Compositions of hyaluronic acid and their use alone and in combination with retinoids to improve skin

Abstract

The present invention relates to a method for increasing the gene expression of one or more of collagen, elastin, fibronectin, and hyaluronic acid in the skin of a subject, comprising topically administering to the subject a hyaluronic acid compound and a retinoid in one or more compositions.The method improves the appearance, feel, and / or appearance of the skin, hydrates the skin, plumps the skin, improves the elasticity of the skin, improves the appearance of fine lines and wrinkles, reduces the depth, length, or width of fine lines and wrinkles, and smooths the skin.The present invention also relates to a cosmetic composition comprising a hyaluronic acid compound, the composition being anhydrous.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 232,561, filed August 12, 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Hyaluronic acid and retinoids have been extensively studied and utilized in skin care in the past decades.However, despite their widespread use, little is known about the effect of hyaluronic acid and retinoids, either individually or in combination, on stimulating the replenishment and / or production of hyaluronic acid in skin, and the corresponding impact on hydration and anti-aging, such as reducing fine lines and wrinkles, and improving skin firmness and plumpness.The present invention is directed to improved cosmetic formulations and treatment methods that utilize these unexplored beneficial effects of hyaluronic acid and retinoids, such as retinol, and deliver them to skin. Summary of the Invention

[0003] One aspect of the present invention includes a cosmetic composition of hyaluronic acid, which is anhydrous. Another aspect of the present invention is a method of improving the skin comprising topically administering to the skin of a subject a hyaluronic acid (HA) compound and a retinoid in one or more compositions, wherein the improvement of the skin comprises (a) increasing the gene expression of one or more of collagen, elastin, fibronectin, and hyaluronic acid in the skin of the subject, and / or (b) improving the look, feel and / or appearance of the skin by hydrating the skin; plumping the skin, improving skin elasticity; improving the appearance of fine lines and wrinkles; reducing the depth, length, or width of fine lines and wrinkles; and / or smoothing the skin, and / or (c) increasing and / or replenishing the level of hyaluronic acid at and / or within the skin, wherein the HA compound is hyaluronic acid or a salt thereof. Another aspect of the present invention includes a method of improving the skin by administering a cosmetic composition to improve the look, feel and / or appearance of the skin. Another aspect of the present invention includes a method of improving the skin by topically administering hyaluronic acid and a retinoid to the skin to improve the look, feel and / or appearance of the skin. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0004] The embodiments of the present invention are described in detail below. In describing the embodiments, specific terms are used for clarity. However, the present invention is not intended to be limited to the specific terms so selected. Although specific exemplary embodiments are discussed, it should be understood that this is done for illustrative purposes only. Those skilled in the art will recognize that other components and configurations can be used without departing from the spirit and scope of the present invention. All references cited herein are incorporated by reference as if each were individually incorporated. All parts and percentages are by weight unless otherwise indicated. As used herein, the term "about" refers to plus or minus 10% of the indicated value. Unless otherwise indicated or clear from the context, percentages by weight are provided based on the total amount of the composition in which they are described. As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Described herein is a method for treating the skin of a subject, comprising topically administering hyaluronic acid and a retinoid.Described herein is also a cosmetic composition comprising hyaluronic acid.Described herein is also a cosmetic composition comprising a retinoid, such as retinol.Described herein is also a cosmetic composition comprising hyaluronic acid and a retinoid in combination with each other.

[0005] Hyaluronic acid In this specification, the terms "hyaluronic acid compound" and "HA compound" are used interchangeably and refer to free hyaluronic acid, hyaluronic acid derivatives (e.g. cross-linked hyaluronic acid) that have the same activity as the free acid, and salts of the free acid or its derivatives.Unless otherwise required by context, the terms "hyaluronic acid" and "HA" are used interchangeably to refer to either or both of the free acid or its acceptable salts.Acceptable salts include, but are not limited to, alkali metal salts such as potassium hyaluronate and sodium hyaluronate.In an exemplary embodiment, HA is sodium hyaluronate. According to the present invention, the HA compound can be derived from any source, including but not limited to synthetic and natural sources. Traditionally, HA was extracted from rooster combs. However, this traditional method has faced growing concerns over the use of animal-derived ingredients in biomedical, pharmaceutical, and cosmetic applications. HA can also be produced by streptococcal fermentation, which has lower production costs, less environmental pollution, and produces a mixture of HA with different molecular weights. Other recent HA production processes include recombinant production from gram-positive and gram-negative bacteria such as Bacillus spp., Lactococcos lactis, Agrobacterium spp., and Escherichia coli. Furthermore, recombinant microorganisms such as Bacilli and E. coli are endotoxin-free, making them safer alternative sources of HA production.

[0006] According to the present invention, one or more HA compounds having a specific molecular weight can be used in the methods and compositions of the present invention, which may be linear, cross-linked, or cross-linked with other components. Typically, HA has a molecular weight of about 1 kDa to about 20,000 kDa. In one embodiment of the present invention, the HA compound has a molecular weight of about 1 kDa to about 20,000 kDa, for example, about 1 kDa to about 10,000, about 1 kDa to about 5,000 kDa, about 1 kDa to about 1,000 kDa, about 1 kDa to about 100 kDa, about 25 kDa to about 100 kDa, about 25 kDa to about 50 kDa, or about 50 kDa or less. In other embodiments of the present invention, the HA compound has a molecular weight of about 10 kDa to about 40 kDa, for example, about 1 kDa to about 20 kDa, or about 3 kDa to about 10 kDa. In another embodiment of the invention, the HA compound has a molecular weight of about 500 kDa to about 2000 kDa, for example about 600 kDa to about 1000 kDa. In a preferred embodiment, the HA compound has a molecular weight of 10 kDa to 40 kDa. HA of different molecular weights can be obtained by selective manufacturing methods that produce specific molecular weight ranges or by controlled hydrolysis of high molecular weight HA.

[0007] HA composition The HA compositions of the present invention can be formulated as creams, gels, lotions, emulsions, or serums, any of which may be anhydrous, aqueous, oil-in-water, or water-in-oil formulations.Thus, according to some embodiments, the HA compositions can include additional cosmetic ingredients or excipients, such as preservatives, humectants, surfactants, and other polymers. Preferably, the HA composition is anhydrous. Most preferably, the anhydrous composition is stored in a disposable capsule to maintain the anhydrous nature of the formulation. It is well known that HA absorbs large amounts of water and expands in volume up to 1000 times when in contact with sufficient water. The anhydrous nature of the formulations disclosed herein prevents the HA compound from activating and retaining moisture until it comes into contact with the skin. By applying an anhydrous formulation, the HA compound penetrates the skin better because it has not yet had time to activate and expand. Once in the skin, the HA compound molecules in the anhydrous formulation are activated and draw water into the skin both from the air and from within the deeper layers of the skin itself. This allows for the administration of significantly less HA compound compared to known aqueous HA formulations, while still achieving the same and / or increased efficacy as the methods disclosed herein. In an embodiment of the present invention, the HA composition contains about 0.001% to about 3.00% by mass of the HA compound.In an embodiment of the present invention, the HA composition contains about 0.001% by mass of the HA compound, about 0.005% by mass of the HA compound, about 0.010% by mass of the HA compound, about 0.015% by mass of the HA compound, about 0.2% by mass of the HA compound, about 0.3% by mass of the HA compound, about 0.4% by mass of the HA compound, about 0.5% by mass of the HA compound, about 0.6% by mass of the HA compound, about 0.7% by mass of the HA compound, about 0.8% by mass of the HA compound, about 0.9% by mass of the HA compound, about 1.0% by mass of the HA compound, about 1.5% by mass of the HA compound, about 2.0% by mass of the HA compound, about 2.5% by mass of the HA compound, or about 3.0% by mass of the HA compound.In an exemplary embodiment, the HA composition contains about 0.006% by mass of the HA compound.

