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

Description

AttyDktNo.: 66462-703601COMPOSITIONS, USES, KITS, AND FORMULATIONS OF A TOPICAL ESTROGEN CREAM CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 763628 filed February 26, 2025 and U.S. Provisional Application No. 63 / 821787 filed June 11, 2025, 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, one or more peptides, and a pharmaceutically acceptable vehicle for delivering the estrogen and one or more peptides 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 0.01% to about 5.0 % of the estrogen. In some embodiments, the composition comprises about 0.5% to about 2.0% of the estrogen. In some embodiments, the composition comprises at most about 1.5% of the estrogen. In some embodiments, the composition comprises about 1.0% of the estrogen. In some embodiments, the one or more peptides is acetyl dipeptide-1 cetyl ester, copper tripeptide, palmitoyl pentapeptide-4, acetyl hexapeptide-8, palmitoyl oligopeptide, trifluoroacetyl-tripeptide-2, carnosine, or a combination thereof. In some embodiments, the one or more peptides is palmitoyl pentapeptide-4, acetyl hexapeptide-8, or both. In some embodiments, the one or more peptides are each included in the composition at about 0.01% to about 0.2% by weight. In some embodiments, the one or more peptides are each included in the composition at about 0.05% to about 0.15% by weight. In some embodiments, the one or more peptides are each included in the composition at about 0.1% by weight. 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 - 1 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601or 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 Squalane, 1,2-Hexanediol, Butylene Glycol, Caprylyl Methicone, Cyclopentasiloxane, Dimethicone, Dimethicone Crosspolymer, Glycerin, Hydroxyacetophenone, PEG- 12 Dimethicone / PPG-20 Crosspolymer, PEG-40 Hydrogenated Castor Oil, Pentylene Glycol, Polyglyceryl-3 Diisostearate, Tocopheryl Acetate (Vitamin E), water, or any combination thereof. In some embodiments, the pharmaceutically acceptable vehicle comprises C12 - 15 alkyl benzoate, capryl ic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxy ethyl 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.

[0004] In an aspect of the present disclosure is a composition comprising an estrogen, one or more peptides, a glycosaminoglycan, and a pharmaceutically acceptable vehicle for delivering the estrogen, a glycosaminoglycan, and one or more peptides 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 estrogen is estriol. In some embodiments, the composition comprises about 0.01% to about 5.0 % of the estrogen. In some embodiments, the composition comprises about 0.01% to about 2.0% 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 one or more peptides is acetyl dipeptide-1 cetyl ester, copper tripeptide, palmitoyl pentapeptide-4, acetyl hexapeptide-8, palmitoyl oligopeptide, trifluoroacetyl-tripeptide-2, carnosine, or a combination thereof. In some embodiments, the one or more peptides is palmitoyl pentapeptide-4, acetyl hexapeptide-8, or both. In some embodiments, the one or more peptides are each included in the composition at about 0.01% to about 0.2% by weight. In some embodiments, the one or more peptides are each included in the composition at about 0.05% to about 0.15% by weight. In some embodiments, the one or more peptides are each included in the composition at about 0.1% by weight. In some embodiments, the glycosaminoglycan comprises hyaluronic acid, chondroitin sulfate, dermatan sulfate, or heparan sulfate. In some embodiments, the- 2 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601glycosaminoglycan is hyaluronic acid. In some embodiments, the glycosaminoglycan is included in the composition at about 0.01% to about 5% by weight. In some embodiments, the glycosaminoglycan is included in the composition at about 0.1% to about 2% by weight. In some embodiments, the glycosaminoglycan is included in the composition at about 0.5% by weight. In some embodiments, the pharmaceutically acceptable vehicle comprises cyclopentasiloxane, caprylyl methicone, polysilicone-11, PEG-12 dimethicone / PPG-20 Crosspolymer, or any combination thereof. In some embodiments, the pharmaceutically acceptable vehicle comprises PEG-16 Macadamia Glycerides, PEG-12 dimethicone / PPG-20 Crosspolymer, or both. In some embodiments, the pharmaceutically acceptable vehicle comprises jojoba esters, jojoba alcohol, or both. In some embodiments, the pharmaceutically acceptable vehicle comprises ethyl alcohol, cyclopentasiloxane, caprylyl methicone, PEG- 16 Macadamia Glycerides, polysilicone-11, PEG- 12 dimethicone / PPG-20 Crosspolymer, 1,2-Hexanediol, phosphatidylcholinejojoba esters, jojoba alcohol, tocopheryl acetate, 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, crow’s feet, 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.

[0005] 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, crow’s feet, 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.- 3 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0006] 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 eye 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, burn 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, estrogen spray, 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 0.05 mL to about 0.4 mL at least once daily to face. In some embodiments, the composition is applied at about 0.1 mL at least once daily to an eye area. In some embodiments, the composition is safely used with retinoids, vitamin c, or spot treatments. In some embodiments, the composition is applied to an eye area. In some embodiments, the eye areas comprise under-eye, outer comers, eyelids, or a combination thereof.

[0007] In an aspect of the present disclosure is a kit comprising a composition of an estrogen, one or more peptides, and a pharmaceutically acceptable vehicle for delivering the estrogen and one or more peptides 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.- 4 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0008] 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, one or more peptides, and a pharmaceutically acceptable vehicle for delivering the estrogen and one or more peptides 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 composition improves deep skin hydration in the subject by about 1% to about 10% compared to baseline. In some embodiments, the composition improves deep skin hydration in the subject at 12 weeks by about 5% to about 10% compared to baseline. In some embodiments, the composition improves skin elasticity in the subject by about 1% to about 30% compared to baseline. In some embodiments, the composition improves skin elasticity in the subject at 12 weeks by about 10% to about 25% compared to baseline. 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.

[0009] In an aspect of the present disclosure is a method of formulating a composition comprising an estrogen, one or more peptides, and a pharmaceutically acceptable vehicle for delivering the estrogen and one or more peptides to a non-vaginal area of a subject in need thereof wherein the method comprises mixing an estrogen, one or more peptides, 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.

[0010] 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 Palmitoyl Pentapeptide-4, Acetyl Hexapeptide-8, 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 0.01% to about 5.0 % of the estrogen. In some embodiments, the composition comprises about 0.5% to about 2.0% of the estrogen. In some - 5 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601embodiments, the composition comprises at most about 1.5% of the estrogen. In some embodiments, the composition comprises about 1.0% of the estrogen. In some embodiments, the composition comprises about 0.01% to about 1.0% of Palmitoyl Pentapeptide-4. In some embodiments, the composition comprises about 0.01% to about 1.0% of Acetyl Hexapeptide-8. In some embodiments, the composition comprises about 0.1% of Palmitoyl Pentapeptide-4 and about 0.1% of Acetyl Hexapeptide-8.

[0011] 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 Palmitoyl Pentapeptide-4, Acetyl Hexapeptide-8, hyaluronic acid, ethyl alcohol, cyclopentasiloxane, caprylyl methicone, PEG- 16 Macadamia Glycerides, polysilicone-11, PEG- 12 dimethicone / PPG-20 Crosspolymer, 1,2-Hexanediol, phosphatidylcholinejojoba esters, jojoba alcohol, and tocopheryl 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 0.01% to about 5.0 % of the estrogen. In some embodiments, the composition comprises about 0.01% to about 2.0% 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 0.01% to about 1.0% of Palmitoyl Pentapeptide-4. In some embodiments, the composition comprises about 0.01% to about 1.0% of Acetyl Hexapeptide-8. In some embodiments, the composition comprises about 0.1% of Palmitoyl Pentapeptide-4 and about 0.1% of Acetyl Hexapeptide-8. In some embodiments, the composition comprises about 0.01% to about 5% of the hyaluronic acid. In some embodiments, the composition comprises about 0.1% to about 2% of the hyaluronic acid. In some embodiments, the composition comprises about 0.5% by of the hyaluronic acid.

[0012] 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 Palmitoyl Pentapeptide-4, Acetyl Hexapeptide-8, Squalane, 1,2-Hexanediol, Butylene Glycol, Caprylyl Methicone, Cyclopentasiloxane, Dimethicone, Dimethicone Crosspolymer, Glycerin, Hydroxyacetophenone, PEG-12 Dimethicone / PPG-20 Crosspolymer, PEG-40 Hydrogenated Castor Oil, Pentylene Glycol, Polyglyceryl-3 Diisostearate, Tocopheryl Acetate (Vitamin E), and water. 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 0.01% to about 5.0 % of the estrogen. In some embodiments, the composition comprises about 0.01% to about 2.0% of the estrogen. In some - 6 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601embodiments, 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 0.01% to about 1.0% of Palmitoyl Pentapeptide-4. In some embodiments, the composition comprises about 0.01% to about 1.0% of Acetyl Hexapeptide-8. In some embodiments, the composition comprises about 0.1% of Palmitoyl Pentapeptide-4 and about 0.1% of Acetyl Hexapeptide-8. In some embodiments, the composition comprises about 1% to about 10% of squalane. In some embodiments, the composition comprises about 3% to about 10% squalane. In some embodiments, the composition comprises about 5% squalane.

[0013] In some aspects, the compositions described herein are eye cream compositions. In some embodiments, the eye cream composition improves collagen production, hydration, elasticity, hormonal skin repair, skin resilience, or a combination thereof. In some embodiments, the eye cream composition is applied to an eye area of a subject.

[0014] In some aspects, the compositions described herein are serum compositions. In some embodiments, the serum composition improves elasticity, hydration, overall skin health, skin texture or a combination thereof. In some embodiments, the serum composition is applied to the face of a subject.

[0015] 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

[0016] 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

[0017] 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 - 7 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601example 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.

[0018] Estrogens play major roles in maintaining physiological functions in the human body. Peri-menopause, menopause, and post-menopause represent 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.

[0019] 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. Additionally, formulating compositions for administration to the eye area or other areas of skin add an extra dimension of difficulty. In particular, skin around the eye area is thin and susceptible to irritation, such as through redness, erythema, puffiness, dark circles, milia production, among other symptoms. Furthermore, the eye area is one of the first regions of the face to show fine lines and wrinkles. Thus, there is a need for a safe topical composition (e.g., cream, serum, gel, or the like) that addresses skin aging due to estrogen deficiency without increasing a blood serum level of estrogen.

[0020] DEFINITIONS

[0021] 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.

[0022] 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 - 8 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601+ / - 10% thereof, or 10% below the lower listed limit and 10% above the higher listed limit for the values listed for a range.

[0023] 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 an outpatient, or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker.

[0024] 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.

[0025] 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.

[0026] 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;- 9 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601malt; gelatin; talc; excipients, such as cocoa butter, myristyl myristate, Shea butter, and suppository waxes; oils, such as acai palm fruit oil, calendula flower oil, corn 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; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0027] As used herein, the ingredient amounts in the compositions described herein are expressed in % by weight (or weight %, w / w, % w / w, w / w %, etc.), based on the total weight of the compositions.

[0028] COMPOSITIONS

[0029] In certain aspects of the present disclosure is a composition comprising an estrogen, one or more peptides, and a pharmaceutically acceptable vehicle for delivering the estrogen and one or more peptides 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 an eye area of the subject. In some embodiments, the eye area comprises under-eye, outer comers, eyelids, or a combination thereof. In some embodiments, the non-vaginal area is a face, neck, hands, arms, eyelids, undereye, knees, and / or legs of a subject. In some embodiments, the composition provides anti-wrinkle benefits, stimulates collagen production, or both. Without being bound by any particular theory, the composition is formulated to enable penetration of the estrogen to the dermis of skin and also enable the one or more peptides to penetrate the dermal-epidermal junction, such as the eye area. In some embodiments, the estrogen and the one or more peptides work synergistically to stimulate collagen production in the dermis, and the one or more peptides strengthen muscles in the eye area In some embodiments, the composition is formulated to minimize irritation of the eye area or discomfort to the subject (e.g., causing excessive rubbing, which may lead to removing the composition from the eye area, or tearing).

[0030] 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% w / w to about 1.0 % w / w of the - 10 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601estrogen. 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- 11 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601%, 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 estriol. 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 estriol. 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 estriol.

[0031] 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 % to about 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 %, about 3 % 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 %, about 4 % 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 %, about 5.5 %, 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 %, - 12 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601about 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 estriol. 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 estriol. 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 estriol.

[0032] 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 %, 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 at least about 2 %, about 3 %, about 4 %, 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 estriol. 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 estriol. 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 estriol.

[0033] In some embodiments, the composition comprises one or more peptides. In some embodiments, the one or more peptides are anti-aging or anti-aging properties. In some embodiments, the one or more peptides are natural peptides. In some embodiments, the one or - 13 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601more peptides are synthetic peptides. In some embodiments, the one or more peptides is acetyl dipeptide- 1 cetyl ester, copper tripeptide, palmitoyl pentapeptide-4, acetyl hexapeptide-8, palmitoyl oligopeptide, trifluoroacetyl-tripeptide-2, carnosine, or a combination thereof. In some embodiments, the one or more peptides is palmitoyl pentapeptide-4 (Pal-KTTKS). In some embodiments, the one or more peptides is acetyl hexapeptide-8 (Ac-EEMQRR-NH2). In some embodiments, the one or more peptides are anti-aging ingredients linked to performance relative to improvement of lines / wrinkles, loss of elasticity, firmness and discolorations. Acetyl hexapeptide-8, also known as argireline or acetyl hexapeptide-3, is a neurotransmitter peptide that interferes with the assembly of the SNARE complex and inhibits Ca2+dependent catecholamine release causing muscle paralysis. Acetyl hexapeptide-8 can be used for cosmetic applications and may have anti-wrinkle effects, especially in a periorbital area, and improve skin firmness and tone. Palmitoyl pentapeptide-4, also known as palmitoyl pentapeptide-3, is a signal peptide that stimulates collagen (specifically Types I, III, and IV), fibronectin, elastin, and glycosaminoglycan production. Palmitoyl pentapeptide-4 can be used for cosmetic applications and may reduce fine lines and wrinkles and improve skin texture.

[0034] In some embodiments, the composition comprises one peptide. In some embodiments, the composition comprises two peptides. In some embodiments, the composition comprises two or more peptides. In some embodiments, the composition comprises three peptides.

