21-23, wherein the composition treats a disease or condition in the subject.

25. Use of any one of claims 21-24, wherein the subject has a Fitzpatrick skin type I, II, III, IV, V, or VI.

26. Use of any one of claims 21-25, wherein the subject is ages 13-80.

27. Use of claim 26, wherein the subject is ages 35-80.

28. Use of any one of claims 21-27, wherein the disease or condition is skin aging due to estrogen deficiency.

29. Use of any one of claims 21-27, wherein the disease or condition is perimenopause or menopause.

30. Use of any one of claims 21-29, wherein the disease or condition is skin aging due to perimenopause or menopause.

31. Use of any one of claims 21-30, wherein the treatment is most effective when started around perimenopause.

32. Use of any one of claims 21-31, wherein the composition treats or ameliorates a condition of the subject’s skin.

33. Use of any one of claims 21-32, wherein the condition is derived from menopause and / or perimenopause.

34. Use of any one of claims 21-33, wherein the condition is selected from the group consisting of acne scarring, wound healing, bum healing, skin dryness, epidermal thinning, decreased skin firmness, decreased skin elasticity, loss of collagen, loss of elastin, loss of fibroblast function, loss of vascularity, increased matrix metalloproteinase(s) enzymatic activities, and any combinations thereof.

35. Use of any one of claims 21-34, for treating symptoms of menopause and / or perimenopause.

36. Use of any one of claims 21-35, wherein the subject further uses other treatments for menopause hormone therapy.

37. Use of claim 36, wherein the other treatments for menopause hormone therapy comprise estrogen vaginal cream, estrogen pills, estrogen vaginal rings, estrogen patch, estrogen spray, estrogen progesterone combination pill, estrogen progesterone combination patch, vaginal dehydroepiandrosterone insert, or a combination thereof.

38. Use of any one of claims 21-37, wherein the composition is applied at least once daily to a face of a subject in need thereof.

39. Use of any one of claims 21-38, wherein the composition is applied at least once daily at nighttime to a face of a subject in need thereof.

40. Use of any one of claims 21-39, wherein the composition is applied at about 0.2 mL to about 0.4 mL at least once daily to face.

41. Use of claim 40, wherein the composition is applied at about 0.3 mL at least once daily to face.

42. Use of any one of claims 21-41, wherein the composition is safely used with retinoids, vitamin c, or spot treatments.

43. Use of any one of claims 21-42, wherein the composition is applied safely to under-eye areas.

44. A kit comprising: a. A composition of any one of claims 1-20; and b. A sealed container for housing the composition.

45. The kit of claim 44, wherein the kit further comprises instructions for use.

46. A method for the treatment of skin conditions in a subject in need thereof comprising administering to a skin of a subject a composition of any one of claims 1-20.

47. The method of claim 46, wherein the skin conditions are due to menopause and / or perimenopause.

48. The method of any one of claims 46-47, wherein the skin conditions are one or more selected from skin dryness, decreased skin firmness, decreased skin elasticity, loss of collagen, loss of elastin, loss of fibroblast function, and loss of vascularity.

49. The method of any one of claims 46-48, wherein the subject is perimenopausal or menopausal.

50. The method of any one of claims 46-49, wherein the treatment decreases loss of structural architecture of the skin and / or decreases propensity to skin damage.

51. The method of any one of claims 46-50, wherein the treatment mitigates skin aging.

52. The method of any one of claims 46-51, wherein the treatment elevates levels of mucopolysaccharides and hyaluronic acids in a dermis of the subject.

53. The method of any one of claims 46-52, wherein the treatment increases a relative collagen synthesis in the skin of the subject.

54. A method of formulating a composition comprising an estrogen and a pharmaceutically acceptable vehicle for delivering the estrogen to a non- vaginal area of a subject in need thereof wherein the method comprises: a. mixing an estrogen and a portion of the pharmaceutically acceptable vehicle to an unguator, b. adding the remaining amount of the pharmaceutically acceptable vehicle to the unguator; and c. mixing the estrogen and the pharmaceutically acceptable vehicle in the unguator to create the composition.

55. The method of claim 54, wherein the estrogen is a powder.

56. A composition comprising: an estrogen for topical application to a skin of a subject in need thereof, wherein the composition further comprises C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate,hydroxyethyl acrylate / sodium acryloyldimethyl, a taurate copolymer, oleic acid, olive oil, PEG- 100 stearate, phenoxyethanol, polymethylsiloxane, purified water, stearic acid, trolamine NF, and vitamin E acetate.

57. The composition of claim 56, wherein the estrogen is selected from the group consisting of estriol, estradiol, and estrone.

58. The composition of claim 57, wherein the estrogen is estriol.

59. The composition of claim 56, wherein the composition comprises about 0.001% to about 1.0 % of the estrogen.

60. The composition of claim 59, wherein the composition comprises about 0.001% to about 0.5% of the estrogen.

61. The composition of claim 56, wherein the composition comprises at most about 1.0% of the estrogen.

62. The composition of claim 56, wherein the composition comprises about 0.3% of the estrogen.

63. The composition of any one of claims 56-62, wherein the composition further comprises about 0.2 % to about 0.5% of tretinoin.

64. The composition of any one of claims 56-63, wherein the composition further comprises about 4% to about 10% of niacinamide.

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