[0008] Retinoids Retinoids are a class of compounds that are derivatives and analogues of vitamin A and are used in cosmetics and pharmaceuticals to regulate epithelial cell growth and treat photoaging and skin wrinkling. There are four generations of retinoids. First generation retinoids include retinol, retinal, tretinoin (ie, retinoic acid or retin-A), isotretinoin, and alitretinoin. Second generation retinoids include etretinate and its metabolite acitretin. Third generation retinoids include adapalene, bexarotene, and tazarotene. Fourth generation retinoids include trifarotene. Retinol is the retinoid most frequently recommended by dermatologists to help slow the signs of skin aging and maintain a youthful appearance. Retinol is a form of vitamin A that occurs naturally in human skin. When used regularly in topical treatments, it can improve skin firmness, visibly reduce the appearance of fine lines and wrinkles, and also minimize the appearance of crow's feet and dark circles around the eyes.

[0009] Although any retinoid can be used in the disclosed methods and compositions, retinol is preferred. In accordance with the present invention, the retinoid can be administered in a separate retinoid composition or can be present in the HA composition (ie, as a combined composition). In an embodiment of the invention, the retinol composition of the invention (i.e., a retinol composition for practicing the methods of the invention, either in combination with a separate hyaluronic acid composition or as part of a combination composition of the invention) contains from about 0.001% to about 5.0% by weight of a retinoid. In an embodiment of the invention, the composition contains about 0.001% by weight of a retinoid, about 0.005% by weight of a retinoid, about 0.010% by weight of a retinoid, about 0.015% by weight of a retinoid, about 0.2% by weight of a retinoid, about 0.3% by weight of a retinoid, about 0.4% by weight of a retinoid, about 0.5% by weight of a retinoid, about 0.6% by weight of a retinoid, about 0.7% by weight of a retinoid, about 0.8% by weight of a retinoid, about 0.9% by weight of a retinoid, about 1.0% by weight of a retinoid, about 1.5% by weight of a retinoid, about 2.0% by weight of a retinoid, about 2.5% by weight of a retinoid, about 3.0% by weight of a retinoid, about 3.5% by weight of a retinoid, about 4.0% by weight of a retinoid, about 4.5% by weight of a retinoid, or about 5.0% by weight of a retinoid. Preferably, the composition contains about 0.15% or about 0.20% by weight. Preferably, the retinoid is retinol.

[0010] An exemplary commercial source of retinoid is Retinol 10S (BASF), which contains 10.0% by weight retinol and 0.1% by weight BHT in soybean oil. Other sources of retinoids can be used in the present invention. Retinoid Compositions The retinoid compositions of the present invention may be formulated as creams, gels, lotions, or serums, any of which may be anhydrous, aqueous, oil-in-water, or water-in-oil formulations. Preferably, the retinoid composition is an anhydrous serum composition. Most preferably, the anhydrous serum composition is stored in a disposable capsule to maintain the anhydrous nature of the formulation. Additionally, storing the retinol serum in a disposable capsule seals it from air, preventing oxidation of the retinol and maintaining its efficacy.

[0011] Konjac Glucomannan Konjac glucomannan is a plant polysaccharide with a high molecular weight, typically in the range of 200 kDa to 2000 kDa, and has excellent hygroscopic properties that can absorb up to 200 times its mass in water. Konjac glucomannan is derived from the root powder of Amorphophallus konjac, a plant of the Araceae family native to the forests of Thailand, Vietnam, and southern China. In traditional Chinese medicine and Asian herbalism, konjac is known as "devil's tongue" because of its detoxifying and sedative properties. In an exemplary embodiment, an HA compound, such as free hyaluronic acid or a salt thereof, is crosslinked with konjac glucomannan in the form of anhydrous Ultra Filling Spheres™ (BASF), as disclosed in U.S. Patent Application Publication No. 2015 / 0283055, the entire contents of which are incorporated by reference. Ultra Filling Spheres™ have been shown to penetrate the epidermis and absorb moisture to smooth fine lines and wrinkles, improve elasticity, and provide long-term hydration.

[0012] Ultra Filling Spheres™ contains HA as a combination of about 97.5% HA and about 2.5% konjac glucomannan by weight, dispersed at a concentration of about 0.2% by weight in ethylhexyl palmitate (about 97.8% by weight of the total Ultra Filling Spheres™ formulation) and trihydroxystearin (about 2.0% by weight of the total Ultra Filling Spheres™ formulation). The sodium hyaluronate present in Ultra Filling Spheres™ typically has a molecular weight of 10 kDa to 40 kDa. In an embodiment of the invention, the HA composition of the invention contains about 1.0% to about 10.0% by weight of Ultra Filling Spheres™. In an embodiment of the invention, the HA composition contains about 1.0%, about 2.0%, about 3.0%, about 4.0%, about 5.0%, about 6.0%, about 7.0%, about 8.0%, about 9.0%, or about 10.0% by weight of Ultra Filling Spheres™. In a preferred embodiment, the HA composition contains about 3.0% by weight of Ultra Filling Spheres™. Ultra Filling Spheres™ can be used, but other HA microspheres are also suitable for use in the methods and compositions of the present invention.Alternative HA microspheres include, but are not limited to, Hyaluronic Filling Spheres®, also provided by BASF, which uses hygroscopic material to make spheres, but does not contain konjac glucomannan.Other hyaluronic acid-filled sphere technologies are based on the use of crosslinked spheres.

[0013] method Hyaluronic acid is an anionic, non-sulfated glycosaminoglycan that is widely distributed throughout connective, epithelial, and nervous tissues and is a major component of skin. As skin ages, the most dramatic change in skin chemistry is the marked loss of epidermal HA, the main molecule involved in binding and retaining water molecules. This results in a significant loss of skin moisture. Although HA remains in the dermis, the size of HA polymers in skin progressively decreases with age. Furthermore, the ability of HA to be extracted into the extracellular space decreases significantly with age, increasing the need to increase the amount of HA within tissue structures. This occurs in conjunction with the progressive cross-linking of collagen and the steady loss of collagen extractability with age. The combined loss of HA and collagen results in skin dehydration, atrophy, and loss of skin elasticity, resulting in the obvious signs of aging such as fine lines and wrinkles. HA is synthesized by specific enzymes called hyaluronan synthases or HAS, and there are three different mammalian HAS enzymes: HAS1, HAS2, and HAS3. These are membrane-bound enzymes that synthesize HA on the inner surface of the plasma membrane, where it is then extruded through pore-like structures into the extracellular space. Studies evaluating photoprotected skin tissue specimens from adult and young patients have shown that intrinsic skin aging is associated not only with a significant decrease in HA content, but also with a downregulation of HAS-1 and HAS-2.

[0014] To effectively combat the signs of skin aging, one strategy would be to first turn on the genes involved in the expression of HAS, to promote the skin's production of high molecular weight HA and its extrusion into the dermal extracellular matrix. According to embodiments of the invention, the methods disclosed herein involve topically administering a hyaluronic acid compound, alone or in combination with a retinoid, to the skin of a subject to improve the skin, where the improvement achieves one or more of the following benefits: i. Increased collagen gene expression. The increased collagen gene expression can be selected from one or more of collagen type I (COL1A1), collagen type III (COL3A1), and collagen type IV (COL4A1). ii. Increased elastin (i.e., ELN) gene expression. iii. Increased fibronectin (i.e., FN1) gene expression. iv. Increased Hyaluronic Acid Gene Expression. The increased hyaluronic acid gene expression can be selected from one or more of hyaluronic acid synthase 1 (i.e., HAS1) and hyaluronic acid synthase 2 (i.e., HAS2).