[0035] In some embodiments, the composition comprises one or more peptides. In some embodiments, the total concentration (%w / w) of the one of more peptides in the composition is about 0.01% to about 5%. In some embodiments, the total concentration of one or more peptides in the composition is about 0.01 % to about 5 %. In some embodiments, the total concentration of one or more peptides in the composition is about 0.01 % to about 0.05 %, about 0.01 % to about 0.1 %, about 0.01 % to about 0.3 %, about 0.01 % to about 0.5 %, about 0.01 % to about 1 %, about 0.01 % to about 1.5 %, about 0.01 % to about 2 %, about 0.01 % to about 3 %, about 0.01 % to about 4 %, about 0.01 % to about 5 %, about 0.05 % to about 0.1 %, about 0.05 % to about 0.3 %, about 0.05 % to about 0.5 %, about 0.05 % to about 1 %, about 0.05 % to about 1.5 %, about 0.05 % to about 2 %, about 0.05 % to about 3 %, about 0.05 % to about 4 %, about 0.05 % to about 5 %, about 0.1 % to about 0.3 %, about 0.1 % to about 0.5 %, about 0.1 % to about 1 %, about 0.1 % to about 1.5 %, 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 0.3 % to about 0.5 %, about 0.3 % to about 1 %, about 0.3 % to about 1.5 %, about 0.3 % to about 2 %, about 0.3 % to about 3 %, about 0.3 % to about 4 %, about 0.3 % to about 5 %, about 0.5 % to about 1 %, about 0.5 % to about 1.5 %, - 14 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601about 0.5 % to about 2 %, about 0.5 % to about 3 %, about 0.5 % to about 4 %, about 0.5 % to about 5 %, about 1 % to about 1.5 %, about 1 % to about 2 %, about 1 % to about 3 %, about 1 % to about 4 %, about 1 % to about 5 %, about 1.5 % to about 2 %, about 1.5 % to about 3 %, about 1.5 % to about 4 %, about 1.5 % to about 5 %, about 2 % to about 3 %, about 2 % to about 4 %, about 2 % to about 5 %, about 3 % to about 4 %, about 3 % to about 5 %, or about 4 % to about 5 %. In some embodiments, the total concentration of one or more peptides in the composition is about 0.01 %, about 0.05 %, about 0.1 %, about 0.3 %, about 0.5 %, about 1 %, about 1.5 %, about 2 %, about 3 %, about 4 %, or about 5 %. In some embodiments, the total concentration of one or more peptides in the composition is at least about 0.01 %, about 0.05 %, about 0.1 %, about 0.3 %, about 0.5 %, about 1 %, about 1.5 %, about 2 %, about 3 %, or about 4 %. In some embodiments, the total concentration of one or more peptides in the composition is at most about 0.05 %, about 0.1 %, about 0.3 %, about 0.5 %, about 1 %, about 1.5 %, about 2 %, about 3 %, about 4 %, or about 5 %.

[0036] In some embodiments, the composition comprises one or more peptides. In some embodiments, the concentration (%w / w) of each of the one of more peptides in the composition is about 0.01% to about 5%. In some embodiments, the one or more peptides are each included in the composition at about 0.01 % to about 5 %. In some embodiments, the one or more peptides are each included in the composition at about 0.01 % to about 0.05 %, about 0.01 % to about 0.1 %, about 0.01 % to about 0.3 %, about 0.01 % to about 0.5 %, about 0.01 % to about 1 %, about 0.01 % to about 1.5 %, about 0.01 % to about 2 %, about 0.01 % to about 3 %, about 0.01 % to about 4 %, about 0.01 % to about 5 %, about 0.05 % to about 0.1 %, about 0.05 % to about 0.3 %, about 0.05 % to about 0.5 %, about 0.05 % to about 1 %, about 0.05 % to about 1.5 %, about 0.05 % to about 2 %, about 0.05 % to about 3 %, about 0.05 % to about 4 %, about 0.05 % to about 5 %, about 0.1 % to about 0.3 %, about 0.1 % to about 0.5 %, about 0.1 % to about 1 %, about 0.1 % to about 1.5 %, 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 0.3 % to about 0.5 %, about 0.3 % to about 1 %, about 0.3 % to about 1.5 %, about 0.3 % to about 2 %, about 0.3 % to about 3 %, about 0.3 % to about 4 %, about 0.3 % to about 5 %, about 0.5 % to about 1 %, about 0.5 % to about 1.5 %, 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 1 % to about 1.5 %, about 1 % to about 2 %, about 1 % to about 3 %, about 1 % to about 4 %, about 1 % to about 5 %, about 1.5 % to about 2 %, about 1.5 % to about 3 %, about 1.5 % to about 4 %, about 1.5 % to about 5 %, about 2 % to about 3 %, about 2 % to about 4 %, about 2 % to about 5 %, about 3 % to about 4 %, about 3 % to about 5 %, or about 4 % to about 5 %. In some embodiments, the one or more peptides are each included in the composition - 15 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601at about 0.01 %, about 0.05 %, about 0.1 %, about 0.3 %, about 0.5 %, about 1 %, about 1.5 %, about 2 %, about 3 %, about 4 %, or about 5 %. In some embodiments, the one or more peptides are each included in the composition at at least about 0.01 %, about 0.05 %, about 0.1 %, about 0.3 %, about 0.5 %, about 1 %, about 1.5 %, about 2 %, about 3 %, or about 4 %. In some embodiments, the one or more peptides are each included in the composition at at most about 0.05 %, about 0.1 %, about 0.3 %, about 0.5 %, about 1 %, about 1.5 %, about 2 %, about 3 %, about 4 %, or about 5 %.

[0037] In some embodiments, the composition further comprises squalane. In some embodiments, the composition further comprises about 1 % to about 10 % squalane. In some embodiments, the composition further comprises 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 % squalane. In some embodiments, the composition further comprises about 1 %, about 2 %, about 3 %, about 4 %, about 5 %, about 6 %, about 7 %, about 8 %, about 9 %, or about 10 % squalane. In some embodiments, the composition further comprises at least about 1 %, about 2 %, about 3 %, about 4 %, about 5 %, about 6 %, about 7 %, about 8 %, or about 9 % squalane. In some embodiments, the composition further comprises at most about 2 %, about 3 %, about 4 %, about 5 %, about 6 %, about 7 %, about 8 %, about 9 %, or about 10 % squalane.

[0038] In some embodiments, the composition further comprises tretinoin. In some embodiments, the composition further comprises about 0.2 % w / w to about 0.5% w / w 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 %, about 0.001 % to about 0.4 %, about 0.001 % to about 0.5 %, about 0.001 % to about 0.6 %,- 16 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601about 0.001 % to about 0.7 %, about 0.001 % to about 0.8 %, about 0.001 % to about 0.9 %, about 0.001 % 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.

[0039] In some embodiments, the composition further comprises niacinamide. In some embodiments, the composition further comprises about 0.1 % w / w to about 10 % w / w 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 - 17 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-7036010.5 % 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 %, 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 niacinamide.

[0040] In some embodiments, the composition further comprises azelaic acid. In some embodiments, the composition further comprises about 0.1 % w / w to about 10 % w / w 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 - 18 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-7036012 % 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.

[0041] 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.

[0042] 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, ataurate copolymer, oleic - 19 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601acid, olive oil, PEG-100 stearate, phenoxyethanol, polymethylsiloxane, purified water, stearic acid, trolamine NF, vitamin E acetate, or any combination thereof.

[0043] In some embodiments, the composition comprises an estrogen, one or more peptides, C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxyethyl acrylate / sodium acryloyldimethyl, ataurate 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, one or more peptides, C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxy ethyl acrylate / sodium acryloyldimethyl, ataurate 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, one or more peptides, niacinamide, C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxy ethyl 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, one or more peptides, C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxyethyl acrylate / sodium acryloyldimethyl, ataurate copolymer, oleic acid, olive oil, PEG- 100 stearate, phenoxyethanol, polymethylsiloxane, purified water, stearic acid, trolamine NF, and vitamin E acetate.

[0044] 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, Tri ethylene Glycol, or any combination thereof.

[0045] In some embodiments, the composition comprises an estrogen, one or more peptides, 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, one or more peptides, 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, one or more peptides, Aloe Barbadensis Leaf Juice, C 12 - 14 Isoparaffin, Caprylic / Capric Triglyceride, Deionized Water, Laureth-7, Phenoxyethanol, Polyacrylamide, - 20 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601Tocopheryl Acetate, and Triethylene Glycol. In some embodiments, the composition comprises an estrogen, niacinamide, one or more peptides, Aloe Barbadensis Leaf Juice, C 12 - 14 Isoparaffin, Caprylic / Capric Triglyceride, Deionized Water, Laureth-7, Phenoxyethanol, Polyacrylamide, Tocopheryl Acetate, and Triethylene Glycol.

[0046] 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.

[0047] 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 one or more peptides, C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxy ethyl 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.

[0048] 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 one or more peptides, Aloe Barbadensis Leaf Juice , C 12 - 14 Isoparaffin, Caprylic / Capric Triglyceride, Deionized Water, Laureth-7, Phenoxyethanol, Polyacrylamide, Tocopheryl Acetate, and Triethylene Glycol.

[0049] In some embodiments, the composition is formulated to penetrate the dermis surrounding an eye of a subject. In some embodiments, the composition is formulated to reduce wrinkles, reduce pigmentation, improve skin elasticity, or a combination thereof. In some embodiments, wrinkle reduction is determined visually by a professional. In some embodiments, pigmentation is determined using TEWL, or similar method. In some embodiments, viscoelastic properties of the skin is determined using a cutometer. In some embodiments, hydration of the epidermis and upper dermis is determined using a moisturemeter. In some embodiments, skin surface hydration is determined using a comeometer. In some embodiments, skin topography and colorimetry are determined using Antera.

[0050] In certain aspects of the present disclosure is a composition comprising an estrogen, one or more peptides, a glycosaminoglycan, and a pharmaceutically acceptable vehicle for delivering the estrogen, a glycosaminoglycan, and one or more peptides 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 an eye area 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.- 21 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0051] 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% (w / w) to about 1.0 % (w / w) of the estrogen. In some embodiments, the composition comprises about 0.01% to about 5.0 % of the estrogen. In some embodiments, the composition comprises about 0.01% to about 2.0 % 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 - 22 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601at 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 estriol. 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 estriol. 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 estriol.

[0052] In some embodiments, the composition comprises one or more peptides. In some embodiments, the one or more peptides are anti-aging or have anti-aging properties. In some embodiments, the one or more peptides are natural peptides. In some embodiments, the one or more peptides are synthetic peptides. In some embodiments, the one or more peptides is acetyl dipeptide- 1 cetyl ester, copper tripeptide, palmitoyl pentapeptide-4, acetyl hexapeptide-8, palmitoyl oligopeptide, trifluoroacetyl-tripeptide-2, carnosine, or a combination thereof. In some embodiments, the one or more peptides is palmitoyl pentapeptide-4 (Pal-KTTKS). In some embodiments, the one or more peptides is acetyl hexapeptide-8 (AC-EEMQRR-NH2). In some embodiments, the one or more peptides are anti-aging ingredients linked to performance relative to improvement of lines / wrinkles, loss of elasticity, firmness and discolorations. Acetyl hexapeptide-8, also known as argireline or acetyl hexapeptide-3, is a neurotransmitter peptide that interferes with the assembly of the SNARE complex and inhibits Ca2+dependent catecholamine release causing muscle paralysis. Acetyl hexapeptide-8 can be used for cosmetic applications and may have anti-wrinkle effects, especially in a periorbital area, and improve skin firmness and tone. Palmitoyl pentapeptide-4, also known as palmitoyl pentapeptide-3, is a signal peptide that stimulates collagen (specifically Types I, III, and IV), fibronectin, elastin, and glycosaminoglycan production. Palmitoyl pentapeptide-4 can be used for cosmetic applications and may reduce fine lines and wrinkles and improve skin texture.- 23 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0053] In some embodiments, the composition comprises one peptide. In some embodiments, the composition comprises two peptides. In some embodiments, the composition comprises two or more peptides. In some embodiments, the composition comprises three peptides.

[0054] In some embodiments, the composition comprises one or more peptides. In some embodiments, the total concentration (%w / w) of the one of more peptides in the composition is about 0.01% to about 5%. In some embodiments, the total concentration of one or more peptides in the composition is about 0.01 % to about 5 %. In some embodiments, the total concentration of one or more peptides in the composition is about 0.01 % to about 0.05 %, about 0.01 % to about 0.1 %, about 0.01 % to about 0.3 %, about 0.01 % to about 0.5 %, about 0.01 % to about 1 %, about 0.01 % to about 1.5 %, about 0.01 % to about 2 %, about 0.01 % to about 3 %, about 0.01 % to about 4 %, about 0.01 % to about 5 %, about 0.05 % to about 0.1 %, about 0.05 % to about 0.3 %, about 0.05 % to about 0.5 %, about 0.05 % to about 1 %, about 0.05 % to about 1.5 %, about 0.05 % to about 2 %, about 0.05 % to about 3 %, about 0.05 % to about 4 %, about 0.05 % to about 5 %, about 0.1 % to about 0.3 %, about 0.1 % to about 0.5 %, about 0.1 % to about 1 %, about 0.1 % to about 1.5 %, 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 0.3 % to about 0.5 %, about 0.3 % to about 1 %, about 0.3 % to about 1.5 %, about 0.3 % to about 2 %, about 0.3 % to about 3 %, about 0.3 % to about 4 %, about 0.3 % to about 5 %, about 0.5 % to about 1 %, about 0.5 % to about 1.5 %, 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 1 % to about 1.5 %, about 1 % to about 2 %, about 1 % to about 3 %, about 1 % to about 4 %, about 1 % to about 5 %, about 1.5 % to about 2 %, about 1.5 % to about 3 %, about 1.5 % to about 4 %, about 1.5 % to about 5 %, about 2 % to about 3 %, about 2 % to about 4 %, about 2 % to about 5 %, about 3 % to about 4 %, about 3 % to about 5 %, or about 4 % to about 5 %. In some embodiments, the total concentration of one or more peptides in the composition is about 0.01 %, about 0.05 %, about 0.1 %, about 0.3 %, about 0.5 %, about 1 %, about 1.5 %, about 2 %, about 3 %, about 4 %, or about 5 %. In some embodiments, the total concentration of one or more peptides in the composition is at least about 0.01 %, about 0.05 %, about 0.1 %, about 0.3 %, about 0.5 %, about 1 %, about 1.5 %, about 2 %, about 3 %, or about 4 %. In some embodiments, the total concentration of one or more peptides in the composition is at most about 0.05 %, about 0.1 %, about 0.3 %, about 0.5 %, about 1 %, about 1.5 %, about 2 %, about 3 %, about 4 %, or about 5 %.

[0055] In some embodiments, the composition comprises one or more peptides. In some embodiments, the concentration (%w / w) of each of the one of more peptides in the composition - 24 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601is about 0.01% to about 5%. In some embodiments, the one or more peptides are each included in the composition at about 0.01 % to about 5 %. In some embodiments, the one or more peptides are each included in the composition at about 0.01 % to about 0.05 %, about 0.01 % to about 0.1 %, about 0.01 % to about 0.3 %, about 0.01 % to about 0.5 %, about 0.01 % to about 1 %, about 0.01 % to about 1.5 %, about 0.01 % to about 2 %, about 0.01 % to about 3 %, about 0.01 % to about 4 %, about 0.01 % to about 5 %, about 0.05 % to about 0.1 %, about 0.05 % to about 0.3 %, about 0.05 % to about 0.5 %, about 0.05 % to about 1 %, about 0.05 % to about 1.5 %, about 0.05 % to about 2 %, about 0.05 % to about 3 %, about 0.05 % to about 4 %, about 0.05 % to about 5 %, about 0.1 % to about 0.3 %, about 0.1 % to about 0.5 %, about 0.1 % to about 1 %, about 0.1 % to about 1.5 %, 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 0.3 % to about 0.5 %, about 0.3 % to about 1 %, about 0.3 % to about 1.5 %, about 0.3 % to about 2 %, about 0.3 % to about 3 %, about 0.3 % to about 4 %, about 0.3 % to about 5 %, about 0.5 % to about 1 %, about 0.5 % to about 1.5 %, 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 1 % to about 1.5 %, about 1 % to about 2 %, about 1 % to about 3 %, about 1 % to about 4 %, about 1 % to about 5 %, about 1.5 % to about 2 %, about 1.5 % to about 3 %, about 1.5 % to about 4 %, about 1.5 % to about 5 %, about 2 % to about 3 %, about 2 % to about 4 %, about 2 % to about 5 %, about 3 % to about 4 %, about 3 % to about 5 %, or about 4 % to about 5 %. In some embodiments, the one or more peptides are each included in the composition at about 0.01 %, about 0.05 %, about 0.1 %, about 0.3 %, about 0.5 %, about 1 %, about 1.5 %, about 2 %, about 3 %, about 4 %, or about 5 %. In some embodiments, the one or more peptides are each included in the composition at a concentration of at least about 0.01 %, about 0.05 %, about 0.1 %, about 0.3 %, about 0.5 %, about 1 %, about 1.5 %, about 2 %, about 3 %, or about 4 %. In some embodiments, the one or more peptides are each included in the composition at a concentration of at most about 0.05 %, about 0.1 %, about 0.3 %, about 0.5 %, about 1 %, about 1.5 %, about 2 %, about 3 %, about 4 %, or about 5 %.

