Method for improving the penetration of vitamin B3 compounds into the skin

Abstract

The present invention discloses a method for improving the penetration of a vitamin B3 compound into the skin. The method involves the following skin care regimen, in which at least two skin care compositions are used in sequence to treat a target skin portion for a desired skin health or appearance benefit. The first composition applied to the skin is a low-pH skin care composition containing a first concentration of the vitamin B3 compound. The second skin care composition applied to the skin is a conventional skin care composition containing a higher concentration of the vitamin B3 compound than the first composition. When applied in the appropriate sequence, the regimen results in an unexpectedly high vitamin B3 flux into the skin.

Description

Technical Field

[0001] The present invention generally relates to a method for improving vitamin B 3 More specifically, the present invention relates to a skin care regimen in which a compound containing vitamin B12 is applied to the skin. 3 A low pH skin care composition containing a compound and then applied with a higher amount of vitamin B 3 Another skin care composition comprising the compound. Background Art

[0002] Skin is the first line of defense against environmental insults that would otherwise damage sensitive underlying tissues and organs. For example, skin maintains a relatively water-impermeable barrier between an organism and its environment to prevent dehydration. In addition, skin plays a key role in a person's physical appearance. Generally speaking, most people would like to have younger, healthier-looking skin. And for some of these people, telling signs of skin aging, such as thinning skin, wrinkles and age spots are undesirable hints of lost youth.

[0003] Both intrinsic and extrinsic factors can lead to a decline in the appearance and performance of the skin. For example, as the skin ages naturally, the cells and blood vessels that supply the skin usually decrease and the dermis-epidermal junction flattens, which leads to thinning and general degradation of the skin barrier function. In addition, lifestyle choices and exposure to the environment (e.g., ultraviolet radiation, pollution, cigarette smoke, smog, wind, heat, low humidity, harsh surfactants, abrasives) may lead to premature appearance of age spots and uneven skin tone. Therefore, in today's youth-oriented society, processing signs of skin aging has become a rapidly developing industry. Treatments range from cosmetic creams and moisturizers to various forms of cosmetic surgery.

[0004] Many natural and synthetic agents are known for use in skin care compositions that are marketed to treat various skin conditions, especially those associated with aging. An example of a well-known class of skin care agents is vitamin B12. 3Compounds such as niacinamide have been used in the cosmetic industry to provide a variety of skin health benefits. For example, US 5,833,998 discloses the use of niacinamide for regulating the oily / glossy appearance of the skin, and US 5,968,528 discloses the use of niacinamide for regulating signs of skin aging. Recent studies have shown that low-pH compositions containing niacinamide can improve efficacy, for example, as described in US Patent 9,833,398 and US Publication 2020 / 0009123. However, low-pH niacinamide compositions can sometimes suffer from stability problems due to their ionization and ability to complex with other components in the composition. Thus, formulating with niacinamide at low pH may limit formulation flexibility. Additionally, without being bound by theory, it is believed that the ionized form of niacinamide can inhibit penetration through the skin barrier, which is composed of highly keratinized keratinocytes in a lipid matrix.

[0005] Accordingly, there is a desire to provide a method for improving the skin penetration of vitamin B 3 compounds. There is also a desire to improve the skin penetration of stable vitamin B 3 compounds from low-pH compositions. SUMMARY OF THE INVENTION

[0006] A method for improving the skin penetration of vitamin B 3 compounds, comprising: identifying a target skin portion desiring a skin health or appearance benefit; applying a low-pH skin care composition to the target skin portion, wherein the low-pH skin care composition comprises a first concentration of vitamin B 3 compounds; and subsequently applying a second skin care composition to the target skin portion, wherein the second skin care composition comprises a second concentration of vitamin B 3 compounds, and the second concentration is higher than the first concentration. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Figure 1 Shows the results of a skin penetration assay.

[0008] Figure 2 Shows the results of a skin penetration assay.

[0009] Figure 3 Shows the results of an in vitro low irritation test. DETAILED DESCRIPTION

[0010] The ability of vitamin B 3 compounds to provide skin health and / or appearance benefits is well known. However, in order to provide the desired benefits, vitamin B 3 compounds must be able to penetrate the skin, which is generally determined by Fick's law of diffusion. Fick's law of diffusion provides for the vitamin B passing through the skin3 The flux of the compound is proportional to the concentration difference of vitamin B 3 The flux of the compound is proportional to the concentration difference. Fick's law can be applied using the following formula:

[0011] J = KD(ΔC / h),

[0012] Where:

[0013] J is the material flux;

[0014] K is the partition coefficient from the formulation;

[0015] D is the diffusion coefficient into the skin;

[0016] ΔC is the concentration difference; and

[0017] H is the distance traveled (e.g., stratum corneum thickness).