[0015] In other embodiments of the present invention, by upregulating expression of these specific genes in the skin, one or more of the following benefits in the skin are also achieved by topically administering hyaluronic acid, alone or in combination with a retinoid, to the skin of a subject: i.Increased hydration within the skin. ii. Increasing and replenishing hyaluronic acid levels at the skin's surface. iii. Increasing and replenishing hyaluronic acid levels in the skin.

[0016] In another embodiment of the invention, topical administration of hyaluronic acid in combination with a retinoid results in one or more of the following improvements in the look, feel, and appearance of the skin: i. Increased Skin Firmness. Increased skin firmness includes a 1.5 fold increase in the appearance / look of firmer skin. A 1.5 fold increase in the appearance / look of firmer skin includes a 1.5 fold increase in collagen support within the skin. ii. Increased skin plumpness. Increased skin plumpness includes a seven-fold increase in the appearance / look of plumper, fuller skin. A seven-fold increase in the appearance / look of plumper, fuller skin includes a seven-fold increase in hyaluronic acid levels in the skin. iii. Improvement of skin lines and wrinkles. Improvement of skin lines and wrinkles includes reducing the length, depth, and / or width of fine lines and / or wrinkles and / or reducing the appearance of fine lines and / or wrinkles. iv. Increased smoothness of the skin. v.Increased elasticity of the skin.

[0017] According to the present invention, hyaluronic acid and retinoid can be administered in one or more compositions. Administration can be performed in separate compositions, i.e., HA composition and retinoid composition, or in one composition (combination composition) to administer hyaluronic acid and retinoid simultaneously. When administered in two separate compositions, the hyaluronic acid composition can be administered before the retinoid composition or after the retinoid composition. When administered in two separate compositions, the hyaluronic acid composition is preferably administered before the retinoid composition, and the retinoid composition is preferably administered immediately after the hyaluronic acid composition is administered to the skin. Preferably, the retinoid composition is a retinol composition. According to the present invention, the method includes administration at any time of day, including morning, afternoon, and evening. In some embodiments of the present invention, the HA and retinoid composition or the combination composition is administered in the morning and / or evening. In an exemplary embodiment, the HA and retinoid composition or the combination composition is administered in the evening, such as when the subject goes to bed. In other exemplary embodiments, one of the HA composition or the retinoid composition is administered in the morning and the other of the retinoid composition or the HA composition is administered in the evening.

[0018] In some embodiments of the method, the composition to be administered is contained in a capsule. For such compositions, the method includes the steps of: 1) Twist open the capsule; 2) administering (or applying) the hyaluronic acid composition from the capsule to the skin; 3) administering (or applying) the retinol composition to the skin from the capsule. Alternatively, the hyaluronic acid composition from the hyaluronic acid capsules and the retinol composition from the retinol capsules can be administered simultaneously, for example by mixing them together in the palm of the subject's hand and applying them simultaneously, or by applying the HA composition immediately followed by applying the retinol composition. In an embodiment, in the first administration, the subject applies the composition every other night until the skin becomes accustomed to the product.The frequency of administration can be increased as necessary, preferably until the composition can be administered every night / night.When applying the composition during the day, the subject can also apply a sunscreen with SPF 15 or higher after applying the retinol-containing composition. According to the present invention, the skin to be treated can be washed prior to administration of the HA and retinoid composition or combination composition. According to the present invention, any area of ​​the skin can be treated. In an exemplary embodiment of the present invention, the skin to be treated is facial skin, neck skin, or both facial and neck skin. In another exemplary embodiment of the present invention, the skin is chest / décolletage skin.

[0019] Other components Coconut Alkanes Coconut alkanes are natural products obtained from the complete reduction and hydrogenation of a mixture of fatty acids derived from coconut oil, and function as emollients in skin and hair care applications. In an embodiment of the invention, the HA composition contains about 30.0% to about 45.0% coconut alkane by weight. In a preferred embodiment, the HA composition contains about 37.4% coconut alkane by weight. Coco-Caprylate / Caprate Coco-caprylate / caprate is a botanical ingredient derived from coconut that has a high level of biocompatibility with the skin. It has the ability to penetrate deeply, help the skin repair itself, and act as an emollient, providing softness to the skin.

[0020] In an embodiment of the invention, the HA composition contains about 1.0% to about 5.0% coco-caprylate / caprate by weight. In a preferred embodiment, the HA composition contains about 2.4% coco-caprylate / caprate by weight. An exemplary commercial source of coco-caprylate / caprate is Vegelight 1214LC, a volatile, low-odor alkane derived from vegetable oil. It is a clear, colorless emollient with volatility properties similar to petroleum-derived isododecane and synthetically derived cyclomethicone. It is ideal for use in skin care, color cosmetics, sun care, deodorants, and hair care formulations. Vegelight 1214LC contains 6.0% by weight of coco-caprylate / caprate in coconut alkane and is supplied by Grant Industries. Other sources of coco-caprylate / caprate are also acceptable.

[0021] Jojoba Seed Oil Jojoba seed oil is an emollient, fragrance-free oil extracted from the seeds of a perennial shrub. Jojoba oil has been shown to enhance skin repair. Jojoba oil is a rich source of numerous fatty acids and can also provide topical skin soothing benefits. In an embodiment of the invention, the HA composition of the invention contains about 20.0% to about 25.0% jojoba seed oil by mass. In a preferred embodiment, the HA composition contains about 22.0% jojoba seed oil by mass. Ethylene / propylene / styrene copolymer and butylene / ethylene / propylene copolymer Ethylene / propylene / styrene copolymers are auxiliary ingredients used as oil gelling agents along with the related compound butylene / ethylene / styrene copolymers. The two can be combined with different types of hydrocarbons (e.g., mineral oils or different emollient esters) to form gels with different sensory and physical properties. The resulting hydrocarbon gels improve skin occlusion, reduce transepidermal water loss, and can also form suspensions.

[0022] In an embodiment of the invention, the HA composition of the invention contains about 1.0% to about 5.0% by weight of ethylene / propylene / styrene copolymer. In a preferred embodiment, the HA composition contains about 2.5% by weight of ethylene / propylene / styrene copolymer. In an embodiment of the invention, the HA composition of the invention contains about 0.1% to about 1.0% by weight of butylene / ethylene / styrene copolymer. In a preferred embodiment, the HA composition contains about 0.5% by weight of butylene / ethylene / styrene copolymer. An exemplary commercial source of ethylene / propylene / styrene copolymer in combination with butylene / ethylene / styrene copolymer is Jojoba Glaze HV BF, a clear, high viscosity gel composed almost entirely of jojoba oil, which imparts shine and luster to skin and hair while providing substantial emollient benefits. It provides excellent suspension properties for glitter, sugar, and other particles. Jojoba Glaze HV BF contains i) 9.9% by weight ethylene / propylene / styrene copolymer, ii) 2.0% by weight butylene / ethylene / propylene copolymer, and iii) 0.10% by weight butylated hydroxytoluene (i.e., BHT) in jojoba seed oil, and is supplied by Vantage Personal Care. Other commercial sources of ethylene / propylene / styrene copolymer and butylene / ethylene / styrene are also acceptable.