[0056] In some embodiments, the glycosaminoglycan comprises hyaluronic acid, chondroitin sulfate, dermatan sulfate, heparan sulfate, or a combination thereof. In some embodiments, the glycosaminoglycan comprises hyaluronic acid. In some embodiments, the glycosaminoglycan comprises chondroitin sulfate. In some embodiments, the glycosaminoglycan comprises dermatan sulfate. In some embodiments, the glycosaminoglycan comprises heparan sulfate. In some embodiments, the glycosaminoglycan has an average molecular weight of about 10 kDa to about 2,000 kDa. In some embodiments, the glycosaminoglycan has an average molecular weight of about 10 kDa to about 50 kDa, about 10 kDa to about 100 kDa, about 10 kDa to about - 25 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601500 kDa, about 10 kDa to about 1,000 kDa, about 10 kDa to about 1,500 kDa, about 10 kDa to about 2,000 kDa, about 50 kDa to about 100 kDa, about 50 kDa to about 500 kDa, about 50 kDa to about 1,000 kDa, about 50 kDa to about 1,500 kDa, about 50 kDa to about 2,000 kDa, about 100 kDa to about 500 kDa, about 100 kDa to about 1,000 kDa, about 100 kDa to about 1,500 kDa, about 100 kDa to about 2,000 kDa, about 500 kDa to about 1,000 kDa, about 500 kDa to about 1,500 kDa, about 500 kDa to about 2,000 kDa, about 1,000 kDa to about 1,500 kDa, about 1,000 kDa to about 2,000 kDa, or about 1,500 kDa to about 2,000 kDa. In some embodiments, the glycosaminoglycan has an average molecular weight of about 10 kDa, about 50 kDa, about 100 kDa, about 500 kDa, about 1,000 kDa, about 1,500 kDa, or about 2,000 kDa. In some embodiments, the glycosaminoglycan has an average molecular weight of at least about 10 kDa, about 50 kDa, about 100 kDa, about 500 kDa, about 1,000 kDa, or about 1,500 kDa. In some embodiments, the glycosaminoglycan has an average molecular weight of at most about 50 kDa, about 100 kDa, about 500 kDa, about 1,000 kDa, about 1,500 kDa, or about 2,000 kDa.

[0057] In some embodiments, the glycosaminoglycan is selected from hyaluronic acid, chondroitin sulfate, dermatan sulfate, and heparan sulfate. In some embodiments, the glycosaminoglycan is hyaluronic acid. In some embodiments, the glycosaminoglycan is chondroitin sulfate. In some embodiments, the glycosaminoglycan is dermatan sulfate. In some embodiments, the glycosaminoglycan is heparan sulfate.

[0058] In some embodiments, the glycosaminoglycan is included in the composition at about 0.01% to about 5% by weight. In some embodiments, the glycosaminoglycan is included in the composition at about 0.1% to about 2% by weight. In some embodiments, the glycosaminoglycan is included in the composition at about 0.5% by weight. In some embodiments, the glycosaminoglycan is included in the composition at about 0.01 % to about 3 % by weight. In some embodiments, the glycosaminoglycan is included in the composition at about 0.01 % to about 0.1 %, 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 1 %, about 0.01 % to about 1.5 %, about 0.01 % to about 2 %, about 0.01 % to about 2.5 %, about 0.01 % to about 3 %, 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 1 %, about 0.1 % to about 1.5 %, about 0.1 % to about 2 %, about 0.1 % to about 2.5 %, about 0.1 % to about 3 %, 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 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 0.4 % to about 0.5 %, about 0.4 % to about 0.6 %, about 0.4 % to about 0.7 %, about 0.4 % to about 1 %,- 26 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601about 0.4 % to about 1.5 %, about 0.4 % to about 2 %, about 0.4 % to about 2.5 %, about 0.4 % to about 3 %, about 0.5 % to about 0.6 %, about 0.5 % to about 0.7 %, about 0.5 % to about 1 %, about 0.5 % to about 1.5 %, about 0.5 % to about 2 %, about 0.5 % to about 2.5 %, about 0.5 % to about 3 %, about 0.6 % to about 0.7 %, about 0.6 % to about 1 %, about 0.6 % to about 1.5 %, about 0.6 % to about 2 %, about 0.6 % to about 2.5 %, about 0.6 % to about 3 %, about 0.7 % to about 1 %, about 0.7 % to about 1.5 %, about 0.7 % to about 2 %, about 0.7 % to about 2.5 %, about 0.7 % to about 3 %, about 1 % to about 1.5 %, about 1 % to about 2 %, about 1 % to about 2.5 %, about 1 % to about 3 %, about 1.5 % to about 2 %, about 1.5 % to about 2.5 %, about 1.5 % to about 3 %, about 2 % to about 2.5 %, about 2 % to about 3 %, or about 2.5 % to about 3 % by weight. In some embodiments, the glycosaminoglycan is included in the composition at about 0.01 %, about 0.1 %, about 0.3 %, about 0.4 %, about 0.5 %, about 0.6 %, about 0.7 %, about 1 %, about 1.5 %, about 2 %, about 2.5 %, about 3 %, about 3.5%, about 4.0%, about 4.5%, or about 5% by weight. In some embodiments, the glycosaminoglycan is included in the composition at at least about 0.01 %, about 0.1 %, about 0.3 %, about 0.4 %, about 0.5 %, about 0.6 %, about 0.7 %, about 1 %, about 1.5 %, about 2 %, about 2.5 %, about 3 %, about 3.5%, about 4.0%, about 4.5%, or about 5% by weight. In some embodiments, the glycosaminoglycan is included in the composition at at most about 0.1 %, about 0.3 %, about 0.4 %, about 0.5 %, about 0.6 %, about 0.7 %, about 1 %, about 1.5 %, about 2 %, about 2.5 %, about 3 %, about 3.5%, about 4.0%, about 4.5%, or about 5% by weight. In some embodiments, the glycosaminoglycan is hyaluronic acid.

[0059] In some embodiments, the pharmaceutically acceptable vehicle comprises silicones. In some embodiments, the pharmaceutically acceptable vehicle comprises siloxanes.

[0060] In some embodiments, the pharmaceutically acceptable vehicle comprises cyclopentasiloxane, caprylyl methicone, poly silicone- 11, PEG-12 dimethicone / PPG-20 Crosspolymer, or any combination thereof.

[0061] In some embodiments, the pharmaceutically acceptable vehicle comprises PEG- 16 Macadamia Glycerides, PEG-12 dimethicone / PPG-20 Crosspolymer, or any combination thereof.

[0062] In some embodiments, the pharmaceutically acceptable vehicle comprises jojoba esters, jojoba alcohol, or both.

[0063] In some embodiments, the pharmaceutically acceptable vehicle comprises ethyl alcohol, cyclopentasiloxane, caprylyl methicone, PEG- 16 Macadamia Glycerides, polysilicone-11, PEG-12 dimethicone / PPG-20 Crosspolymer, 1,2-Hexanediol, phosphatidylcholinejojoba esters, jojoba alcohol, tocopheryl acetate, or any combination thereof.- 27 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0064] 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 composition is formulated as a topical face serum.

[0065] 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 Palmitoyl Pentapeptide-4, Acetyl Hexapeptide-8, hyaluronic acid, ethyl alcohol, cyclopentasiloxane, caprylyl methicone, PEG- 16 Macadamia Glycerides, polysilicone-11, PEG- 12 dimethicone / PPG-20 Crosspolymer, 1,2-Hexanediol, phosphatidylcholinejojoba esters, jojoba alcohol, and tocopheryl acetate, or any combination thereof.

[0066] AREAS FOR APPLICATION

[0067] 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, scalp, 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. In some embodiments, the composition is applied on a subject’s scalp. In some embodiments, the composition is applied on a subject’s eye area. In some embodiments, the composition is applied on a subject’s under-eye, outer corners, eyelids, or a combination thereof.

[0068] 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 0.1 mL to about 0.3 mL - 28 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601daily 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 0.6 mL, 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- 29 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601most 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.

[0069] 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 to about 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.- 30 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0070] 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.

[0071] 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. In some embodiments, the composition is a serum.

[0072] EFFECTS

[0073] In some embodiments, the composition reduces a severity of one or more symptoms comprising skin dryness, decreased skin firmness, decreased skin elasticity, decreased crepiness, loss of collagen, loss of 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 burn healing of the skin.

[0074] In some embodiments, the composition increases one or more symptoms comprising skin hydration, deep skin hydration, skin firmness, skin elasticity, smoothness (or diminished presence of wrinkles), or a combination thereof.

[0075] In some embodiments, the one or more symptoms are assessed by a comeometer, moisturemeter, Antera 3D, cutometer, venipuncture, or a combination thereof.

[0076] In an aspect of the present disclosure, the composition improves skin elasticity. In some embodiments, the composition improves skin elasticity by about 10% to about 100% compared to a placebo. In some embodiments, the composition improves skin elasticity by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more compared to a placebo. In some embodiments, the improvement is seen in about 4 weeks to about 12 weeks. In some embodiments, the improvement is seen in about 4 weeks, 8 - 31 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601weeks, or 12 weeks. In some embodiments, skin elasticity is measured by Cutometer. In some embodiments, the composition is a serum.

[0077] In an aspect of the present disclosure, the composition improves skin hydration. In some embodiments, the composition improves skin hydration by about 10% to about 100% compared to a placebo. In some embodiments, the composition improves skin hydration by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more compare to a placebo. In some embodiments, the improvement is seen in about 4 weeks to about 12 weeks. In some embodiments, the improvement is seen in about 4 weeks, 8 weeks, or 12 weeks. In some embodiments, skin hydration is measured via comeometer. In some embodiments, skin hydration is measured by moisturemeter EpiD. In some embodiments, the composition is a serum.

[0078] In an aspect of the present disclosure, the composition improves skin texture. In some embodiments, the composition improves skin texture by about 10% to about 100% compared to a placebo. In some embodiments, the composition improves skin texture by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more compared to a placebo. In some embodiments, the improvement is seen in about 4 weeks to about 12 weeks. In some embodiments, the improvement is seen in about 4 weeks, 8 weeks, or 12 weeks. In some embodiments, skin texture is measured by Antera 3D. In some embodiments, skin texture is measured by visual expert grading. In some embodiments, the composition is a serum.

[0079] In an aspect of the present disclosure, the composition improves wrinkle reduction. In some embodiments, the composition improves wrinkle reduction by about 5% to about 50% compared to baseline. In some embodiments, the composition improves wrinkle reduction by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or more compared to a placebo. In some embodiments, the improvement is seen in about 4 weeks to about 12 weeks. In some embodiments, the improvement is seen in about 4 weeks, 8 weeks, or 12 weeks. In some embodiments, wrinkle reduction is measured by Antera 3D. In some embodiments, the composition is an eye cream.

[0080] In an aspect of the present disclosure, the composition improves skin firmness. In some embodiments, the composition improves skin firmness by about 5% to about 50% compared to baseline. In some embodiments, the composition improves skin firmness by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or more compared to a placebo. In some embodiments, the improvement is seen in about 4 weeks to about 12 weeks. In some embodiments, the improvement is seen in about 4 weeks, 8 - 32 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601weeks, or 12 weeks. In some embodiments, skin firmness is measured by cutometer. In some embodiments, skin firmness is measured by visual expert grading. In some embodiments, the composition is an eye cream.

[0081] In an aspect of the present disclosure, the composition improves skin elasticity. In some embodiments, the composition improves skin elasticity by about 5% to about 50% compared to baseline. In some embodiments, the composition improves skin elasticity by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or more compared to a placebo. In some embodiments, the improvement is seen in about 4 weeks to about 12 weeks. In some embodiments, the improvement is seen in about 4 weeks, 8 weeks, or 12 weeks. In some embodiments, skin elasticity is measured by cutometer. In some embodiments, skin elasticity is measured by visual expert grading. In some embodiments, the composition is an eye cream.

[0082] In an aspect of the present disclosure, the composition improves skin crepiness. In some embodiments, the composition improves skin crepiness by about 5% to about 50% compared to baseline. In some embodiments, the composition improves skin crepiness by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or more compared to a placebo. In some embodiments, the improvement is seen in about 4 weeks to about 12 weeks. In some embodiments, the improvement is seen in about 4 weeks, 8 weeks, or 12 weeks. In some embodiments, skin crepiness is measured by visual expert grading. In some embodiments, the skin crepiness is eyelid crepiness. In some embodiments, the composition is an eye cream.

[0083] SUBJECT POPULATION

[0084] 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 - 33 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-7036017G, 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 nor menopausal but is experiencing symptoms of aging. In some embodiments, the subject is not perimenopausal nor menopausal but is experiencing symptoms of estrogen deficiency.

[0085] 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.

[0086] 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.

[0087] 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 - 34 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601months, 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.

[0088] 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.

[0089] METHODS OF TREATMENT

[0090] 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, one or more peptides, and a pharmaceutically acceptable vehicle for delivering the estrogen and one or more peptides to a non-vaginal area of the subject in need thereof.

[0091] 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.

[0092] In some embodiments, the subject is estrogen deficient. In some embodiments, the subject is a male subject. In some embodiments, the subject is a female subject. In some embodiments, the subject is perimenopausal or menopausal. In some embodiments, the subject is perimenopausal. In some embodiments, the subject is menopausal.

[0093] 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.

[0094] 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, one or - 35 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601more peptides, and a pharmaceutically acceptable vehicle for delivering the estrogen and one or more peptides to a non-vaginal area of the subject in need thereof.

[0095] 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, one or more peptides, a glycosaminoglycan, and a pharmaceutically acceptable vehicle for delivering the estrogen, one or more peptides, and the glycosaminoglycan to a non-vaginal area of the subject in need thereof.

[0096] 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, one or more peptides, and a pharmaceutically acceptable vehicle for delivering the estrogen and one or more peptides to a non-vaginal area of the subject in need thereof.

[0097] 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, one or more peptides, a glycosaminoglycan, and a pharmaceutically acceptable vehicle for delivering the estrogen, one or more peptides, and the glycosaminoglycan to a non-vaginal area of the subject in need thereof.

[0098] 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, one or more peptides, and a pharmaceutically acceptable vehicle for delivering the estrogen and one or more peptides to a non-vaginal area of the subject in need thereof.

[0099] 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, one or more peptides, a glycosaminoglycan, and a pharmaceutically acceptable vehicle for delivering the estrogen, one or more peptides, and the glycosaminoglycan to a non-vaginal area of the subject in need thereof.

[0100] 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, one or more peptides, and a pharmaceutically acceptable vehicle for delivering the estrogen and one or more peptides to a non-vaginal area of the subject in need thereof.