[0018] Thus, when applying to the skin (e.g., as a regimen (i.e., sequentially)) a combination of compositions comprising different concentrations of vitamin B 3 compound, the lower concentration composition effectively dilutes the higher concentration composition, which should result in a lower overall flux of niacinamide through the skin compared to the higher concentration composition alone. However, it has been surprisingly found that by first applying to the skin a low pH composition containing vitamin B 3 compound and then applying a second skin care composition containing a higher concentration of niacinamide, the flux of vitamin B 3 compound through the skin is much higher than expected and, in some cases, even exceeds the individual flux of the higher concentration composition. This finding is particularly unexpected because the low pH formulation promotes greater ionization of vitamin B 3 thereby reducing its expected permeability. This synergistic increase in the flux of vitamin B 3 through the skin provides many potential beneficial effects such as formulation flexibility and improved efficacy of skin care compositions and / or regimens.

[0019] References in the specification to "embodiments" or similar terms mean that the specific materials, features, structures, and / or properties described in connection with that embodiment are included in at least one embodiment, optionally in multiple embodiments, but this does not mean that all embodiments include the described materials, features, structures, and / or properties. Additionally, the materials, features, structures, and / or properties may be combined in any suitable manner in different embodiments, and the materials, features, structures, and / or properties may be omitted or substituted for those described. Thus, unless otherwise stated or declared to be incompatible, the embodiments and aspects described herein may include elements or components of other embodiments and / or aspects or may be combined with elements or components of other embodiments and / or aspects even though not explicitly illustrated in the combination.

[0020] In all embodiments, unless otherwise specifically stated, all percentages are by weight of the cosmetic composition. Unless otherwise specifically stated, all ratios are weight ratios. All ranges are inclusive and combinable. The number of significant figures represents neither a limitation on the indicated amounts nor on the accuracy of the measurements. All numerical values should be understood to be modified by the word "about" unless otherwise specifically indicated. Unless otherwise indicated, all measurements are understood to be made at about 25 °C and under ambient conditions, where "ambient conditions" means conditions at about 1 atmosphere and about 50% relative humidity. All numerical ranges are narrower ranges that include the end values; the upper and lower limits of the described ranges are interchangeable to further form ranges not explicitly described.

[0021] The compositions of the present invention may contain the essential components described herein, as well as optional ingredients, consist essentially of, or consist of the same. As used herein, "consisting essentially of" means that the composition or component may contain additional ingredients, provided that the additional ingredients do not substantially alter the basic and novel characteristics of the composition or method claimed. As used in the specification and the appended claims, unless the context clearly indicates otherwise, the singular forms "a", "an", and "the" are intended to include the plural forms as well.

[0022] Definition

[0023] "Apply" or "application" as used in reference to a composition means applying or spreading the composition of the present invention onto the surface of human skin, such as the epidermis.

[0024] "Cosmetic agent" means any substance and any of its components intended to be rubbed, poured, sprayed, atomized, introduced, or otherwise applied to the body of a mammal or any part thereof to provide a cosmetic effect. Cosmetic agents may contain substances generally recognized as safe (GRAS) by the U.S. Food and Drug Administration, food additives, and materials used in non-cosmetic consumer products, including over-the-counter drugs.

[0025] "Effective amount" means the amount of a compound or composition sufficient to induce a positive beneficial effect on keratinous tissue during treatment. The positive beneficial effect may be a health, appearance, and / or sensory beneficial effect, which includes the beneficial effects disclosed herein, either independently or in combination. In vitro and / or ex vivo methods may be used to demonstrate the effective amount of a compound or composition.

[0026] "Improve appearance" means providing a measurable, desirable change or beneficial effect in the appearance of the skin, which may be quantified, for example, by a reduction in redness, inflammation, and / or plaque scale.

[0027] "Low pH" means a pH less than 5.0 (e.g., 1.5 to 4.9, 2.0 to 4.5, 2.5 to 4.0, or 3.5 to 4.0). Suitable methods for determining the pH of a composition are described in more detail below.

[0028] "Neutral pH" refers to a pH between 5.0 and 8.0.

[0029] "Skin care" means regulating and / or improving the condition of the skin. Some non-limiting examples include improving the appearance and / or feel of the skin by providing a smoother, more even appearance and / or feel; increasing the thickness of one or more layers of the skin; improving the elasticity or resilence of the skin; improving the firmness of the skin; and reducing the oily, shiny, and / or dull appearance of the skin, improving the hydration or moisturization state of the skin, improving the appearance of fine lines and / or wrinkles, improving skin flaking or peeling, plumping the skin, improving the skin barrier properties, improving skin tone, reducing the appearance of redness or skin blotches, and / or improving the brightness, radiance, or translucency of the skin.