[0023] Polyurethane-79 Polyurethane-79 is a copolymer formed by reacting hydrogenated polybutanediol, 1,6-hexamethylene diisocyanate, hydrogenated dilinoleyl alcohol, and 1,4-butanediol. The polymer is capped with stearyl alcohol. Polyurethane-79 is utilized in cosmetics as a film former on skin, hair, and nails, and as a viscosity modifier. In an embodiment of the invention, the HA composition contains about 0.5% to about 2.5% by weight of polyurethane-79. In a preferred embodiment, the HA composition contains about 1.2% by weight of polyurethane-79. An exemplary commercial source of polyurethane-79 is Oilkemia 5S polymer, which is an oil-soluble rheology modifier that provides excellent thickening efficiency, clarity, suspension, and stability, while creating an appealing texture across skin care, sun care, and color cosmetic applications with a pleasant non-sticky feel.An exemplary source of polyurethane-79 is Oilkemia 5S polymer, which contains 30.0% by weight polyurethane-79 in caprylic / capric triglyceride and is supplied by Lubrizol.Other sources of polyurethane-79 are also acceptable.

[0024] Caprylic / Capric Triglyceride Caprylic / capric triglyceride is a traditional medium spreading emollient for modern cosmetic applications. Caprylic / capric triglyceride is a clear, slightly yellowish, polar, odorless oil with a spreading value of approximately 550 mm. 2 / 10 min. Caprylic / capric triglyceride has a refractive index (20° C.) of 1.448-1.450, a density (20° C.) of 0.943-0.950 g / ml, and a saponification number of 330-340. An exemplary commercial source of caprylic / capric triglyceride is Myritol 312 supplied by BASF. Other sources of caprylic / capric triglyceride are acceptable. In an embodiment of the invention, the HA composition contains about 15.0% to about 25.0% caprylic / capric triglyceride by weight. In a preferred embodiment, the HA composition contains about 19.0% caprylic / capric triglyceride by weight.

[0025] Coconut oil Coconut oil is derived from the flesh of the coconut. The oil is extracted, refined, bleached, and deodorized and has applications in the cosmetics industry as an ingredient in soaps, skin moisturizers, and suntan lotions, among others. An exemplary commercial source of coconut oil is Brenntag. Other sources of coconut oil are also acceptable. In an embodiment of the invention, the HA composition contains about 5.0% to about 15.0% coconut oil by weight. In a preferred embodiment, the HA composition contains about 10.0% coconut oil by weight. Isosorbide dicaprylate Isosorbide dicaprylate is a natural, excellent lipophilic moisturizer and skin barrier builder. Isosorbide dicaprylate stimulates aquaporin-3, provides long-lasting hydration (>48 hours), and contributes to maintaining healthy barrier function by upregulating tight junctions, desmosomes, and ceramide synthase. An exemplary commercial source of isosorbide dicaprylate is Hydra Synol DOI, supplied by Syntheon. Other sources of isosorbide dicaprylate are also acceptable. In an embodiment of the invention, the HA composition contains about 1.0% to about 3.0% by weight of isosorbide dicaprylate. In a preferred embodiment, the HA composition contains about 2.0% by weight of isosorbide dicaprylate.

[0026] Cyclopentasiloxane Cyclopentasiloxane is a cyclic volatile silicone fluid that can be used in a wide variety of skin, hair, and color personal care applications. Cyclopentasiloxane has excellent temporary emollient properties and is one of the most widely used and important cosmetic solvents today. Cyclopentasiloxane is recommended for use in antiperspirants and deodorants, skin lotions, hairsprays, nail polish, shaving lotions, perfumes and colognes, and makeup. It can also be used in air care vaporization applications such as diffusers. In an embodiment of the invention, the retinol composition of the invention (i.e., a retinol composition for practicing the methods of the invention, either in combination with a separate hyaluronic acid composition or as part of a combination composition of the invention) contains about 55.0% to about 70.0% by weight cyclopentasiloxane. In a preferred embodiment, the retinol composition contains about 61.2% by weight cyclopentasiloxane.

[0027] Dimethiconol Dimethiconol, also known as silicone gum, is a polymer similar to dimethicone. Dimethiconol is a type of silicone used in skin care and hair care products. As a silicone, dimethiconol improves the appearance, texture, and feel of the product, helps prevent moisture loss from the skin, and enhances the effectiveness of the product. In an embodiment of the invention, the retinol composition of the invention (i.e., a retinol composition for practicing the methods of the invention, either in combination with a separate hyaluronic acid composition or as part of a combination composition of the invention) contains about 5.0% to about 15.0% dimethiconol by weight. In a preferred embodiment, the retinol composition contains about 10.8% dimethiconol by weight. An exemplary commercial source of dimethiconol is Xiameter PMX-1501 Fluid, which is a blend of ultra-high viscosity dimethiconol in cyclopentasiloxane. This film-forming, clear, viscous fluid is long-lasting and does not wash off easily, making it suitable for durable cosmetics. In hair care products, dimethiconol conditions hair, especially split ends. In skin care products, dimethiconol provides a soft, velvety skin feel. This product can be used in a wide range of cosmetic and toiletry applications, including skin care, color cosmetics, sun care, hair care, shower gels, antiperspirants, and deodorants. Xiameter PMX-1501 Fluid contains 15.0% by weight dimethiconol in cyclopentasiloxane and is supplied by Univar Solutions. Other sources of dimethiconol and cyclopentasiloxane are acceptable.

[0028] Ethylhexyl Cocoate Ethylhexyl cocoate is an ester that can be used to limit the level of silicone in a formulation, providing a surface feel alternative that is perceived as more natural, and produces a perceptible soft finish, especially in facial and body care formulas. In an embodiment of the invention, the retinol composition of the invention (i.e., a retinol composition for practicing a method of the invention, either in combination with a separate hyaluronic acid composition or as part of a combination composition of the invention) contains about 15.0% to about 25.0% ethylhexyl cocoate by weight. In a preferred embodiment, the retinol composition contains about 20.0% ethylhexyl cocoate by weight.

[0029] soybean oil Soybean oil (glycine soja oil) is an oil that also contains unsaturated fatty acids, soybean lecithin, and essential alpha-linolenic acid that is used in cosmetics, foods, and medicines. An exemplary commercial source of soybean oil is Refined Soybean Oil IP supplied by Gustav Heess. Other sources of soybean oil are acceptable. In an embodiment of the invention, the retinol composition contains about 1.0% to about 10.0% soybean oil by weight. In a preferred embodiment, the retinol composition contains about 7.0% soybean oil by weight. Phenoxyethanol Phenoxyethanol is an antibacterial preservative. Phenoxyethanol is widely used as an antibacterial preservative in cosmetics, toiletries, and pharmaceutical applications, such as shampoos, bubble baths, shower gels, or liquid detergents. The product is chemically inert, making it compatible with most types of chemical compounds. An exemplary commercial source of phenoxyethanol is Phenoxetol, supplied by Clariant. Other sources of phenoxyethanol are also acceptable. In an embodiment of the invention, the retinol composition of the invention (i.e., a retinol composition for practicing the methods of the invention, either in combination with a separate hyaluronic acid composition or as part of a combination composition of the invention) contains about 0.5% to about 1.5% phenoxyethanol by weight. In a preferred embodiment, the retinol composition contains about 0.8% phenoxyethanol by weight.

[0030] Dimethylmethoxychromanol Dimethylmethoxychromanol is an antioxidant that is an analogue of gamma-tocopherol that provides triple protection from reactive species (ROS, RNS, RCS) and may aid in detoxification. When applied to the skin, it improves antioxidant and aging-related parameters, while hypopigmenting activity has also been measured. An exemplary commercial source of dimethylmethoxychromanol is the Lipochroman molecule supplied by Lipotec. Other sources of dimethylmethoxychromanol are acceptable. In an embodiment of the invention, the retinol composition of the invention (i.e., a retinol composition for practicing the methods of the invention, either in combination with a separate hyaluronic acid composition or as part of a combination composition of the invention) contains about 0.005% to about 0.015% by weight of dimethylmethoxychromanol. In a preferred embodiment, the retinol composition contains about 0.01% by weight of dimethylmethoxychromanol.