[0101] 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, one or more peptides, a glycosaminoglycan, and a pharmaceutically acceptable vehicle for delivering the estrogen, one or more peptides, and the glycosaminoglycan to a non-vaginal area of the subject in need thereof.- 36 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0102] 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, one or more peptides, and a pharmaceutically acceptable vehicle for delivering the estrogen and one or more peptides 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.

[0103] 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, one or more peptides, a glycosaminoglycan, and a pharmaceutically acceptable vehicle for delivering the estrogen, one or more peptides, and the glycosaminoglycan 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.

[0104] USES

[0105] In an aspect of the present disclosure is use of the composition comprising an estrogen, one or more peptides, and a pharmaceutically acceptable vehicle for delivering the estrogen and one or more peptides to a non-vaginal area for the treatment of a disease or a condition in a subject in need thereof.

[0106] In an aspect of the present disclosure is use of the composition comprising an estrogen, one or more peptides, a glycosaminoglycan, and a pharmaceutically acceptable vehicle for delivering the estrogen, one or more peptides, and the glycosaminoglycan to a non-vaginal area for the treatment of a disease or a condition in a subject in need thereof.

[0107] 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 0.01% to about 5.0 % of the estrogen. In some embodiments, the composition comprises at most about 1.5% of the estrogen. In some embodiments, the composition comprises about 1.0% of the estrogen. In some embodiments, the - 37 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601composition comprises about 0.01 % 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 0.5 % to about 6 % of the estrogen. In some embodiments, the composition comprises about 1 % to about 10 % of the estrogen. In some embodiments, the estrogen, one or more peptides, and glycosaminoglycan work synergistically to improve wrinkle reduction, firmness, elasticity, crepiness of skin, crepiness of eyelids, or a combination thereof.

[0108] In some embodiments, the composition comprises about 0.01% to about 1.0% of Palmitoyl Pentapeptide-4. In some embodiments, the composition comprises about 0.01 % to about 1 %. In some embodiments, the composition comprises about 0.01 % to about 0.05 %, 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 0.1 %, about 0.01 % to about 0.15 %, about 0.01 % to about 0.2 %, about 0.01 % to about 0.3 %, about 0.01 % to about 0.5 %, about 0.01 % to about 1 %, about 0.05 % to about 0.7 %, about 0.05 % to about 0.8 %, about 0.05 % to about 0.9 %, about 0.05 % to about 0.1 %, about 0.05 % to about 0.15 %, about 0.05 % to about 0.2 %, about 0.05 % to about 0.3 %, about 0.05 % to about 0.5 %, about 0.05 % to about 1 %, about 0.7 % to about 0.8 %, about 0.7 % to about 0.9 %, about 0.7 % to about 0.1 %, about 0.7 % to about 0.15 %, about 0.7 % to about 0.2 %, about 0.7 % to about 0.3 %, about 0.7 % to about 0.5 %, about 0.7 % to about 1 %, about 0.8 % to about 0.9 %, about 0.8 % to about 0.1 %, about 0.8 % to about 0.15 %, about 0.8 % to about 0.2 %, about 0.8 % to about 0.3 %, about 0.8 % to about 0.5 %, about 0.8 % to about 1 %, about 0.9 % to about 0.1 %, about 0.9 % to about 0.15 %, about 0.9 % to about 0.2 %, about 0.9 % to about 0.3 %, about 0.9 % to about 0.5 %, about 0.9 % to about 1 %, about 0.1 % to about 0.15 %, about 0.1 % to about 0.2 %, about 0.1 % to about 0.3 %, about 0.1 % to about 0.5 %, about 0.1 % to about 1 %, about 0.15 % to about 0.2 %, about 0.15 % to about 0.3 %, about 0.15 % to about 0.5 %, about 0.15 % to about 1 %, about 0.2 % to about 0.3 %, about 0.2 % to about 0.5 %, about 0.2 % to about 1 %, about 0.3 % to about 0.5 %, about 0.3 % to about 1 %, or about 0.5 % to about 1 % of Palmitoyl Pentapeptide-4. In some embodiments, the composition comprises about 0.01 %, about 0.05 %, about 0.7 %, about 0.8 %, about 0.9 %, about 0.1 %, about 0.15 %, about 0.2 %, about 0.3 %, about 0.5 %, or about 1 % of Palmitoyl Pentapeptide-4. In some embodiments, the composition comprises at least about 0.01 %, about 0.05 %, about 0.7 %, about 0.8 %, about 0.9 %, about 0.1 %, about 0.15 %, about 0.2 %, about 0.3 %, or about 0.5 % of Palmitoyl Pentapeptide-4. In some embodiments, the composition comprises at most about 0.05 %, about 0.7 %, about 0.8 %, about 0.9 %, about 0.1 %, about 0.15 %, about 0.2 %, about 0.3 %, about 0.5 %, or about 1 % of Palmitoyl Pentapeptide-4. In some embodiments, the composition comprises about 0.01% to about 1.0% of Acetyl Hexapeptide- 8. In some- 38 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601embodiments, the composition comprises about 0.01 % to about 0.05 %, 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 0.1 %, about 0.01 % to about 0.15 %, about 0.01 % to about 0.2 %, about 0.01 % to about 0.3 %, about 0.01 % to about 0.5 %, about 0.01 % to about 1 %, about 0.05 % to about 0.7 %, about 0.05 % to about 0.8 %, about 0.05 % to about 0.9 %, about 0.05 % to about 0.1 %, about 0.05 % to about 0.15 %, about 0.05 % to about 0.2 %, about 0.05 % to about 0.3 %, about 0.05 % to about 0.5 %, about 0.05 % to about 1 %, about 0.7 % to about 0.8 %, about 0.7 % to about 0.9 %, about 0.7 % to about 0.1 %, about 0.7 % to about 0.15 %, about 0.7 % to about 0.2 %, about 0.7 % to about 0.3 %, about 0.7 % to about 0.5 %, about 0.7 % to about 1 %, about 0.8 % to about 0.9 %, about 0.8 % to about 0.1 %, about 0.8 % to about 0.15 %, about 0.8 % to about 0.2 %, about 0.8 % to about 0.3 %, about 0.8 % to about 0.5 %, about 0.8 % to about 1 %, about 0.9 % to about 0.1 %, about 0.9 % to about 0.15 %, about 0.9 % to about 0.2 %, about 0.9 % to about 0.3 %, about 0.9 % to about 0.5 %, about 0.9 % to about 1 %, about 0.1 % to about 0.15 %, about 0.1 % to about 0.2 %, about 0.1 % to about 0.3 %, about 0.1 % to about 0.5 %, about 0.1 % to about 1 %, about 0.15 % to about 0.2 %, about 0.15 % to about 0.3 %, about 0.15 % to about 0.5 %, about 0.15 % to about 1 %, about 0.2 % to about 0.3 %, about 0.2 % to about 0.5 %, about 0.2 % to about 1 %, about 0.3 % to about 0.5 %, about 0.3 % to about 1 %, or about 0.5 % to about 1 % Acetyl Hexapeptide-8. In some embodiments, the composition comprises about 0.01 %, about 0.05 %, about 0.7 %, about 0.8 %, about 0.9 %, about 0.1 %, about 0.15 %, about 0.2 %, about 0.3 %, about 0.5 %, or about 1 % Acetyl Hexapeptide-8. In some embodiments, the composition comprises at least about 0.01 %, about 0.05 %, about 0.7 %, about 0.8 %, about 0.9 %, about 0.1 %, about 0.15 %, about 0.2 %, about 0.3 %, or about 0.5 % Acetyl Hexapeptide-8. In some embodiments, the composition comprises at most about 0.05 %, about 0.7 %, about 0.8 %, about 0.9 %, about 0.1 %, about 0.15 %, about 0.2 %, about 0.3 %, about 0.5 %, or about 1 % Acetyl Hexapeptide-8. In some embodiments, the composition comprises about 0.1% of Palmitoyl Pentapeptide-4 and about 0.1% of Acetyl Hexapeptide-8.

[0109] In some embodiments, the glycosaminoglycan is included in the composition at about 0.01% to about 5% by weight. In some embodiments, the glycosaminoglycan is included in the composition at about 0.1% to about 2% by weight. In some embodiments, the glycosaminoglycan is included in the composition at about 0.5% by weight. In some embodiments, the glycosaminoglycan is hyaluronic acid.

[0110] 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 an eye of the subject. In some embodiments, the non- - 39 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601vaginal area is an eye area of the subject. In some embodiments, the non-vaginal area is a scalp of the subject. In some embodiments, the non-vaginal area is under-eye, outer comers, and eyelid. 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.

[0111] 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.

[0112] In some embodiments, the composition further comprises niacinamide. In some embodiments, the composition further comprises about 0.1 % to about 10 % of niacinamide.

[0113] 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.

[0114] 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.

[0115] In some embodiments, the pharmaceutically acceptable vehicle comprises C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxy ethyl acrylate / sodium acryloyldimethyl taurate copolymer, oleic acid, olive oil, PEG- 100 stearate, phenoxyethanol, polymethylsiloxane, purified water, stearic acid, trolamine NF, vitamin E acetate, or any combination thereof.- 40 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0116] In some embodiments, the pharmaceutically acceptable vehicle comprises Squalane, 1,2-Hexanediol, Butylene Glycol, Caprylyl Methicone, Cyclopentasiloxane, Dimethicone, Dimethicone Crosspolymer, Glycerin, Hydroxyacetophenone, PEG- 12 Dimethicone / PPG-20 Crosspolymer, PEG-40 Hydrogenated Castor Oil, Pentylene Glycol, Polyglyceryl-3 Diisostearate, Tocopheryl Acetate (Vitamin E), water, or any combination thereof. In some embodiments, the pharmaceutically acceptable vehicle comprises Squalane, 1,2-Hexanediol, Butylene Glycol, Caprylyl Methicone, Cyclopentasiloxane, Dimethicone, Dimethicone Crosspolymer, Glycerin, Hydroxyacetophenone, PEG- 12 Dimethicone / PPG-20 Crosspolymer, PEG-40 Hydrogenated Castor Oil, Pentylene Glycol, Polyglyceryl-3 Diisostearate, Tocopheryl Acetate (Vitamin E), and water. In some embodiments, the addition of squalane further prevents moisture loss and restores suppleness. In some embodiments, the pharmaceutically acceptable vehicle is silicone-based. In some embodiments, the pharmaceutically acceptable vehicle helps create a compatible and breathable layer to prevent transepidermal water loss while promoting the permeation of estriol through the stratum corneum.

[0117] In some embodiments, the composition comprises an estrogen, Palmitoyl Pentapeptide-4, Acetyl Hexapeptide-8, 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, Palmitoyl Pentapeptide-4, Acetyl Hexapeptide-8, C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxy ethyl 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, Palmitoyl Pentapeptide-4, Acetyl Hexapeptide-8, C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxy ethyl 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, Palmitoyl Pentapeptide-4, Acetyl Hexapeptide-8, 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.- 41 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0118] In some embodiments, the composition comprises an estrogen, Palmitoyl Pentapeptide-4, Acetyl Hexapeptide-8, hyaluronic acid, ethyl alcohol, cyclopentasiloxane, caprylyl methicone, PEG-16 Macadamia Glycerides, poly silicone- 11, PEG-12 dimethicone / PPG-20 Crosspolymer, 1,2-Hexanediol, phosphatidylcholine, jojoba esters, jojoba alcohol, and tocopheryl acetate.

[0119] In some embodiments, the composition comprises an estrogen, Palmitoyl Pentapeptide-4, Acetyl Hexapeptide-8, Squalane, 1,2-Hexanediol, Butylene Glycol, Caprylyl Methicone, Cyclopentasiloxane, Dimethicone, Dimethicone Crosspolymer, Glycerin, Hydroxyacetophenone, PEG- 12 Dimethicone / PPG-20 Crosspolymer, PEG-40 Hydrogenated Castor Oil, Pentylene Glycol, Polyglyceryl-3 Diisostearate, Tocopheryl Acetate (Vitamin E), and water. IN some embodiments, the composition comprises about 1% to about 10% of squalane. In some embodiments, the composition comprises about 3% to about 10% squalane. In some embodiments, the composition comprises about 5% squalane. In some embodiments, the composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% squalane.

[0120] 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 burn healing. In some embodiments, the treatment reduces acne, acne scarring, and / or dark spots of the skin.

[0121] In some embodiments, the composition improves deep skin hydration in the subject by about 1% to about 10% compared to baseline. In some embodiments, the composition improves deep skin hydration in the subject by about 5% to about 10% compared to baseline. In some embodiments, the composition improves deep skin hydration in the subject by at least about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, or more compared to baseline. In some embodiments, the composition improved deep skin hydration in the subject by at most about 10%, about 9%, about 8%, about 7%, or less compared to baseline.- 42 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601In some embodiments, the improvement is seen after 4 weeks, 6 weeks, 8 weeks, 10 weeks, or 12 weeks of use.

[0122] In some embodiments, the composition improves skin elasticity in the subject by about 1% to about 30% compared to baseline. In some embodiments, the composition improves skin elasticity in the subject by about 5% to about 25% compared to baseline. In some embodiments, the composition improves skin elasticity in the subject by at least about 5%, about 10%, about 15%, about 20%, about 25%, or more compared to baseline. In some embodiments, the composition improves skin elasticity in the subject by at most about 25%, about 20%, about 15%, about 10%, about 5%, or less compared to baseline. In some embodiments, the improvement is seen after 4 weeks, 6 weeks, 8 weeks, 10 weeks, or 12 weeks of use.

[0123] KITS

[0124] In an aspect of the present disclosure is a kit comprising a composition comprising an estrogen, one or more peptides, and a pharmaceutically acceptable vehicle for delivering the estrogen and one or more peptides 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. In some embodiments, the sealed container is a dropper bottle.

[0125] In an aspect of the present disclosure is a kit comprising a composition comprising an estrogen, one or more peptides, a glycosaminoglycan, and a pharmaceutically acceptable vehicle for delivering the estrogen, one or more peptides, and the glycosaminoglycan 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.

[0126] METHODS OF FORMULATING

[0127] In an aspect of the present disclosure is a method of formulating a composition comprising an estrogen, one or more peptides, and a pharmaceutically acceptable vehicle for delivering the estrogen and one or more peptides to a 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.- 43 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0128] In an aspect of the present disclosure is a method of formulating a composition comprising an estrogen, one or more peptides, and a pharmaceutically acceptable vehicle for delivering the estrogen and one or more peptides to a non-vaginal area of a subject in need thereof wherein the method comprises mixing the estrogen, one or more peptides, 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.

[0129] In an aspect of the present disclosure is a method of formulating a composition comprising an estrogen, one or more peptides, a glycosaminoglycan, and a pharmaceutically acceptable vehicle for delivering the estrogen, the glycosaminoglycan, and one or more peptides to a 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.

[0130] In an aspect of the present disclosure is a method of formulating a composition comprising an estrogen, one or more peptides, a glycosaminoglycan, and a pharmaceutically acceptable vehicle for delivering the estrogen, one or more peptides, and the glycosaminoglycan to a non-vaginal area of a subject in need thereof wherein the method comprises mixing the estrogen, one or more peptides, the glycosaminoglycan, 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, one or more peptides, the glycosaminoglycan, and pharmaceutically acceptable 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 - 44 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601homogenous mixture prior to adding into the unguator. In some embodiments, the pharmaceutically acceptable vehicle is a homogenous mixture prior to adding into the unguator.