[0030] "Skin care active" means a compound or combination of compounds that, when applied to the skin, provides immediate and / or long-term beneficial effects to the skin or cell types normally present therein. Skin care actives can regulate and / or improve the skin or its associated cells (e.g., improving skin elasticity, hydration, skin barrier function, and / or improving cell metabolism).

[0031] "Skin care composition" means a composition that contains a skin care active and regulates and / or improves the condition of the skin.

[0032] "Synergism" and variations thereof mean that the effect provided by the combination of two or more compounds, materials, and / or compositions is greater than their individual expected effects. For example, synergism can be demonstrated by the skin penetration of vitamin B 3 compounds in two compositions of the compounds being greater than the expected skin penetration. 3 compounds.

[0033] As used herein, "treatment period" means the length of time and / or frequency of application of a material or composition to a target skin surface.

[0034] "Vehicle control" means a negative control that is the same as the test composition, except that it does not contain the specific active of interest (e.g., does not contain vitamin B 3 compound).

[0035] Solution

[0036] The method of the present disclosure includes sequentially applying at least two skin care compositions to a target skin portion to be treated. The first skin care composition is a low pH composition that contains niacinamide and optionally other ingredients commonly used in cosmetic skin care compositions. The low pH composition is formulated to provide skin health or appearance benefits while providing good sensory properties and a low potential for skin irritation. The second skin care composition is applied after the low pH composition (e.g., after 30 seconds to 5 minutes). The second skin care composition contains a higher concentration of vitamin B 3 compounds and optionally includes other optional ingredients commonly used in skin care compositions. The first composition and the second composition are described in more detail below. Although the present scheme is described in the context of sequentially applying two skin care compositions, it should be understood that the method contemplates sequentially applying any number of skin care compositions after the low pH composition.

[0037] The method of the present invention involves identifying a target skin portion of a person in need of treatment or desiring treatment (e.g., a skin portion exhibiting signs of skin aging such as fine lines, wrinkles, dryness, uneven skin tone, hyperpigmented spots), and applying an effective amount of a first skin care composition and a second skin care composition to the target skin portion during treatment. The effective amount of the composition can vary based on the skin benefits desired by the user, the size of the treatment area, and / or the concentration of the skin care active (e.g., vitamin B 3 compounds). In some cases, the effective amount can be in the range of 0.1 g to 5 g (e.g., 0.2 g to 4 g, 0.3 g to 2 g, or even 0.5 g to 1 g). The target skin portion can be on the facial skin surface (such as the forehead, perioral area, chin, periorbital area, nose, and / or cheeks) or another part of the body (e.g., hands, arms, legs, back, chest). In some cases, a target skin portion can be selected that does not currently exhibit signs of skin aging (such as hyperpigmented spots or uneven skin tone), but is a skin area that typically exhibits such characteristics with age. In these cases, the low pH composition can be used to help prevent the occurrence of such undesirable skin characteristics.

[0038] The composition may be topically applied to the target skin portion in need of treatment at least once a day, twice a day, or more frequently during the treatment period, and, if desired, to the surrounding skin. When applied twice a day, the first and second applications are separated by at least 1 to 12 hours. Generally, the composition may be applied in the morning and / or before bedtime at night. When used according to the methods herein, the compositions of the invention can improve the appearance and / or function of the skin, e.g., by improving skin texture. Improvement in skin texture can be provided, for example, by reducing pore size, reducing skin roughness, reducing the presence and / or size of wrinkles, combinations thereof, and the like.

[0039] The treatment period is desirably of sufficient duration for the low pH composition to improve the appearance and / or function of the target skin portion. The treatment period generally lasts at least 1 week (e.g., about 2 weeks, 4 weeks, 8 weeks, or even 12 weeks). In some cases, the treatment period can be extended to multiple months (i.e., 3 to 12 months). In some cases, the composition is applied at least once a day or even twice a day for most days of the week (e.g., at least 4 days, 5 days, or 6 days per week) during a treatment period of at least 2 weeks, 4 weeks, 8 weeks, or 12 weeks.

[0040] The step of applying the composition can be achieved by topical application. With respect to the application of the composition, the terms “topical,” “topically,” “topical application” refer to delivering the composition to the target area (e.g., a psoriasis plaque) while minimizing delivery to the skin surface not desired to be treated. The composition can be applied to and gently rubbed into the skin area. The form of the composition or dermatologically acceptable carrier should be selected to facilitate topical application. While some embodiments herein contemplate topical application of the composition to a particular area, it should be understood that the compositions herein can be applied more generally or broadly to one or more skin surfaces. In certain embodiments, the compositions herein can be used as part of a multi-step beauty regimen, where the compositions of the invention can be applied before and / or after one or more other compositions.