[0031] Ceramide III Ceramide III is a ceramide that strengthens the skin's natural protective lipid barrier. Ceramide III is composed of a phytosphingosine backbone acylated with saturated fatty acid (stearic acid). Ceramide III and ceramide IIIB support the regeneration of the skin's natural protective layer and form an effective barrier against moisture loss. Thus, these human skin-identical molecules are particularly suitable for long-term protection and repair of sensitive and dry skin. In hair care formulations, ceramide III and ceramide IIIB can repair damaged hair and protect it from chemical and UV damage. An exemplary commercial source of ceramide III is Evonik. Other sources of ceramide III are acceptable. In an embodiment of the invention, the retinol composition of the invention (i.e., a retinol composition for practicing the methods of the invention, either in combination with a separate hyaluronic acid composition or as part of a combination composition of the invention) contains about 0.00005% to about 0.00015% by weight of ceramide III. In a preferred embodiment, the retinol composition contains about 0.0001% by weight of ceramide III.

[0032] Exemplary Compositions Exemplary HA compositions according to the present invention are disclosed in Table A below. [Table 1]

[0033] Specific examples of HA compositions according to the present invention are disclosed in Table B below. [Table 2]

[0034] In the above composition of Table B, the ingredients can be provided as follows: coconut alkanes and coco-caprylate / caprate can be provided by Vegelight 1214LC; Simmondsia chinensis (jojoba) seed oil, ethylene / propylene / styrene copolymer, butylene / ethylene / propylene copolymer, and BHT can be provided as Jojoba Glaze HV; caprylic / capric triglyceride can be provided as Myritol 312; Cocos Nucifera oil can be provided as Olio DI COCCO Raffinate; caprylic / capric triglyceride and polyurethane-79 can be provided as Oilkemia 5S polymer; ethylhexyl palmitate, trihydroxystearin, sodium hyaluronate, and konjac glucomannan can be provided as Ultra Filling Spheres; and isosorbide dicaprylate can be provided as HydraSynol DOI.

[0035] Anhydrous HA serum capsules containing 0.006% by weight of the HA compound disclosed herein were tested against a commercially available aqueous HA serum formulation containing 1.5% by weight HA (Example 2 below). Despite the 1.5% by weight aqueous HA formulation containing over 25,000% HA, the anhydrous capsules achieved significantly better results than the aqueous formulation when HA levels were measured in both culture medium and tissue lysates. Furthermore, the anhydrous HA formulation was successful in inducing the expression of HAS1 and FN1, which was not observed in the aqueous HA formulation. When combined with retinoids, the anhydrous HA serum unexpectedly performed even better. Notably, when the HA anhydrous formulation was combined with retinol, a significant increase was observed in COL1A1 (48%), COL3A1 (58%), and COL4A1 (79%), which was not observed with either the product alone or with the comparative 1.5% by weight aqueous HA formulation or the commercial 0.3% by weight aqueous retinol formulation. In fact, in the case of COL4A1, gene expression was significantly decreased in both aqueous formulations. Furthermore, the expression levels of ELN and FN1 were significantly higher in the combination according to the present invention, despite the significantly lower HA and retinol concentrations in the corresponding aqueous formulations.

[0036] While an increase of 298% and 233% was observed for HAS2 with the individual aqueous formulations, the combination according to the invention produced an unexpected 638% increase in HAS2 expression levels after 24 hours. It is also important to note that the 0.3% by weight aqueous retinol serum tested also contains hyaluronic acid, present as sodium hyaluronate at even higher levels than retinol. Thus, even though the aqueous retinol product also contains a HA / retinol combination, the aqueous retinol product only increased expression levels by one-third of the increase observed with the combination according to the invention. In one embodiment, the HA composition comprises konjac glucomannan and an HA compound crosslinked with one or more additional components selected from coconut alkane, coco-caprylate / caprate, jojoba seed oil, ethylene / propylene / styrene copolymer and butylene / ethylene / propylene copolymer, BHT, caprylic / capric triglyceride, coconut oil, polyurethane-79, ethylhexyl palmitate, trihydroxystearin, and isosorbide dicaprylate. In any of the above compositions, the HA compounds crosslinked with konjac glucomannan, coconut alkane, coco-caprylate / caprate, jojoba seed oil, ethylene / propylene / styrene copolymer and butylene / ethylene / propylene copolymer, BHT, caprylic / capric triglyceride, coconut oil, polyurethane-79, ethylhexyl palmitate, trihydroxystearin, and isosorbide dicaprylate can be provided using the commercially available products Ultra Filling Spheres™, Vegelight 1214LC, Jojoba Glaze HV BF, Myritol 312, coconut oil, Oilkemia 5S polymer, and HydraSynol DOI.

[0037] Retinoid compositions according to the present invention are disclosed in Table C below. [Table 3]

[0038] Specific examples of retinoid compositions according to the present invention are disclosed in Table D below. [Table 4] In the above compositions of Table D, the ingredients can be provided as follows: Cyclopentasiloxane and Dimethiconol can be provided as Xiameter PMX-1501 Fluid; Ethylhexyl Cocoate can be provided from any suitable commercial source; Glycine Soya Oil can be provided as Refined Soybean Oil IP; Glycine Soya Oil, Retinol and BHT can be provided as Retinol 10S; Phenoxyethanol can be provided as Phenoxetol; Dimethylmethoxychromanol can be provided as Liopchroman Molecule; Ceramide NP can be provided as Ceramide III.

[0039] In one embodiment, the retinoid composition comprises retinol and one or more additional ingredients selected from cyclopentasiloxane, dimethiconol, ethylhexyl cocoate, soybean oil, phenoxyethanol, dimethylmethoxychromanol, and ceramides. In any of the above compositions, retinol, cyclopentasiloxane, dimethiconol, ethylhexyl cocoate, soybean oil, phenoxyethanol, dimethylmethoxychromanol, and ceramides can be provided using the commercially available products Retinol 10S, Xiameter PMX-1501 Fluid, ethylhexyl cocoate, refined soybean oil IP, Phenoxetol, Lipochroman molecule, and ceramide III.

[0040] Combination Compositions As mentioned above, the benefits of the present invention can be obtained by applying HA and retinoid in separate compositions or in a single combined HA / retinoid composition. The combined HA / retinoid composition can be formulated as a cream, gel, lotion, or serum, any of which can be anhydrous, aqueous, oil-in-water, or water-in-oil formulations. Preferably, the combined HA / retinoid composition is an anhydrous serum composition. Most preferably, the anhydrous serum composition is stored in a disposable capsule to maintain the anhydrous nature of the formulation. Combining the HA compound and the retinoid in a single anhydrous formulation and storing it in a sealed disposable capsule can prevent activation of the HA compound and simultaneously prevent oxidation and degradation of the retinoid before application to the skin. This ideal formulation and storage strategy can significantly increase the efficacy of the products and methods of the present invention, as well as the stability of the product.

[0041] In one embodiment, the combination composition comprises a HA compound crosslinked with konjac glucomannan, a retinoid, and one or more additional components selected from coconut alkane, coco-caprylate / caprate, jojoba seed oil, ethylene / propylene / styrene copolymer and butylene / ethylene / propylene copolymer, BHT, caprylic / capric triglyceride, coconut oil, polyurethane-79, ethylhexyl palmitate, trihydroxystearin, and isosorbide dicaprylate. In a preferred embodiment, the retinoid is retinol. In any of the above compositions, HA compounds crosslinked with konjac glucomannan, retinoids, coconut alkanes, coco-caprylate / caprate, jojoba seed oil, ethylene / propylene / styrene copolymers and butylene / ethylene / propylene copolymers, BHT, caprylic / capric triglyceride, coconut oil, polyurethane-79, ethylhexyl palmitate, trihydroxystearin, and isosorbide dicaprylate can be provided using the commercially available products Ultra Filling Spheres™, Retinol 10S, Vegelight 1214LC, Jojoba Glaze HV BF, Myritol 312, coconut oil, Oilkemia 5S polymer, and HydraSynol DOI.