[0131] EVALUATION OF TREATMENT

[0132] 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), cutometric assessment, topographic evaluation, colorimetry measurement, 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 Estriol Eye Cream

[0133] Objectives:1. To assess the efficacy of a topical product to improve skin hydration, as demonstrated by Comeometer readings.2. To assess the efficacy of a topical product to improve deep skin Hydration, as demonstrated by Moisturemeter EpiD readings.3. To assess the efficacy of a topical product to improve skin firmness and / or skin elasticity, as demonstrated by Cutometer readings.4. To assess the efficacy of a topical product to improve skin texture and crow’s feet, as demonstrated by Antera 3D readings.5. To assess the efficacy of a topical product to improve the appearance of Fine Lines / Wrinkles, Firmness (Visual), Elasticity (Tactile), and Crepiness on the eyelid.6. To assess the effect of a topical product on estrogen levels.

[0134] Test Products:

[0135] Upon reception of samples at study center, the test material, which is assigned a unique code, is digitally logged into the system. Products are stored in a secure location and- 45 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601unused products are returned to the Sponsor or disposed upon issue of the final report. The test product is one of the formulations provided in Table A.Table A. Eye Cream Compositions

[0136] Use instructions:

[0137] Apply 1 pump to eye area once a day using your ring finger for gentler application. Gently pat the product around the entire eye area, focusing on the under-eye, outer corners, and eyelids if suitable. Allow it to absorb fully before applying additional skincare if using. Follow up with moisturizer. If it's daytime, apply SPF for protection. For the initial use at the Baseline visit, subjects will apply test product in-clinic.

[0138] Study Population: Female subjects, age 40-70 years, open to all races and ethnicities (at least 4 Black subjects).

[0139] Duration: 12 Weeks [Screening / Baseline / Immediate, Week 1, Week 8, and Week 12]

[0140] Inclusion Criteria1. Female subjects of any race (at least 4 black subjects), in good general health, aged 40-70 years old, inclusive at enrollment.2. Individuals who are willing to use a prescription eye cream that contains estrogen.3. Individuals who are willing to have a blood draw by a licensed phlebotomist at the Baseline and Week 1 visits.4. Individuals who are on HRT (Hormone Replacement Therapy), Oral Contraceptives, or neither.5. Individuals who are able to cooperate with the Principal Investigator and study personnel throughout the duration of the study and are willing to comply with all study procedures, methods, evaluations, and study product use.6. Individuals who are able to read, understand and willing to sign an informed consent for this specific study and have completed all site required documentation prior to study enrollment (Registration and Medical History).- 46 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-7036017. Individuals who are able to receive emails on their cellular phones and are capable of completing electronic Informed Consents, Photo Model Releases, and / or Questionnaires on their device.8. Individuals willing to be photographed and sign a model release. (Photo subset only)

[0141] Exclusion Criteria1. Individuals currently participating in other clinical studies that are testing a face / eye and / or product that contains hormones.2. Individuals with uncontrolled medical condition(s), including dermatological problems, which could put them at risk in the opinion of the Principal Investigator or compromise the study outcome and / or chronic or serious diseases and conditions which would prevent participation in this clinical study such as cancer, AIDS, insulin-dependent diabetes, renal impairment, mental illness, and / or drug / alcohol addiction.3. Individuals with a history of melanoma, or a treated skin cancer within the last 5 years.4. Individuals who are pregnant, lactating, or planning to become pregnant. Individuals who become pregnant during the study must inform the Principal Investigator immediately. 5. Individuals who are unreliable or unlikely to be available for the duration of the study. 6. Individuals with a history of allergic reactions, skin sensitization and / or known allergies to cosmetic and personal care products / ingredients.7. Individuals who are immunocompromised.8. Individuals who are employees of the study center or other testing firms / laboratories, cosmetic or raw goods manufacturers or suppliers.9. Individuals who are unable to communicate or cooperate with the Principal Investigator / study personnel due to language problems, poor mental development, or impaired cerebral function.10. Individuals who started hormones within the last three months preceding the commencement of the study.11. Individuals who are using oral contraception for less than three months before study commencement or who have changed their contraceptive method within the three months before the Baseline visit or planning to modify their contraception treatment within the duration of the study.12. Individuals who have regular salon and / or dermatological procedures that can interfere with study results (Microdermabrasion, Fillers, Facial Peels, etc.) and are not willing to stop throughout the study.- 47 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-70360113. Individuals with facial tattoos and facial piercings (that can’t be removed).14. Individuals with tattooed / permanent make up (i.e., eyeliner, eyebrows, lip liner, etc.), eyebrow microblading, and / or eyelash extensions. (Photo subset only)15. Individuals who plan to change their hairstyle throughout the course of the study or who wear hair coverings regularly (i.e., wigs, coloring, extensions, etc.). (Photo subset only)

[0142] Study Design

[0143] This was a twelve-week study of the performance of the test product (Example B of Table A). The test product was used by each subject per Sponsor instructions. 40 healthy subjects were enrolled in the study and 34 completed. 6 subjects discontinued. Changes in skin condition were assessed by expert grading and instrumental measurements. Consumer perception of the product and its effects were determined from analysis of results from subjective questionnaires. Clinical Photography was conducted on a subset of 5 subjects. Evaluation points occurred at Baseline (BL), Immediate (IMM), Week 1, Week 8 (W8), and after twelve weeks of use (W12).

[0144] Methods

[0145] Instrumentation:

[0146] Comeometer: The measuring principle of the Courage + Khazaka Corneometer® CM 825 is based on capacitance measurement of a dielectric medium. Any change in the dielectric constant due to skin surface hydration variation alters the capacitance of a precision measuring capacitor. An advantage of this method, compared to others, is the fact that intrinsic capacitance of products applied to the skin only have minimal influence on the measurements. The measurement can detect even slight changes in the hydration level. The reproducibility of the measurement is very high, and the measurement time is very short (Is). The design of the measuring head is such that the measurement depth is very small. This is important for investigation of epidermal hydration if the influence of deeper skin layers (e.g., from the blood vessels) is to be avoided. The Corneometer® probe design ensures these layers are not being measured. This technique is a well-established method to reproducibly and accurately determine the hydration level of the skin surface, i.e., the humidity level of the most external cutaneous layers of the Stratum Corneum (10-20 pm depth). The measurements are given in arbitrary units (AU) ranging from 0 AU to 130 AU. Increase Corneometer® Measurements = Increase in Moisture Level on the Superficial Skin Layer = Moisturizing Effect. All subjects had Comeometer measurements taken in triplicate and averaged on the right or left eye area, per randomization, at Baseline, Immediate, Week 8, and Week 12.- 48 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0147] Moisturemeter EpiD: The Moisturemeter (Delfin Technologies Ltd., Finland) measures deep hydration in the epidermis and upper dermis. The Moisturemeter consists of an electronic control unit and an integrated probe to measure the dielectric constant of the measurement site. The device generates a high frequency electromagnetic (EM) wave of 265MHZ and sends it in the coaxial probe and the skin down to 0.5mm depth. The reflected EM wave is registered. This wave contains information of the water content of the measure tissue (skin). The MoisturemeterEpiD measures the tissue dielectric constant (TDC), which is a dimensionless physical quantity. It is known that tissue water has a high dielectric constant value and fat and tissue macromolecules, especially protons, have a very low dielectric constant. The MoisturemeterEpiD converts automatically the measured TDC value into percentage water content (PWC) of the measurement site and displays the PWC (%). A higher PWC indicates TDC—1 higher water content. The PWC value is calculated using the formula: PWC = — ^7— xl00% where TDC is the measured tissue dielectric constant. The PWC value is an accurate objective indicator of tissue water when following subject's tissue water changes on a single site over time or detecting site to site differences. All subjects had Moisturemeter measurements taken in triplicate and averaged on the right or left eye area, per randomization, at Baseline, Week 8, and Week 12.

[0148] Cutometer: The Cutometer MPA 580 (Courage + Khazaka, Germany) measures the viscoelastic properties of the skin by applying suction to the skin surface, drawing the skin into the aperture of the probe, and determining the penetration depth using an optical measuring system. The resistance of the skin to be sucked up by the negative pressure (firmness) and its ability to return to its original position (elasticity) are calculated and displayed as curves. The Cutometer outputs include many parameters of different portions of the measurement curve including R0 (Uf, firmness), R2 (Ua / Uf, gross elasticity), R5 (Ur / Ue, net elasticity), R7 (Ur / Uf, elastic portion) and R9 (R3[last max amp]-R0[Uf], fatigue). Elasticity was reported using the R5 (Ur / Ue) parameter, as the skin becomes more elastic this value increased. Skin Firmness was reported using the R0 (Uf) parameter, as the skin becomes firmer this value will decrease. R0 (elasticity) and R5 (firmness) were the only two parameters provided and analyzed for the final report. All subjects hadCutometer measurements taken in triplicate and averaged on the right or left eye area, per randomization, at Baseline, Week 8, and Week 12.

[0149] Anter a 3D: Antera 3D (Miravex Limited, Ireland) is an instrument combining skin profilometry, multi-spectral analysis, and colorimetry to provide reconstruction of the skin surface in three dimensions and subsequent image analysis. The skin profilometry, or topography measurements, include wrinkles, texture, pores, depressions, and elevations, the spectral or - 49 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601chromophore measurements include pigmentation and redness, and the colorimetry measurements include L*a*b* values and variation in these values. All subjects hadthree images of the Left or Right Crow’s Feet area (based on the more severe condition), at Baseline, Week 8, and Week 12, and analyzed using the Antera 3D software by the study center for Wrinkles (Crow’s Feet) and Texture. All analyzed images for reported data will be provided. The number of subjects included in the final data analysis depends upon images / analysis variability guidelines provided by manufacturer.

[0150] Expert Grading: Ordinal scales allow a number to be directly and objectively attached to the quality of a given attribute. When responding to an ordinal scale item, the expert grader specifies their level of agreement to a statement by choosing a set grade, or level. All subjects hadeye area Fine Lines / Wrinkles, Firmness (Visual), Elasticity (Tactile), and Crepiness on the eyelid assessed by an expert grader at Baseline, Week 8, and Week 12 utilizing a 10-point ordinal scale. Clinical grading was performed in the same room at each study visit using overhead lighting as well as a lighted magnifying loop as needed.

[0151] The following 10-point ordinal scales will be used:

[0152] Questionnaire: Subjective questionnaires allow the Sponsor to gauge the subjects’ opinions of the test product and its effects. Questions asked for subjects’ agreement to a statement. The Sponsor provided a questionnaire, and the study center analyzed the results.Subjects completed the questionnaire at Week 8 and Week 12.

[0153] Venipuncture and Analysis: Subjects had their blood drawn following standard venipuncture techniques at Baseline and Week 1 by a licensed phlebotomist. The blood samples were collected and processed according to Labcorp provided instructions (serum). The processed samples were submitted to Labcorp for analysis as requested by the Sponsor. Results were analyzed by the study center and included in the final report.

[0154] Clinical Photography: Validated Clinical Photography involves a fully controlled, high resolution image capture process of multiple timepoints throughout a given treatment or- 50 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601product use regimen. Panelist positioning and equipment are standardized for consistency throughout study. All photographs are taken in a temperature-controlled studio. Subjects are provided with a non-constricting black headband to prevent hair from falling into the face without pulling on the scalp, and a black cape to ensure panelists’ clothing is covered. All photos are taken on a black background. Subjects are guided throughout the process by a professional photographer and / or a clinical technician. Images were cropped, aligned, and put into side-by-side format, but otherwise unedited and unretouched. Images are taken from the best representative angles as determined by the study team. The following camera settings were used:&

[0155] Images were taken of the face, utilizing the following angles: 45 degrees right, straight on, 45 degrees let. Delivery of images will be approximately 4 weeks from study completion via secure cloud-based storage link with a naming convention that will be described in the report. All timepoints were cropped, aligned, and put into a side-by-side format to highlight key changes or improvements in condition. Photos were taken on a subset of 5 at Baseline Week 8, and Week 12.

[0156] Procedure

[0157] Screening / Baseline / Immediate Visit

[0158] Potential subjects arrived at the test site with clean facial skin, having used no other face products, including cleanser and underwent the following Screening procedures. All findings were reported on the appropriate CRFs: Read and sign an informed consent form as described; Complete or update personal / medical history; and Be screened for qualification using an Inclusion / Exclusion criteria checklist.

[0159] Subjects that met entrance criteria were enrolled and proceeded with study participation.

[0160] Subjects washed their face and acclimate to the clinic environment for 15 minutes prior to assessments allowing subjects to relax and let their skin balance to the environment.

[0161] All enrolled subjects completed the following Baseline procedures: Expert Grading assessments, Instrumental assessments, Venipuncture, Clinical Photography.- 51 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0162] Subjects were given test product, and verbal application instructions as described above as well as detailed written application instructions and a log to record product use.

[0163] Subjects applied the test product as described above and waited approximately 15 minutes.

[0164] After application subjects completed the following Immediate (IMM) procedures: Instrumental assessments.

[0165] Subjects were reminded to inform the study center immediately of any adverse reactions or events which may occur.

[0166] After completion of all Baseline and Immediate procedures, subjects received an appointment time for their Week 1 visit and were dismissed from the Baseline visit.

[0167] Week 1 Visit:

[0168] Subjects arrived at the test site and were questioned for any changes in medical history since their last visit and screened for any adverse events. All subjects completed the following Week 1 procedures. Subjects were reminded to inform the study center immediately of any adverse reactions or events which may occur. After completion of all Week 1 procedures, subjects received an appointment time for their Week 8 visit and were dismissed from the Week 1 visit.

[0169] Week 8 Visit:

[0170] Subjects arrived at the test site with clean facial skin, having used no other face products, including cleanser. Upon arrival, subjects washed their face and acclimated to the clinic environment for 15 minutes prior to assessments allowing subjects to relax and let their skin balance to the environment.

[0171] Subjects were questioned for any changes in medical history since their last visit and screened for any adverse events.

[0172] After acclimation, subjects completed the following Week 8 procedures: Expert Grading assessments, Instrumental assessments, Clinical Photography, Questionnaire completion.

[0173] Subject Daily logs and products were collected. Daily logs were reviewed, and products were inspected to verify protocol compliance with product use instructions. Daily logs and products were returned to subjects.

[0174] Subjects were reminded to inform the study center immediately of any adverse reactions or events which may occur.

[0175] After completion of all Week 8 procedures, subjects received an appointment time for their Week 12 visit and were dismissed from the Week 8 visit.- 52 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0176] Week 12 Visit:

[0177] Subjects arrived at the test site with clean facial skin, having used no other face products, including cleanser. Upon arrival, subjects washed their face and acclimated to the clinic environment for 15 minutes prior to assessments allowing subjects to relax and let their skin balance to the environment.

[0178] Subjects were questioned for any changes in medical history since their last visit and screened for any adverse events.

[0179] Subject Daily logs and products were collected. Daily logs were reviewed, and products were inspected to verify protocol compliance with product use instructions.

[0180] After acclimation all subjects completed the following Week 12 procedures: Expert Grading assessments, Instrumental assessments, Clinical Photography, Questionnaire completion.

[0181] Subjects were advised to inform the study center immediately of any adverse reactions or events which may develop within 48 hours.

[0182] After completion of Week 12 procedures, subjects received a stipend for their participation and were dismissed from the study.