[0042] Chromenone Certain chromenone derivatives have been shown to exhibit anti-aging benefits. U.S. Patent No. 8,518,986, the entire contents of which are incorporated by reference, describes chromenone derivatives of formula (I): [ka] or a salt thereof. (In the formula, R 1 and R 2 are the same or different, H, -(C=O)-R 7 , -C(=O)-OR 7 , linear or branched chain C1- to C 20 -alkyl group, where alkyl is oxygen, linear or branched C-C 20 -Alkenyl group, linear or branched C1-C 20 -hydroxyalkyl group, or di- or polyhydroxyalkyl group, where the hydroxyl group is bonded to a primary or secondary carbon atom of the alkyl, and the alkyl may be oxygen, C3-C 10 -Cycloalkyl groups and C3-C 12 -cycloalkenyl group (wherein the cyclic group is -(CH2)n - groups (wherein n=1 to 3); R 3 is H or a linear or branched C1- to C 20 - is an alkyl group; R 4 is H or -OR 8 and; R 5 and R 6 are the same or different, H or hydroxyl (OH), linear or branched C1- to C 20 -Alkyl group (wherein the alkyl group may be interrupted at least once by oxygen), linear or branched C3- to C 20 -Alkenyl groups, and straight or branched C1- to C 20 -hydroxyalkyl groups, where the hydroxyl group is bonded to a primary or secondary carbon atom of the alkyl, where the alkyl may be interrupted at least once by oxygen; R 7 is H, straight or branched chain C1- to C 20 -alkyl groups, where alkyl is selected from the group consisting of oxygen, linear or branched C-C 20 -Alkenyl groups, and straight or branched C1- to C 20 -hydroxyalkyl, or di- or polyhydroxyalkyl, groups, in which the hydroxyl groups are bonded to a primary or secondary carbon atom of the alkyl, and in which the alkyl is optionally interrupted at least once by oxygen, R 8 is H or a linear or branched C1- to C 20 -alkyl group)

[0043] The chromenones of formula (I) effectively enhance the topical efficacy of retinoids. Preferred compounds of formula (I) for use in the methods, HA compositions, or retinoid compositions of the present invention include compounds 1-11 shown below. [ka] TIFF2024529700000007.tif21490

[0044] In certain embodiments, the HA or retinoid composition may contain from about 0.1% to about 2% by weight of at least one chromenone compound of formula (I). If the HA composition also contains a retinoid, preferably the HA composition contains only chromenone compounds. Retinol is the preferred retinoid for use in combination with the compound of formula (I). EXAMPLES

[0045] Clinical Efficacy Studies The hyaluronic acid serum capsule formulation of Table B was utilized in the following clinical efficacy studies. The study was conducted on 33 female subjects to determine if the formulation improved overall fine lines and wrinkles, skin moisture, skin firmness, skin elasticity and skin barrier function immediately after the first use and after 1, 4 and 8 weeks of product use when used once daily.

[0046] Example 1.1 Overall Fine Lines and Wrinkles - Image Analysis Digital images of each subject's face were taken by trained technicians at baseline and after 1, 4, and 8 weeks of product use. Images were analyzed using ImagePro® software to determine changes in overall wrinkle appearance. A decrease in score represented improvement; an increase represented worsening. Table 1.1 summarizes the fine line and wrinkle analysis. [Table 5] When images taken after 1, 4, and 8 weeks of product use were compared to baseline images, there was a mean improvement of 11.8%, 15.8, and 21.4%, respectively, based on image analysis. The improvements observed were highly significant compared to baseline. A total of 100%, 97%, and 100% of subjects showed improvement after 1, 4, and 8 weeks of product use, respectively.

[0047] (Example 1.2) Corneometer® Measurements - Face At baseline, immediately after first use, and after 1, 4, and 8 weeks of product use, Corneometer® measurements were obtained on each subject's face by a trained technician to measure skin moisture content. An increase in Corneometer® measurements indicates improvement. Table 1.2 provides a summary of the Corneometer® measurements. [Table 6] Based on Corneometer® measurements, there was a mean improvement of 73.6%, 118%, 117% and 92.7% when measurements taken immediately after application and after 1, 4 and 8 weeks of product use were compared to baseline measurements, respectively. The improvements observed were highly significant compared to baseline. All subjects showed improvement immediately after application and after 1, 4 and 8 weeks of product use.

[0048] (Example 1.3) Corneometer® Measurements - Arm At baseline, immediately after application, and 24, 48, and 72 hours after application, a trained technician obtained Corneometer® measurements on the volar arm of each subject to measure skin moisture content. An increase in Corneometer® measurements indicates improvement. Table 1.3 provides a summary of the Corneometer® measurements. [Table 7] Based on Corneometer® measurements, there was a mean improvement of 63.9%, 55.1%, 65.6%, and 49.8% when measurements taken immediately after application and 24, 48, and 72 hours were compared to baseline measurements, respectively. The improvements observed were highly significant compared to baseline. A total of 100%, 100%, 97%, and 100% of subjects showed improvement immediately after application, 24 hours, 48 ​​hours, and 72 hours after application.

[0049] Example 1.4 Cutometer® RO Measurements At baseline, and after 1, 4, and 8 weeks of product use, a trained technician obtained Cutometer® measurements for each subject to measure skin firmness. A decrease in measurements indicates improvement. Table 1.4 provides a summary of the Cutometer® measurements. [Table 8] Based on Cutometer® RO measurements, there was a mean improvement of 45.5%, 50.8%, and 36.6%, respectively, when measurements obtained after 1, 4, and 8 weeks of use were compared to baseline measurements. The improvements observed after 1, 4, and 8 weeks of product use were highly significant compared to baseline. A total of 82%, 91%, and 79% of subjects showed improvement after 1, 4, and 8 weeks of use, respectively.

[0050] Example 1.5 Cutometer® R2 measurement At baseline and after 1, 4 and 8 weeks of product use, a trained technician obtained Cutometer® measurements for each subject to measure skin elasticity. An increase in measurements indicates improvement. Table 1.5 provides a summary of the Cutometer® measurements. [Table 9] Based on Cutometer® measurements, there was a mean improvement of 20.5%, 14.4%, and 25.6%, respectively, when measurements obtained after 1, 4, and 8 weeks of product use were compared to baseline measurements. The improvements observed after 1, 4, and 8 weeks of product use were statistically significant compared to baseline. A total of 85%, 64%, and 85% of subjects showed improvement after 1, 4, and 8 weeks of product use, respectively.

[0051] Example 1.6 Tewameter® Measurements At baseline and after 1, 4 and 8 weeks of product use, a trained technician obtained Tewameter® measurements on each subject's face to measure skin barrier function. A decrease in Tewameter® measurements indicates improvement. Table 2.6 provides a summary of the Tewameter® measurements. [Table 10] Based on Tewameter® measurements, there was a mean improvement of 17.2%, 14.3%, and 26.4%, respectively, when measurements obtained after 1, 4, and 8 weeks of product use were compared to baseline measurements. The improvements observed after 1, 4, and 8 weeks of product use were highly significant compared to baseline. A total of 88%, 76%, and 85% of subjects showed improvement after 1, 4, and 8 weeks of product use, respectively.