[0183] Procedure Summary Table- 53 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0184] Prohibitions & Restrictions for the Duration of the Study: Excessive / direct sun exposure for the purpose of tanning during the study; Use of self-tanning products or tanning beds during the study; Initiating the use of any new cosmetic / personal care products during the study; Use of other eye cream products; Changes to current hormone routine (must not start or stop current), including oral and topical treatments.

[0185] Adverse Events:

[0186] An adverse event may consist of any untoward medical occurrence in a panelist associated with the use of test product and which does not necessarily have a causal relationship with this treatment. Per MoCRA: any health-related event associated with the use of a cosmetic product that is adverse.

[0187] All adverse events are reported according to Good Clinical Practice (GCP) regulations and study center SOPs. Subjects will be advised to report all adverse events to the study personnel as soon as possible. An adverse event (AE) is any untoward medical occurrence experienced by a subject whether or not considered product related. An adverse event must have an onset time after the subject is enrolled in the study and generally within one week after the subject's participation in the study has ended. The endpoint will depend on the nature of the product being tested. Adverse events will be recorded on the appropriate case report form and include the Principal Investigator's assessment of product relationship as follows: none, unlikely, possible, probable, and definite.

[0188] Two (2) adverse events were reported or observed during the study.

[0189] Serious Adverse Events

[0190] An adverse event or suspected adverse reaction is considered "serious" if, in the view of either the investigator or sponsor, it requires, based on reasonable medical judgment, a medical or surgical intervention to prevent an outcome described below, or it results in any of the following outcomes: death, a life-threatening adverse event, an inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial - 54 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601disruption of the ability to conduct normal life functions, a congenital anomaly / birth defect, an infection, a significant disfigurement (including serious and persistent rashes, second- or third-degree burns, significant hair loss, or persistent or significant alteration of appearance), other than as intended under conditions of use that are customary or usual.

[0191] Serious adverse events were recorded on the appropriate case report form and include the Principal Investigator's assessment of product relationship as follows: none, unlikely, possible, probable, and definite.

[0192] Deviations

[0193] In case of any deviation from the protocol, all non-conformances were documented and addressed in accompanying report documentation. The Sponsor (and IRB if applicable) was notified of any such deviations as soon as an appropriate course of action has been determined by the study team.

[0194] Three protocol deviations occurred during the study.

[0195] Safety and Ethics: The study will be conducted in compliance with the main principles of Good Clinical Practice (GCP) under the International Conference of Harmonisation (ICH) Harmonised Tripartite Guideline on GCP E6(2). The practices and procedures conducted - 55 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601during this study pertaining to informed consent, subject safety, investigator responsibility, and adverse event reporting are designed to comply with ICH E6. This study is not intended for submission to the FDA.

[0196] Discontinuation

[0197] There were six subject withdrawals / discontinuations during the study at week 8 due to no show or product-use non-compliance.

[0198] Analysis:

[0199] The following descriptive statistics will be provided for each time point specified in the protocol: mean, Standard Deviation (SD), mean percent change compared to Baseline values and percent of subjects showing improvement. Paired T-Tests will be run comparing Baseline values to Subsequent values. Tests will have a significance level of 5%.

[0200] Demographics

[0201] Table 1-1. Demographic Summary&

[0202] Estriol Levels Summary

[0203] The measurement uncertainty range of this test at the lower control level is 1.26 + / - 0.41. All results fall well within the measurement uncertainty of the analyte and are thus statistically equivalent.

[0204] Table 1-2. Estriol Levels Summary< << << << << << << <- 56 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601< << << << << << << << << << << << << << << << << << << << <<< << << << << << <

[0205] Statistically significant improvement in skin hydration was noted at the Immediate and Week 12 timepoints via Corneometer. Additionally, directional improvement was seen at the Week 8 time point

[0206] Table 1-3. Instrumentation Summary - Skin Hydration<

[0207] Statistically significant improvement in deep skin hydration was noted at the Week 8 and Week 12 timepoints via Moisturemeter EpiD.4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0208] Table 1-4. Instrumentation Summary - Deep Skin Hydration<

[0209] Statistically significant improvement in skin elasticity was seen at Week 8 and Week 12 via Cutometer. Additionally, directional improvement was seen at the Week 12 timepoint for Skin Firmness.

[0210] Table 1-5. Instrumentation Summary - Skin Firmness & Skin Elasticity&<

[0211] Antera 3D analysis revealed directional improvements at the Week 8 and Week 12 timepoints for the following parameters: Fine Lines and Wrinkles. Additionally, directional improvement was observed for Skin Texture at the Week 12 timepoint

[0212] Table 1-6. Instrumentation Summary - Skin Texture, Fine Lines, & WrinklesAntera 3D Summary4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601< _

[0213] Visual expert grading revealed statistically significant improvement at the Week 8 and Week 12 timepoints for the following parameters: Firmness, Elasticity, and Crepiness. Additionally, directional improvement was observed for Fine Lines / Wrinkles at the Week 8 timepoint and statistically significant improvement was noted at Week 12.

[0214] Table 1-7. Expert Grading SummaryExpert Grading Summary<4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0215] Table 1-7A. Highest Individual Improvement Via Expert Grading:

[0216] Table 1-8. Expert Grading Individual Listings - Fine Lines / Wrinkles4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0217] Table 1-9. Expert Grading Individual Listings - Firmness

[0218] Table 1-10. Expert Grading Individual Listings - Elasticity- 61 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0219] Table 1-11. Expert Grading Individual Listings - Crepiness- 62 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0220] Table 1-12. Questionnaire Summary - Week 8>- 63 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-7036014910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601Favorable Response Combined “Agree” & “Strongly Agree”

[0221] Questionnaire data showed a majority of panelists (>50% of the panel) had a favorable response to 24 of the 26 questions at the Week 8 timepoint.

[0222] Table 1-13. Questionnaire Summary - Week 12>4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-7036014910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601Favorable Response Combined “Agree” & “Strongly Agree”

[0223] Questionnaire data showed a majority of panelists (>50% of the panel) had a favorable response to 25 of the 26 questions at the Week 12 timepoint.

[0224] Conclusion: Use of the eye cream disclosed herein led to statistically significant improvement in skin hydration at the Immediate and Week 12 timepoints via Comeometer. Statistically significant improvement in deep skin hydration was noted at the Week 8 and Week 12 timepoints via Moisturemeter EpiD. Statistically significant improvement in skin elasticity was seen at Week 8 and Week 12 via Cutometer. Visual expert grading revealed statistically significant improvement at the Week 8 and Week 12 timepoints for the following parameters: Firmness, Elasticity, and Crepiness. Additionally, statistically significant improvement was noted at Week 12 for Fine Lines / Wrinkles. Questionnaire data showed a majority of panelists (>50% of the panel) had a favorable response to 24 of the 26 questions at the Week 8 timepoint. Questionnaire data showed a majority of panelists (>50% of the panel) had a favorable response to 25 of the 26 questions at the Week 12 timepoint. Further, the formulation did not increase the blood serum level of estrogen.Example 2: Formulation of An Estrogen Cream

[0225] An estrogen composition as disclosed herein is formulated with a pharmaceutically acceptable vehicle.

[0226] To an unguator, the estrogen, one or more peptides, and a first amount of the pharmaceutically acceptable vehicle (e.g. one-third) is added and mixed. After the estrogen, one or more peptides, 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.

[0227] 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.Example 3: A 3 Week Evaluation of the Tolerance and Comedogenicity of an Eye and Face Cream

[0228] As the need for efficacious treatments available to the consumer is evident, these treatments must also be safe for consumers to use. Before new products are introduced into the marketplace, the testing of these products for potential adverse skin effects is an essential element of the overall safety testing and risk assessment process. Dermal studies are particularly - 67 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601helpful since the skin is the primary route of exposure to humans from most cosmetics, toiletries, and fragrances.

[0229] Objectives:1. To evaluate the tolerability of a topical product of the instant disclosure via Tolerance Grading.2. To evaluate the comedogenicity of a topical product of the instant disclosure via Lesion Count / Comedogenicity Assessment.

[0230] Study Design:

[0231] This was a three-week study of the performance of one test product according to the instant disclosure. The test product was used by each subject per Sponsor instructions. 34 subjects completed the study. Changes in skin condition were assessed by tolerance grading and lesion count. Evaluation points occurred at Baseline (BL), Week 1 (Wl), and after three weeks of use (W3). A detailed outline of study visits is provided.

[0232] Test Product: Estriol Eye and Face Cream

[0233] Use Instructions:

[0234] All subjects used the test product per Sponsor instructions for the following three weeks. Sponsor-provided instructions were explained to subjects and provided to subjects in writing along with a daily product log to record use. Study use instructions as follows: Apply 1 pump to eye and facial area once a day. Allow it to absorb fully before applying additional skincare if using. Follow up with moisturizer. If it’s daytime, apply SPF (not provided) for protection.

[0235] Sample size:

[0236] 35 healthy subjects were enrolled in the study and 34 completed. 1 subject discontinued. All subjects completed required documentation, were assigned an MRN (Medical Record Number, a unique identification number), satisfied the study specific inclusion and exclusion criteria and gave written informed consent.

[0237] Inclusion Criteria:1. Female subjects of any race, in good general health, aged 30-75 years old, inclusive at enrollment (at least 50% of subjects with sensitive skin).2. Individuals with less than 5 active lesions (papules or pustules).3. Individuals willing to use a prescription product containing estriol.4. Individuals who are able to cooperate with the Principal Investigator and study personnel throughout the duration of the study and are willing to comply with all study procedures, methods, evaluations, and study product use.- 68 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-7036015. Individuals who are able to read, understand and willing to sign an informed consent for this specific study and have completed all site required documentation prior to study enrollment (Registration and Medical History).6. Individuals who are able to receive emails on their cellular phones and are capable of completing electronic Informed Consents, Photo Model Releases, and / or Questionnaires on their device

[0238] Exclusion Criteria:1. Individuals currently participating in other clinical studies that are testing a face and / or eye product.2. Individuals with uncontrolled medical condition(s), including dermatological problems, which could put them at risk in the opinion of the Principal Investigator or compromise the study outcome and / or chronic or serious diseases and conditions which would prevent participation in this clinical study such as cancer, AIDS, insulin-dependent diabetes, renal impairment, mental illness, and / or drug / alcohol addiction.3. Individuals with a history of melanoma, or a treated skin cancer within the last 5 years.4. Individuals who are pregnant, lactating, or planning to become pregnant. Individuals who become pregnant during the study must inform the Principal Investigator immediately.5. Individuals who are unreliable or unlikely to be available for the duration of the study.6. Individuals with a history of allergic reactions, skin sensitization and / or known allergies to cosmetic and personal care products / ingredients.7. Individuals who are immunocompromised.8. Individuals who are employees of the study center, other testing firms / laboratories, consumer product, and / or raw goods manufacturers / suppliers.9. Individuals who are unable to communicate or cooperate with the Principal Investigator / study personnel due to language problems, poor mental development, or impaired cerebral function.10. Individuals who started hormones within the last three months preceding the commencement of the study.11. Individuals who are using oral contraception for less than three months before study commencement or who have changed their contraceptive method within the three months before the Baseline visit or planning to modify their contraception treatment within the duration of the study.- 69 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-70360112. Individuals who have regular salon and / or dermatological procedures that can interfere with study results (Microdermabrasion, Fillers, Facial Peels, etc.) and are not willing to stop throughout the study.

[0239] Methods

[0240] All evaluations are performed under controlled condition. Prior to evaluations, all panelists were asked to acclimatize to ambient conditions for at least 15 minutes.

[0241] Lesion Count / Comedogenicity Assessment: Acne lesion count / comedogenicity assessment was performed by an expert grader by counting non-inflammatory lesions in the left and right eye area. Non-inflammatory lesions include whitehead / closed comedones and blackhead / open comedones. The total count summed from each area was reported for these lesions. All subjects had the lesion count / comedogenicity assessment performed at Baseline, Week 1, and Week 3.

[0242] Tolerance Grading: Ordinal scales allow a number to be directly and objectively attached to the quality of a given attribute. When responding to an ordinal scale item, the expert grader specifies their level of agreement to a statement by choosing a set grade, or level. All subjects had have Dryness, Erythema, and Edema assessed in the eye area by an expert grader at Baseline, Week 1, and week 3 utilizing a 5-point ordinal scale. Clinical grading was performed in the same room at each study visit using overhead lighting as well as a lighted magnifying loop as needed.- 70 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0243] Procedure

[0244] Screening / Baseline Visit:■ Potential subjects arrived at the test site with clean facial / eye area skin, having used no other face products, including cleanser and underwent the following Screening procedures. All findings were reported on the appropriate CRFs:■ Read and sign an informed consent form as described in Section 12.■ Complete or update personal / medical history.■ Be screened for qualification using an Inclusion / Exclusion criteria checklist.■ Subjects that meet entrance criteria were enrolled and proceed with study participation.■ All enrolled subjects completed the following Baseline procedures:■ Lesion Count / Comedogenicity assessments■ Tolerance grading assessments■ Subjects were given test product, and verbal application instructions as well as detailed written application instructions and a log to record product use.■ Subjects were reminded to inform the study center immediately of any adverse reactions or events which may occur.■ After completion of all Baseline procedures, subjects received an appointment time for their Week 1 visit and were dismissed from the Baseline visit.

[0245] Week 1 Visit:■ Subjects arrived at the test site with clean facial / eye area skin, having used no other face products, including cleanser. Upon arrival, subjects washed their face and acclimated to the clinic environment for 15 minutes prior to assessments allowing subjects to relax and let their skin balance to the environment.■ Subjects were questioned for any changes in medical history since their last visit and screened for any adverse events.■ After acclimation, subjects completed the following Week 1 procedures:■ Lesion Count / Comedogenicity assessments■ Tolerance grading assessments- 71 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601■ Subject Daily logs and products were collected. Daily logs were reviewed, and products were inspected to verify protocol compliance with product use instructions. Daily logs and products were returned to subjects.■ Subjects were reminded to inform the study center immediately of any adverse reactions or events which may occur.■ After completion of all Week 1 procedures, subjects received an appointment time for their Week 3 visit and were dismissed from the Week 1 visit.

[0246] Week 3 Visit:■ Subjects arrived at the test site with clean facial skin, having used no other face products, including cleanser. Upon arrival, subjects washed their face and acclimated to the clinic environment for 15 minutes prior to assessments allowing subjects to relax and let their skin balance to the environment.■ Subjects were questioned for any changes in medical history since their last visit and screened for any adverse events.■ Subject Daily logs and products were collected. Daily logs were reviewed, and products were inspected to verify protocol compliance with product use instructions.■ After acclimation all subjects completed the following Week 3 procedures:■ Lesion Count / Comedogenicity assessments■ Tolerance grading assessments■ Subjects were advised to inform the study center immediately of any adverse reactions or events which may develop within 48 hours.■ After completion of Week 3 procedures, subjects received a stipend for their participation and were dismissed from the study

[0247] Prohibitions & Restrictions for the Duration of the Study■ Excessive / direct sun exposure for the purpose of tanning during the study.■ Use of self-tanning products or tanning beds during the study.■ Initiating the use of any new cosmetic / personal care products during the study.■ Use of other eye product or products containing estriol

[0248] Adverse Events

[0249] An adverse event may consist of any untoward medical occurrence in a panelist associated with the use of test product and which does not necessarily have a causal relationship with this treatment. Per MoCRA: any health-related event associated with the use of a cosmetic product that is adverse.- 72 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0250] All adverse events are reported according to Good Clinical Practice (GCP) regulations and study center SOPs. Subjects will be advised to report all adverse events to the study personnel as soon as possible. An adverse event (AE) is any untoward medical occurrence experienced by a subject whether or not considered product related. An adverse event must have an onset time after the subject is enrolled in the study and generally within one week after the subject's participation in the study has ended. The endpoint will depend on the nature of the product being tested. Adverse events will be recorded on the appropriate case report form and include the Principal Investigator's assessment of product relationship as follows: none, unlikely, possible, probable, and definite.

[0251] No adverse events were reported or observed during the study.

[0252] Serious Adverse Events

[0253] An adverse event or suspected adverse reaction is considered "serious" if, in the view of either the investigator or sponsor, it requires, based on reasonable medical judgment, a medical or surgical intervention to prevent an outcome described below, or it results in any of the following outcomes: death, a life-threatening adverse event, an inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly / birth defect, an infection, a significant disfigurement (including serious and persistent rashes, second- or third-degree burns, significant hair loss, or persistent or significant alteration of appearance), other than as intended under conditions of use that are customary or usual.

[0254] Serious adverse events were recorded on the appropriate case report form and include the Principal Investigator's assessment of product relationship as follows: none, unlikely, possible, probable, and definite.

[0255] No serious adverse events were reported or observed during the study.

[0256] Deviations

[0257] In case of any deviation from the protocol, all non-conformances were documented and addressed in accompanying report documentation. The Sponsor (and IRB if applicable) will be notified of any such deviations as soon as an appropriate course of action has been determined by the study team.

[0258] Safety and Ethics: The study was conducted in compliance with the main principles of Good Clinical Practice (GCP) under the International Conference of Harmonisation (ICH) Harmonised Tripartite Guideline on GCP E6(2).

[0259] Discontinuation: There was one subject withdrawal / discontinuati on during the study due to a no show.- 73 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0260] Statistical Methods

[0261] Statistical analysis was performed internally by the study center personnel. Data analysis excluded subjects who were discontinued from the study.

[0262] Demographics

[0263] Table 3-1. Demographic Summary&

[0264] Lesion Count / Comedogenicity Assessments & Tolerance Grading

[0265] Mean, Standard Deviation (SD), mean percent change compared to Baseline values and percent of subjects showing improvement. Paired T-Tests were run comparing Baselinevalues to Subsequent values. Tests had a significance level of 5%.

[0266] Minimal changes in dryness (increase) and erythema (decrease) were observed over the course of the 3 week treatment period. No significant change in Dryness, Erythema orEdema was noted (Table 3-2)

[0267] Table 3-2. Objective Tolerance Grading SummaryObjective Tolerance Grading- 74 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601Decrease = Improvement* Statistically Significant (p<O.O5O)

[0268] Lesion Count / Comedogenicity revealed directional improvement in total comedones at Week 1 (Table 3-3).

[0269] Table 3-3. Lesion Count / Comedogenicity SummaryLesion Count / Comedogenicity Summary<

[0270] 97% of the panel exhibited no change in total comedone count at Week 1 and82% of the panel had no change at Week 3. No significant changes in comedones were noted throughout the study (Table 3-4).- 75 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0271] Table 3-4. Total Comedones Summary

[0272] Conclusion

[0273] Use of the eye cream and face cream of the disclosure led to minimal change in dryness (increase) and erythema (decrease) over the course of the 3 week treatment period with no significant changes, via Objective Tolerance Grading. Comedogenicity (Lesion Count) assessments revealed that 83% of the panel had no change in total comedones at the 3 week timepoint and no significant changes in comedones throughout the study.Example 4: A 3 Week Evaluation of the Comedogenicity of a Serum

[0274] This was a three-week study of the performance of one test product of the instant disclosure. The test product was used by each subject per Sponsor instructions. A panel of 35 subjects completed the study. Changes in skin condition were assessed by lesion count.Evaluation points occured at Baseline (BL), Week 1 (Wl), and after three weeks of use (W3). A detailed outline of study visits is disclosed.Table B. Serum Compositions

[0275] Use Instructions

[0276] Apply 1 pump of a composition comprising a serum composition of Table B to face once a day. Allow it to absorb fully before applying additional skincare if using. Follow up with moisturizer if desired. If it's daytime, apply SPF for protection.

[0277] Sample Size

[0278] 35 healthy subjects were enrolled in the study and 35 completed. No subjects discontinued All subjects completed required documentation, were assigned an MRN (Medical- 76 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601Record Number, a unique identification number), satisfied the study specific inclusion and exclusion criteria and gave written informed consent.

[0279] Inclusion Criteria1. Female subjects of any race, in good general health, aged 30-75 years old, inclusive at enrollment (at least 50% of subjects with sensitive skin).2. Individuals with less than 5 active lesions (papules or pustules).3. Individuals willing to use a prescription product containing estriol.4. Individuals who are able to cooperate with the Principal Investigator and study personnel throughout the duration of the study and are willing to comply with all study procedures, methods, evaluations, and study product use.5. Individuals who are able to read, understand and willing to sign an informed consent for this specific study and have completed all site required documentation prior to study enrollment (Registration and Medical History).6. Individuals who are able to receive emails on their cellular phones and are capable of completing electronic Informed Consents, Photo Model Releases, and / or Questionnaires on their device

[0280] Exclusion Criteria1. Individuals currently participating in other clinical studies that are testing a face product. 2. Individuals with uncontrolled medical condition(s), including dermatological problems, which could put them at risk in the opinion of the Principal Investigator or compromise the study outcome and / or chronic or serious diseases and conditions which would prevent participation in this clinical study such as cancer, AIDS, insulin-dependent diabetes, renal impairment, mental illness, and / or drug / alcohol addiction.3. Individuals with a history of melanoma, or a treated skin cancer within the last 5 years.4. Individuals who are pregnant, lactating, or planning to become pregnant. Individuals who become pregnant during the study must inform the Principal Investigator immediately.5. Individuals who are unreliable or unlikely to be available for the duration of the study.6. Individuals with a history of allergic reactions, skin sensitization and / or known allergies to cosmetic and personal care products / ingredients.7. Individuals who are immunocompromised.8. Individuals who are employees of the study center, other testing firms / laboratories, consumer product, and / or raw goods manufacturers / suppliers.- 77 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-7036019. Individuals who are unable to communicate or cooperate with the Principal Investigator / study personnel due to language problems, poor mental development, or impaired cerebral function.10. Individuals who started hormones within the last three months preceding the commencement of the study.11. Individuals who are using oral contraception for less than three months before study commencement or who have changed their contraceptive method within the three months before the Baseline visit or planning to modify their contraception treatment within the duration of the study.12. Individuals who have regular salon and / or dermatological procedures that can interfere with study results (Microdermabrasion, Fillers, Facial Peels, etc.) and are not willing to stop throughout the study.

[0281] Methods

[0282] All evaluations were performed under controlled condition. Prior to evaluations, all panelists were asked to acclimatize to ambient conditions for at least 15 minutes.

[0283] Lesion Count / Comedogenicity Assessment: Acne lesion count was performed by an expert grader by counting non-inflammatory lesions in four areas of the face: forehead, left and right cheek, and lip / chin. Non-inflammatory lesions include whitehead / closed comedones and blackhead / open comedones. The total count summed from each area was reported for these lesions. All subjects had the lesion count / comedogenicity assessment performed at Baseline, Week 1, and Week 3.

[0284] Procedure

[0285] Screening / Baseline Visit■ Potential subjects arrived at the test site with clean facial skin, having used no other face products, including cleanser and underwent the following Screening procedures. All findings were reported on the appropriate CRFs:■ Read and sign an informed consent form.■ Complete or update personal / medical history.■ Be screened for qualification using an Inclusion / Exclusion criteria checklist.■ Subjects that meet entrance criteria were enrolled and proceeded with study participation. ■ All enrolled subjects completed the following Baseline procedures:■ Lesion Count / Comedogenicity assessments■ Subjects were given test product, and verbal application instructions as well as detailed written application instructions and a log to record product use.- 78 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601■ Subjects were reminded to inform the study center immediately of any adverse reactions or events which may occur.■ After completion of all Baseline procedures, subjects received an appointment time for their Week 1 visit and were dismissed from the Baseline visit.

[0286] Week 1 Visit■ Subjects arrived at the test site with clean facial / eye area skin, having used no other face products, including cleanser. Upon arrival, subjects washed their face and acclimated to the clinic environment for 15 minutes prior to assessments allowing subjects to relax and let their skin balance to the environment.■ Subjects were questioned for any changes in medical history since their last visit and screened for any adverse events.■ After acclimation, subjects completed the following Week 1 procedures:■ Lesion Count / Comedogenicity assessments■ Subject Daily logs and products were collected. Daily logs were reviewed, and products were inspected to verify protocol compliance with product use instructions. Daily logs and products were returned to subjects.■ Subjects were reminded to inform the study center immediately of any adverse reactions or events which may occur.■ After completion of all Week 1 procedures, subjects received an appointment time for their Week 3 visit and were dismissed from the Week 1 visit.

[0287] Week 3 Visit■ Subjects arrived at the test site with clean facial skin, having used no other face products, including cleanser. Upon arrival, subjects washed their face and acclimate to the clinic environment for 15 minutes prior to assessments allowing subjects to relax and let their skin balance to the environment.■ Subjects were questioned for any changes in medical history since their last visit and screened for any adverse events.■ Subject Daily logs and products were collected. Daily logs were reviewed, and products were inspected to verify protocol compliance with product use instructions.■ After acclimation all subjects completed the following Week 3 procedures:■ Lesion Count / Comedogenicity assessments■ Subjects were advised to inform the study center immediately of any adverse reactions or events which may develop within 48 hours.- 79 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601■ After completion of Week 3 procedures, subjects received a stipend for their participation and were dismissed from the study.

[0288] Prohibitions & Restrictions for the Duration of the Study■ Excessive / direct sun exposure for the purpose of tanning during the study.■ Use of self-tanning products or tanning beds during the study.■ Initiating the use of any new cosmetic / personal care products during the study.■ Use of other products containing estriol.

[0289] Adverse Events

[0290] An adverse event may consist of any untoward medical occurrence in a panelist associated with the use of test product and which does not necessarily have a causal relationship with this treatment. Per MoCRA: any health-related event associated with the use of a cosmetic product that is adverse.

[0291] All adverse events are reported according to Good Clinical Practice (GCP) regulations and study center SOPs. Subjects will be advised to report all adverse events to the study personnel as soon as possible. An adverse event (AE) is any untoward medical occurrence experienced by a subject whether or not considered product related. An adverse event must have an onset time after the subject is enrolled in the study and generally within one week after the subject's participation in the study has ended. The endpoint depends on the nature of the product being tested. Adverse events were recorded on the appropriate case report form and include the Principal Investigator's assessment of product relationship as follows: none, unlikely, possible, probable, and definite.

[0292] One adverse even was reported or observed during the study by one subject: vaginal spotting. The relationship of the reported adverse event to the product is unlikely.

[0293] Serious Adverse Events

[0294] An adverse event or suspected adverse reaction is considered "serious" if, in the view of either the investigator or sponsor, it requires, based on reasonable medical judgment, a medical or surgical intervention to prevent an outcome described below, or it results in any of the following outcomes: death, a life-threatening adverse event, an inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly / birth defect, an infection, a significant disfigurement (including serious and persistent rashes, second- or third-degree burns, significant hair loss, or persistent or significant alteration of appearance), other than as intended under conditions of use that are customary or usual.- 80 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0295] Serious adverse events were recorded on the appropriate case report form and include the Principal Investigator's assessment of product relationship as follows: none, unlikely, possible, probable, and definite.

[0296] No serious adverse events were reported or observed.

[0297] Statistical Methods

[0298] Statistical analysis was performed internally by the study center personnel. Data analysis excluded subjects who were discontinued from the study.

[0299] Demographics

[0300] Table 4-1. Demographic Summary&

[0301] Lesion Count / Comedogenicity Assessments & Tolerance Grading

[0302] The following descriptive statistics were provided for each time point specified in the protocol: mean, Standard Deviation (SD), mean percent change compared to Baseline values and percent of subjects showing improvement. Paired T-Tests were run comparing Baseline values to Subsequent values. Tests had a significance level of 5%.

[0303] Results

[0304] Lesion Count / Comedogenicity revealed directional improvement in total comedones at Week 1 and Week 3 (Table 4-2).4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0305] Table 4-2. Lesion Count / Comedogenicity Summary<

[0306] 66% of the panel exhibited no change in total comedones at Weeks 1 and 3 (Table 4- 3).- 82 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601

[0307] Table 4-3. Total Comedones Summary

[0308] Conclusion

[0309] Following use of the face serum disclosed herein, comedogenicity (Lesion Count) assessments revealed that 66% of the panel had no change in total comedones at the 1 and 3 week timepoints. No significant increase in total comedones was noted at the Week 1 or 3 timepoints.

[0310] Example 5

[0311] Compositions comprising estriol, two peptides, and squalane are prepared. The composition is formulated with estriol at 0.2% to 0.5% (w / w) of a total weight of the composition. The two peptides include Acetyl Hexapeptide-8 (such as Argireline) and Palmitoyl Pentapeptide-4. A total weight of the two peptides present in the composition are 0.1% (w / w) to about 1% (w / w) of a total weight of the composition. Squalane is incorporated into the composition at a concentration of about 1% to about 10% (w / w) of a total weight of the composition. The composition is combined with a base formulation to yield a serum composition.

[0312] The serum composition is administered to the face of test subjects. The test subjects provide a ranking from 0 to 5 based on their subjective assessment of improved moisture or hydration of skin, decrease in visibility of wrinkles, improved brightness, improved smoothness, or improved firmness, or a combination thereof.

[0313] The subjects are also subjected to corneometry, TWEL, moisturemeter, skin topography, colorimetry, and cutometer measurements.

[0314] 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- 83 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601disclosure. 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.- 84 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PM

Claims

AttyDktNo.: 66462-703601CLAIMS WHAT IS CLAIMED IS:

1. A composition comprising:a. an estrogen;b. one or more peptides; andc. a pharmaceutically acceptable vehicle for delivering the estrogen and one or more peptides 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 0.01% to about 5.0 % by weight of the estrogen.

6. The composition of claim 5, wherein the composition comprises about 0.5% to about 2.0% by weight of the estrogen.

7. The composition of claim 1, wherein the composition comprises at most about 1.5% by weight of the estrogen.

8. The composition of any one of claims 1-7, wherein the composition comprises about 1.0% by weight of the estrogen.

9. The composition of any one of claim 1-8, wherein the one or more peptides is acetyl dipeptide- 1 cetyl ester, copper tripeptide, palmitoyl pentapeptide-4, acetyl hexapeptide-8, palmitoyl oligopeptide, trifluoroacetyl-tripeptide-2, carnosine, or a combination thereof.

10. The composition of any one of claim 1-9, wherein the one or more peptides is palmitoyl pentapeptide-4, acetyl hexapeptide-8, or both.

11. The composition of any one of claims 1-10, wherein the one or more peptides are each included in the composition at about 0.01% to about 0.2% by weight.

12. The composition of any one of claims 1-11, wherein the one or more peptides are each included in the composition at about 0.05% to about 0.15% by weight.