[0052] Example 1.7 Skin Irritation - Engineer's Evaluation At each visit, a trained technician assessed each subject's facial irritation according to the following scale: This assessment was for safety purposes only and was not used to determine efficacy. Scale for scoring irritation 0 = no irritation + = Barely perceptible irritation is present 1 = Mild irritation present 2 = Moderate irritation present 3 = Significant irritation present 4 = Severe irritation present

[0053] Table 1.7 gives an overview of the irritation ratings. [Table 11] No irritation was observed in any subjects during the course of the study.

[0054] conclusion Based on image analysis, overall fine lines and wrinkles were significantly improved after 1, 4 and 8 weeks of use. Skin moisture on the face and arms was significantly improved immediately after first use, 24, 48 and 72 hours after first use, and after 1, 4 and 8 weeks of use, based on Corneometer measurements. Skin barrier function was significantly improved after 1, 4, and 8 weeks of use, based on Tewameter measurements. Just overnight, 100% of skin was visibly plumper and showed a visible reduction in lines and wrinkles. At 4 weeks, 91% of skin continued to be visibly firmer and 100% showed a visible reduction in wrinkles.

[0055] Example 2 In vitro combination treatment studies The purpose of this study was to evaluate the hyaluronic acid (HA) expression altering activity of RoC® HA serum capsules (i.e., Example 2.0), RoC® retinol serum capsules (i.e., Example 1.0), a commercial HA serum (1.5% HA by weight), and a commercial retinol serum (0.3% retinol by weight) in cultured human epidermal / dermal skin tissue (EpiDerm-FT™) compared to 0.15% retinol-treated tissue. HA levels from media, tissue lysates, HA histology, and gene expression associated with dermal anti-aging effects were quantified using qPCR methods after 24 and 72 hour incubation with the test materials.

[0056] Example 2.1 Skin hydration After incubation, the tissues were fixed and subjected to the usual steps of tissue preparation for histological analysis, i.e. dehydration, paraffin embedding, sectioning and staining with Alcian blue. Histological activity was analyzed using image analysis including blue deconvolution and brightness per cross-sectional area of ​​the dermal layer. The percent change effect of each treatment was calculated compared to the vehicle-only treated tissue group. The results obtained by image analysis of the densitometric changes for each treatment showed that all test materials produced different spectra in HA staining activity.

[0057] [Table 12]

[0058] The results of hyaluronic acid (HA) levels obtained by ELISA showed that 0.15% retinol formulated in DMSO significantly increased HA levels in both medium (34%) and tissue lysate (52%) after 24 hours. RoC® retinol capsules significantly increased HA levels in medium (81%) and tissue lysate (61%) after 24 hours, and in medium (49%) after 72 hours. Commercial retinol serum only significantly increased HA in medium (19%) after 24 hours. Conversely, RoC® HA capsules significantly increased HA levels in medium (66%) and tissue lysate (97%) after 24 hours, and in medium (52%) after 72 hours. Commercial HA serum only significantly increased HA levels in both medium (48%) and tissue lysate (44%) after 24 hours. When RoC® HA capsules were blended in combination with 0.15% retinol, the treatment significantly increased HA levels in tissue lysates by 84% more than either of the individual treatments after 72 hours.In addition, when RoC® HA capsules were blended in combination with RoC® retinol capsules, the treatment did not significantly increase HA levels more than either of the individual treatments. RoC® retinol capsules and a commercial retinol serum product significantly increased the staining intensity of the dermis layer by 143% and 124%, respectively, after 24 hours. In addition, when RoC® HA capsules were blended in combination with 0.15% retinol or RoC® retinol capsules, both treatments significantly increased HA levels in tissue lysates by 121% and 111%, respectively. In contrast, no significant changes were obtained after 72 hours of treatment.

[0059] Example 2.2 Gene expression Gene expression generated by RT-PCR showed that 0.15% retinol formulated in DMSO significantly increased fibronectin (FN1, 45%) gene after 72 hours. RoC® retinol capsules significantly increased hyaluronan synthase 2 (HAS2, 125%) and FN1 (30%) after 24 hours. Commercial retinol serum significantly increased HAS2 (233%) after 24 hours and elastin (ELN, 40%) after 72 hours. Conversely, RoC® HA capsules significantly increased hyaluronan synthase-1 (HAS1, 463%) after 24 hours and ELN (78%) after 72 hours. Commercial HA serum significantly increased HAS2 (298%) after 24 hours and ELN (37%) after 72 hours. Interestingly, when RoC® HA capsules were blended in combination with 0.15% retinol, the treatment significantly increased collagen type I (COL1A1, 48%), collagen type III (COL3A1, 58%), collagen type IV (COL4A1, 79%), ELN (52%), and FN1 (108%) after 72 hours, more than their individual treatments for these genes. In addition, when RoC® HA capsules were blended in combination with RoC® retinol capsules, the treatment significantly increased HAS2 (638%) after 24 hours, COL3A1 (58%), and FN1 (59%) after 72 hours, again more than their individual treatments for these genes.

[0060] [Table 13]

[0061] conclusion Based on this data, both RoC® Retinol and HA capsules produced the best response in HA production in the cultured skin tissue model (EpiDerm-FT™). In addition, RoC® Retinol and HA capsules produced the best response in increasing fibronectin and hyaluronan synthase-1 genes. Commercially available HA and retinol serum produced the best response in increasing elastin and hyaluronan synthase-2 genes. The combination of RoC® HA capsules with 0.15% retinol capsules or RoC® Retinol capsules resulted in greater increases in collagen, elastin, and hyaluronan synthase-2 gene expression compared to their individual treatments. The embodiments shown and discussed herein are intended only to teach those skilled in the art the best way known to the inventor to make and use the invention. Nothing in this specification should be considered as limiting the scope of the invention. All examples presented are representative and non-limiting. As will be appreciated by those skilled in the art in light of the above teachings, the above-described embodiments of the invention can be modified or varied without departing from the invention. It is therefore to be understood that, within the scope of the claims and their equivalents, the invention can be practiced otherwise than as specifically described.

[0062] Further aspects are provided by the subject matter of the following clauses. A cosmetic composition comprising a hyaluronic acid (HA) compound, said composition being anhydrous. The cosmetic composition according to the preceding clause, wherein the HA compound is free hyaluronic acid or a salt thereof. 4. The cosmetic composition of any preceding clause, further comprising konjac glucomannan. The cosmetic composition of any preceding clause, wherein the HA compound is cross-linked with konjac glucomannan. The cosmetic composition of any preceding clause, further comprising a retinoid. 13. The cosmetic composition of any preceding clause, comprising about 0.001% to about 5,000% by weight of a retinoid. 13. The cosmetic composition of any preceding clause, comprising about 0.1% to about 0.5% by weight of a retinoid.

[0063] The cosmetic composition of any preceding clause, wherein the retinoid is selected from retinol, retinal, tretinoin, isotretinoin, alitretinoin, etretinate acitretin, adapalene, bexarotene, and tazarotene, and trifarotene. The cosmetic composition of any preceding clause, wherein the retinoid is retinol. The cosmetic composition of any preceding clause, comprising about 0.001% to about 3.000% by weight of the HA compound. 2. The cosmetic composition of any one of the preceding clauses, comprising about 0.006% by weight of the HA compound.