13. The composition of any one of claims 1-12, wherein the one or more peptides are each included in the composition at about 0.1% by weight.

14. The composition of any one of claims 1-13, wherein the pharmaceutically acceptable vehicle comprises glycerin, oleic acid, or vitamin E or derivatives thereof.

15. The composition of claim 14, wherein the pharmaceutically acceptable vehicle comprises at least two of glycerin, oleic acid, and vitamin E or derivatives thereof.- 85 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-70360116. The composition of claim 15, wherein the pharmaceutically acceptable vehicle comprises at least glycerin, oleic acid, and vitamin E or derivatives thereof.

17. The composition of any one of claims 1-16, wherein the pharmaceutically acceptable vehicle comprises Squalane, 1,2-Hexanediol, Butylene Glycol, Caprylyl Methicone, Cyclopentasiloxane, Dimethicone, Dimethicone Crosspolymer, Glycerin, Hydroxyacetophenone, PEG- 12 Dimethicone / PPG-20 Crosspolymer, PEG-40 Hydrogenated Castor Oil, Pentylene Glycol, Polyglyceryl-3 Diisostearate, Tocopheryl Acetate (Vitamin E), water, or any combination thereof.

18. The composition of any one of claims 1-16, wherein the pharmaceutically acceptable vehicle comprises C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxy ethyl acrylate / sodium acryloyldimethyl taurate copolymer, oleic acid, olive oil, PEG- 100 stearate, phenoxyethanol, polymethylsiloxane, purified water, stearic acid, trolamine, vitamin E acetate, or any combination thereof.

19. The composition of any one of claims 1-16, 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.

20. The composition of any one of claims 1-19, wherein the composition is formulated as a topical cream.

21. The composition of any one of claims 1-20, wherein the composition is formulated as a topical eye cream.

22. The composition of claim 21, wherein the topical cream is applied on a subject’s face, neck, hands, legs, knees, shoulders, arms, abdomen, or any combination thereof.

23. The composition of any one of claims 1-22, wherein the composition reduces a severity of one or more symptoms selected from skin dryness, crow’s feet, 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.

24. The composition of any one of claim 23, 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.

25. A composition comprising:a. an estrogen;- 86 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601b. one or more peptides;c. a glycosaminoglycan; andd. a pharmaceutically acceptable vehicle for delivering the estrogen, one or more peptides, and the glycosaminoglycan to a non-vaginal area of a subject in need thereof.

26. The composition of claim 25, wherein the non-vaginal area is a face of the subject.

27. The composition of claim 25 or 26, wherein the estrogen is selected from the group consisting of estriol, estradiol, and estrone.

28. The composition of claim 27, wherein the estrogen is estriol.

29. The composition of claim any one of claims 25-28, wherein the composition comprises about 0.01% to about 5.0 % of the estrogen.

30. The composition of claim 29, wherein the composition comprises about 0.01% to about 2.0% of the estrogen.

31. The composition of claim 25, wherein the composition comprises at most about 1.0% of the estrogen.

32. The composition of any one of claims 25-31, wherein the composition comprises about 0.3 % of the estrogen.

33. The composition of any one of claims 25-32, wherein the one or more peptides is acetyl dipeptide- 1 cetyl ester, copper tripeptide, palmitoyl pentapeptide-4, acetyl hexapeptide-8, palmitoyl oligopeptide, trifluoroacetyl-tripeptide-2, carnosine, or a combination thereof.

34. The composition of any one of claim 25-33, wherein the one or more peptides is palmitoyl pentapeptide-4, acetyl hexapeptide-8, or both.

35. The composition of any one of claims 25-34, wherein the one or more peptides are each included in the composition at about 0.01% to about 0.2% by weight.

36. The composition of any one of claims 25-35, wherein the one or more peptides are each included in the composition at about 0.05% to about 0.15% by weight.

37. The composition of any one of claims 25-36, wherein the one or more peptides are each included in the composition at about 0.1% by weight.

38. The composition of any one of claims 25-37, wherein the glycosaminoglycan comprises hyaluronic acid, chondroitin sulfate, dermatan sulfate, or heparan sulfate.

39. The composition of any one of claims 25-38, wherein the glycosaminoglycan is hyaluronic acid.

40. The composition of any one of claims 25-39, wherein the glycosaminoglycan is included in the composition at about 0.01% to about 5% by weight.- 87 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-70360141. The composition of any one of claims 25-40, wherein the glycosaminoglycan is included in the composition at about 0.1% to about 2% by weight.

42. The composition of any one of claims 25-41, wherein the glycosaminoglycan is included in the composition at about 0.5% by weight.

43. The composition of any one of claims 25-42, wherein the pharmaceutically acceptable vehicle comprises cyclopentasiloxane, caprylyl methicone, poly silicone- 11, PEG-12 dimethicone / PPG-20 Crosspolymer, or any combination thereof.

44. The composition of any one of claims 25-43, wherein the pharmaceutically acceptable vehicle comprises PEG-16 Macadamia Glycerides, PEG-12 dimethicone / PPG-20 Crosspolymer, or both.

45. The composition of any one of claims 25-44, wherein the pharmaceutically acceptable vehicle comprises jojoba esters, jojoba alcohol, or both.

46. The composition of any one of claims 25-45, wherein the pharmaceutically acceptable vehicle comprises ethyl alcohol, cyclopentasiloxane, caprylyl methicone, PEG- 16 Macadamia Glycerides, polysilicone-11, PEG-12 dimethicone / PPG-20 Crosspolymer, 1,2- Hexanediol, phosphatidylcholinejojoba esters, jojoba alcohol, tocopheryl acetate, or any combination thereof.

47. The composition of any one of claims 25-46, wherein the composition is formulated as a topical cream.

48. The composition of any one of claims 25-47, wherein the composition is formulated as a topical face cream.

49. The composition of claim 48, wherein the topical cream is applied on a subject’s face, neck, hands, legs, knees, shoulders, arms, abdomen, or any combination thereof.

50. The composition of any one of claims 25-49, wherein the composition reduces a severity of one or more symptoms selected from skin dryness, crow’s feet, 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.

51. The composition of any one of claims 25-50, 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.

52. Use of a composition of any one of claims 1-51, for the treatment of a disease or a condition in a subject in need thereof.

53. Use of claim 52, wherein the treatment is formulated as a topical cream.- 88 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-70360154. Use of claim 53, wherein the treatment is formulated as a topical eye cream.

55. Use of claim 53, wherein the treatment is formulated as a topical face serum.

56. Use of any one of claims 52-55, wherein the composition treats a disease or condition in the subject.

57. Use of any one of claims 52-56, wherein the subject has a Fitzpatrick skin type I, II, III, IV, V, or VI.

58. Use of any one of claims 52-57, wherein the subject is ages 13-80.

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

60. Use of any one of claims 52-59, wherein the disease or condition is skin aging due to estrogen deficiency.

61. Use of any one of claims 52-59, wherein the disease or condition is perimenopause or menopause.

62. Use of any one of claims 52-61, wherein the disease or condition is skin aging due to perimenopause or menopause.

63. Use of any one of claims 52-62, wherein the treatment is most effective when started around perimenopause.

64. Use of any one of claims 52-63, wherein the composition treats or ameliorates a condition of the subject’s skin.

65. Use of any one of claims 52-64, wherein the condition is derived from menopause and / or perimenopause.

66. Use of any one of claims 52-65, wherein the condition is selected from the group consisting of acne scarring, wound healing, burn 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.

67. Use of any one of claims 52-66, wherein the composition improves deep skin hydration in the subject by about 1% to about 10% compared to baseline.

68. Use of claim 67, wherein the composition improves deep skin hydration in the subject at 12 weeks by about 5% to about 10% compared to baseline.

69. Use of any one of claims 52-68, wherein the composition improves skin elasticity in the subject by about 1% to about 30% compared to baseline.

70. Use of claim 69, wherein the composition improves skin elasticity in the subject at 12 weeks by about 10% to about 25% compared to baseline.

71. Use of any one of claims 52-70, for treating symptoms of menopause and / or perimenopause.- 89 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-70360172. Use of any one of claims 52-71, wherein the subject further uses other treatments for menopause hormone therapy.

73. Use of claim 72, 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.

74. Use of any one of claims 52-73, wherein the composition is applied at least once daily to a face of a subject in need thereof.

75. Use of any one of claims 52-74, wherein the composition is applied at least once daily at nighttime to a face of a subject in need thereof.

76. Use of any one of claims 52-75, wherein the composition is applied at about 0.05 mL to about 0.4 mL at least once daily to face.

77. Use of claim 76, wherein the composition is applied at about 0.1 mL at least once daily to an eye area.

78. Use of any one of claims 52-77, wherein the composition is safely used with retinoids, vitamin c, or spot treatments.

79. Use of any one of claims 52-78, wherein the composition is applied to an eye area.

80. Use of claim 79, wherein the eye areas comprise under-eye, outer comers, eyelids, or a combination thereof.

81. A kit compri sing :a. A composition of any one of claims 1-51; andb. A sealed container for housing the composition.

82. The kit of claim 81, wherein the kit further comprises instructions for use.

83. 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 1-51.

84. The method of claim 83, wherein the skin conditions are due to menopause and / or perimenopause.

85. The method of any one of claims 83-84, 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.

86. The method of any one of claims 83-85, wherein the subject is perimenopausal or menopausal.

87. The method of any one of claims 83-86, wherein the treatment decreases loss of structural architecture of the skin and / or decreases propensity to skin damage.- 90 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-70360188. The method of any one of claims 83-87, wherein the treatment mitigates skin aging.

89. A method of formulating a composition comprising an estrogen, one or more peptides, and a pharmaceutically acceptable vehicle for delivering the estrogen and one or more peptides to a non-vaginal area of a subject in need thereof wherein the method comprises:(i) mixing an estrogen, one or more peptides, and a portion of the pharmaceutically acceptable vehicle to an unguator,(ii) adding the remaining amount of the pharmaceutically acceptable vehicle to the unguator; and(iii) mixing the estrogen and the pharmaceutically acceptable vehicle in the unguator to create the composition.

90. The method of claim 89, wherein the estrogen is a powder.

91. A composition comprising:an estrogen for topical application to a skin of a subject in need thereof, wherein the composition further comprises Palmitoyl Pentapeptide-4, Acetyl Hexapeptide-8, C12 - 15 alkyl benzoate, caprylic / capric triglycerides, cetyl alcohol, ethylhexylglycerin, glycerin USP, glyceryl stearate, hydroxy ethyl acrylate / sodium acryloyldimethyl taurate copolymer, oleic acid, olive oil, PEG-100 stearate, phenoxyethanol, polymethyl siloxane, purified water, stearic acid, trolamine NF, and vitamin E acetate.

92. The composition of claim 91, wherein the estrogen is selected from the group consisting of estriol, estradiol, and estrone.

93. The composition of claim 92, wherein the estrogen is estriol.

94. The composition of claim 91, wherein the composition comprises about 0.01% to about 5.0 % of the estrogen.

95. The composition of claim 94, wherein the composition comprises about 0.5% to about 2.0% of the estrogen.

96. The composition of claim 91, wherein the composition comprises at most about 1.5% of the estrogen.

97. The composition of claim 91, wherein the composition comprises about 1.0% of the estrogen.

98. The composition of claim 91, wherein the composition comprises about 0.01% to about 1.0% of Palmitoyl Pentapeptide-4.

99. The composition of claim 91, wherein the composition comprises about 0.01% to about 1.0% of Acetyl Hexapeptide-8.- 91 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-703601100. The composition of claim 91, wherein the composition comprises about 0.1% of Palmitoyl Pentapeptide-4 and about 0.1% of Acetyl Hexapeptide-8.

101. A composition comprising:an estrogen for topical application to a skin of a subject in need thereof, wherein the composition further comprises Palmitoyl Pentapeptide-4, Acetyl Hexapeptide-8, hyaluronic acid, ethyl alcohol, cyclopentasiloxane, caprylyl methicone, PEG- 16 Macadamia Glycerides, polysilicone-11, PEG-12 dimethicone / PPG-20 Crosspolymer, 1,2-Hexanediol, phosphatidylcholinejojoba esters, jojoba alcohol, and tocopheryl acetate.

102. The composition of claim 101, wherein the estrogen is selected from the group consisting of estriol, estradiol, and estrone.

103. The composition of claim 102, wherein the estrogen is estriol.

104. The composition of claim 101, wherein the composition comprises about 0.01% to about 5.0 % of the estrogen.

105. The composition of claim 104, wherein the composition comprises about 0.01% to about 2.0% of the estrogen.

106. The composition of claim 101, wherein the composition comprises at most about 1.0% of the estrogen.

107. The composition of claim 101, wherein the composition comprises about 0.3% of the estrogen.

108. The composition of claim 101, wherein the composition comprises about 0.01% to about 1.0% of Palmitoyl Pentapeptide-4.

109. The composition of claim 101, wherein the composition comprises about 0.01% to about 1.0% of Acetyl Hexapeptide-8.

110. The composition of claim 101, wherein the composition comprises about 0.1% of Palmitoyl Pentapeptide-4 and about 0.1% of Acetyl Hexapeptide-8.

111. The composition of claim 101, wherein the composition comprises about 0.01% to about 5% of the hyaluronic acid.

112. The composition of claim 101, wherein the composition comprises about 0.1% to about 2% of the hyaluronic acid.

113. The composition of claim 101, wherein the composition comprises about 0.5% by of the hyaluronic acid.

114. A composition comprising:an estrogen for topical application to a skin of a subject in need thereof, wherein the composition further comprises Palmitoyl Pentapeptide-4, Acetyl Hexapeptide-8, Squalane,- 92 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PMAttyDktNo.: 66462-7036011,2-Hexanediol, Butylene Glycol, Caprylyl Methicone, Cyclopentasiloxane, Dimethicone, Dimethicone Crosspolymer, Glycerin, Hydroxyacetophenone, PEG- 12 Dimethicone / PPG-20 Crosspolymer, PEG-40 Hydrogenated Castor Oil, Pentylene Glycol, Polyglyceryl-3 Diisostearate, Tocopheryl Acetate (Vitamin E), and water.

115. The composition of claim 114, wherein the estrogen is selected from the group consisting of estriol, estradiol, and estrone.

116. The composition of claim 115, wherein the estrogen is estriol.

117. The composition of claim 114, wherein the composition comprises about 0.01% to about 5.0 % of the estrogen.

118. The composition of claim 117, wherein the composition comprises about 0.01% to about 2.0% of the estrogen.

119. The composition of claim 114, wherein the composition comprises at most about 1.0% of the estrogen.

120. The composition of claim 114, wherein the composition comprises about 0.3% of the estrogen.

121. The composition of any one of claims 114-120, wherein the composition comprises about 0.01% to about 1.0% of Palmitoyl Pentapeptide-4.

122. The composition of any one of claims 114-121, wherein the composition comprises about 0.01% to about 1.0% of Acetyl Hexapeptide-8.

123. The composition of any one of claims 114-122, wherein the composition comprises about 0.1% of Palmitoyl Pentapeptide-4 and about 0.1% of Acetyl Hexapeptide-8.

124. The composition of any one of claims 114-123, wherein the composition comprises about 1% to about 10% of squalane.

125. The composition of claim 124, wherein the composition comprises about 3% to about 10% squalane.

126. The composition of claim 125, wherein the composition comprises about 5% squalane.- 93 - 4910-9650-9074.1 - 2 / 24 / 20266:42:31 PM

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