[0064] The cosmetic composition of any preceding clause, wherein the HA has a molecular weight of about 1 kDa to about 10,000 kDa. The cosmetic composition of any preceding clause, wherein the HA compound comprises HA having a molecular weight of about 10 kDa to about 40 kDa. The cosmetic composition of any preceding clause, wherein the HA compound comprises HA having a molecular weight of about 25 kDa to 100 kDa. The cosmetic composition of any preceding clause, wherein the HA compound comprises HA having a molecular weight of about 1 kDa to about 20 kDa. A method of improving skin comprising topically administering to the skin of a subject a hyaluronic acid (HA) compound and a retinoid in one or more compositions, wherein improving the skin comprises (a) increasing gene expression of one or more of collagen, elastin, fibronectin, and hyaluronic acid in the subject's skin, and / or (b) improving the look, feel and / or appearance of the skin by hydrating the skin; plumping the skin, improving skin elasticity; improving the appearance of fine lines and wrinkles; reducing the depth, length or width of fine lines and wrinkles; and / or smoothing the skin, and / or (c) increasing the level and / or replenishing or increasing the production of hyaluronic acid at and / or within the skin.

[0065] The method according to the preceding clause, wherein the HA compound is hyaluronic acid or a salt thereof. The method of any preceding clause, wherein the retinoid is selected from retinol, retinal, tretinoin, isotretinoin, alitretinoin, etretinate, acitretin, adapalene, bexarotene, tazarotene, and trifarotene. The method of any preceding clause, wherein the retinoid is retinol. The method of any preceding clause, further comprising administering konjac glucomannan. The method of any preceding clause, wherein the HA compound is cross-linked with konjac glucomannan. The method of any preceding clause, wherein the composition or compositions are anhydrous. The method according to any preceding clause, improving fine lines and wrinkles of the skin, increasing skin firmness, increasing skin plumpness, increasing skin smoothness, and / or increasing skin elasticity.

[0066] 23. The method according to any preceding clause, wherein the method increases hydration in the skin and / or increases the level of hyaluronic acid on the surface and / or within the skin. The method of any preceding clause, wherein the collagen, elastin, fibronectin, and hyaluronic acid gene expression is selected from one or more of the following gene expression: hyaluronic acid synthase 1 (HAS1), hyaluronic acid synthase 2 (HAS2), type I collagen (COL1A1), type III collagen (COL3A1), and type IV collagen (COL4A1), elastin (ELN), and fibronectin (FN1). The method of any preceding clause, wherein the HA compound and the retinoid are administered in separate compositions. The method of any preceding clause, wherein the HA compound and the retinoid are administered in the same composition. The method of any preceding clause, wherein one of the one or more compositions comprises from about 0.001% to about 5.000% by weight of a retinoid. The method of any preceding clause, wherein one of the one or more compositions comprises about 0.1% to about 0.5% by weight of a retinoid.

[0067] The method of any preceding clause, wherein one of the one or more compositions comprises about 0.2% by weight of a retinoid. The method of any preceding clause, wherein one of the one or more compositions comprises from about 0.001% to about 3.000% by weight of the HA compound. The method of any preceding clause, wherein one of the one or more compositions comprises about 0.006% by weight of the HA compound. The method of any preceding clause, wherein the HA compound has a molecular weight of about 1 kDa to about 10,000 kDa. The method of any preceding clause, wherein the HA compound comprises an HA compound having a molecular weight of about 25 kDa to 100 kDa. The method of any preceding clause, wherein the HA compound comprises an HA compound having a molecular weight of about 1 kDa to about 20 kDa. The method of any preceding clause, wherein the HA compound comprises an HA compound having a molecular weight of about 40 kDa or less.

[0068] The method of any preceding clause, wherein the HA compound comprises an HA compound having a molecular weight of about 10 kDa to about 40 kDa. The method of any preceding clause, wherein the HA compound is administered prior to the retinoid. The method of any preceding clause, wherein the HA compound and the retinoid are administered simultaneously. The method of any preceding clause, wherein the one or more compositions are administered in the evening. The method of any preceding clause, wherein a first composition of the one or more compositions is administered in the morning and a second composition of the one or more compositions is administered in the evening. The method of any preceding clause, wherein the one or more compositions are administered daily. 2. The method according to any preceding clause, wherein the skin is facial skin, neck skin, or both facial and neck skin. The method of any preceding clause, wherein the skin is cleansed prior to administration of the hyaluronic acid and the retinoid. A method of improving the skin comprising administering a composition according to any preceding clause to improve the look, feel and / or appearance of the skin. A method of improving the skin comprising topically administering hyaluronic acid and a retinoid to the skin to improve the look, feel and / or appearance of the skin.

[0069] The method of any preceding clause, wherein improving the look, feel and / or appearance of the skin comprises one or more of hydrating the skin, plumping the skin, improving skin elasticity, improving the appearance of fine lines and wrinkles, reducing the depth, length or width of fine lines and wrinkles, and smoothing the skin. A method of improving skin comprising topically administering a hyaluronic acid (HA) compound in a composition to the skin of a subject, wherein the improvement of the skin comprises (a) increasing the genetic expression of one or more of collagen, elastin, fibronectin, and hyaluronic acid in the subject's skin, and / or (b) improving the look, feel and / or appearance of the skin by hydrating the skin; plumping the skin, improving skin elasticity; improving the appearance of fine lines and wrinkles; reducing the depth, length or width of fine lines and wrinkles; and / or smoothing the skin, and / or (c) increasing the level and / or replenishing or increasing the production of hyaluronic acid at and / or within the skin. The method according to the preceding clause, wherein the composition is a cream, gel, lotion, emulsion, or serum. The method of any preceding clause, wherein the composition is anhydrous. The method of any preceding clause, wherein the HA compound has a molecular weight of about 1 kDa to about 10,000 kDa.

[0070] The method of any preceding clause, wherein the HA compound comprises an HA compound having a molecular weight of about 25 kDa to 100 kDa. The method of any preceding clause, wherein the HA compound comprises an HA compound having a molecular weight of about 1 kDa to about 20 kDa. The method of any preceding clause, wherein the HA compound comprises an HA compound having a molecular weight of about 40 kDa or less. The method of any preceding clause, wherein the HA compound comprises an HA compound having a molecular weight of about 10 kDa to about 40 kDa.

[0071] The method of any preceding clause, wherein the composition is a composition according to any preceding clause. The method of any preceding clause, further comprising administering a retinoid, wherein the HA compound and the retinoid are present in one or more compositions.

Claims

1. A cosmetic composition comprising a hyaluronic acid (HA) compound, said composition being anhydrous.

2. A method for improving skin, comprising topically administering to the skin of a subject a hyaluronic acid (HA) compound and a retinoid in one or more compositions, wherein the improvement of the skin comprises (a) increasing gene expression of one or more of collagen, elastin, fibronectin, and hyaluronic acid in the subject's skin, and / or (b) improving the look, feel, and / or appearance of the skin by hydrating the skin; plumping the skin; improving skin elasticity; improving the appearance of fine lines and wrinkles; reducing the depth, length, or width of fine lines and wrinkles; and / or smoothing the skin, and / or (c) increasing the level and / or replenishing or increasing the production of hyaluronic acid on the surface of and / or within the skin.

3. 1. A method of improving skin comprising topically administering hyaluronic acid and a retinoid to said skin to improve the look, feel and / or appearance of said skin.

4. 1. A method for improving skin, comprising topically administering a hyaluronic acid (HA) compound in a composition to the skin of a subject, wherein the improvement of the skin comprises (a) increasing gene expression of one or more of collagen, elastin, fibronectin, and hyaluronic acid in the skin of the subject, and / or (b) improving the look, feel, and / or appearance of the skin by hydrating the skin; plumping the skin; improving skin elasticity; improving the appearance of fine lines and wrinkles; reducing the depth, length, or width of fine lines and wrinkles; and / or smoothing the skin, and / or (c) increasing the level and / or replenishing or increasing the production of hyaluronic acid on the surface of and / or within the skin.