[0041] Low pH composition

[0042] The skin care compositions herein are low pH compositions intended for topical application to human skin to improve the appearance and / or function of the skin. In some cases, the low pH compositions of the invention can be used for cosmetic (i.e., non-therapeutic) treatment of a variety of skin conditions such as hyperpigmentation (e.g., age spots), uneven skin tone, pale-looking skin, dull skin, erythema, dry skin, sebum secretion, rough texture, fine lines, wrinkles, keratosis, combinations of these conditions, and the like. In some cases, the low pH composition may be particularly suitable for improving hyperpigmented spots, uneven skin tone, and / or pale-looking skin.

[0043] The low pH composition comprises an effective amount of vitamin B 3 compounds, a polymeric thickener that can tolerate a low pH environment, a salt / acid pH buffering system (e.g., lactic acid / sodium lactate and / or glycolic acid / sodium gluconate), and optionally a low molecular weight silicone oil. The composition may optionally comprise a silicone emulsifier and other ingredients commonly present in topical skin care compositions. Without being limited by theory, it is believed that the combination of these ingredients provides an effective skin care composition having good sensory properties and being mild to the skin.

[0044] The low pH compositions herein can be prepared by mixing the ingredients with a dermatologically acceptable carrier using conventional methods known to those skilled in the art. The low pH compositions can be provided in various product forms, such as solutions, suspensions, lotions, creams, gels, toners, bars, sprays, aerosols, ointments, cleansing liquid detergents and solid bars, pastes, foams, mousses, shaving creams, wipes, strips, patches, electric patches, hydrogels, film-forming products, facial and skin masks (with and without insoluble sheets), etc. The composition form can conform to the specific dermatologically acceptable carrier selected. In some cases, the low pH compositions herein can be in the form of a serum. A serum is a form of a topical skin care composition in a relatively concentrated formulation, which typically has a lower viscosity than conventional cream or lotion-type skin care compositions. In some cases, the serum can be provided in the form of a low viscosity liquid, which is marketed specifically for particular skin conditions and / or for the first step in a skin care regimen. The serum products herein can have a dynamic viscosity of from 1 centipoise (cP) to 30,000 cP (e.g., 50 cP to 10,000 cP or 100 cP to 7,500 cP, 200 cP to 5,000 cP, or 300 cP to 2,500 cP) at 25 °C. The viscosity of the low pH compositions herein is determined according to the Rheology Method provided in the Methods section below.

[0045] It has been found that at least some consumers desire a skin care serum having a certain balance of transparency and opacity. If the serum is too transparent, it may look too much like water, and consumers may question the efficacy of the product. However, if the serum is too opaque, consumers may think that the product will not provide the refreshing, cleansing feeling expected from a serum. Accordingly, the low pH serum products herein have an opacity between 15 and 75 (e.g., between 20 and 60 or between 25 and 50) according to the Opacity Test described in more detail below. In some cases, it may be desirable to limit the amount of hydrocarbon oils (such as fatty alcohols) and mineral oils present in the low pH serum, as these ingredients can unfavorably increase the opacity of the serum. Accordingly, it may be desirable to provide a low pH serum that is free or substantially free of hydrocarbon oils (e.g., less than 3%, 2%, 1%, 0.5%, or even 0%). Some non-limiting examples of suitable low pH compositions are described in co-pending U.S. Serial No. 16 / 891,491.

[0046] Vitamin B 3 Compound

[0047] The compositions of the present invention comprise a safe and effective amount of vitamin B 3 compounds for modulating a variety of skin conditions, e.g., as described in U.S. Patent No. 5,939,082. The compositions herein can contain from 0.1% to 10% by weight (e.g., from 0.5% to 5% or from 1% to 4%) of vitamin B 3 compounds, based on the weight or volume of the composition.

[0048] As used herein, "vitamin B 3 compounds" refers to compounds having the formula:

[0049]

[0050] wherein:

[0051] R is CONH 2 (i.e., nicotinamide), COOH (i.e., nicotinic acid) or CH 2 OH (i.e., nicotine alcohol); derivatives thereof; and salts of any of the foregoing substances. Exemplary derivatives of vitamin B 3 compounds include nicotinic acid esters, which include non-vasodilatory nicotinic acid esters (e.g., tocopheryl nicotinate, myristyl nicotinate), nicotinamide riboside, nicotinoyl amino acids, nicotine alcohol esters of carboxylic acids, nicotinic acid N-oxides and nicotinamide N-oxides. In some cases, vitamin B 3 compounds such as nicotinamide can have improved efficacy at lower pHs, e.g., as described in U.S. Patent Publication No. 2020 / 0009123.

[0052] In some cases, it may be desirable for the ring nitrogen of the vitamin B 3 compound to be "uncomplexed" (e.g., chemically unbound and / or unhindered) in the composition and / or prior to administration to the target skin surface. For example, the compositions herein can be free or substantially free (i.e., less than 3%, 2%, 1% or even less than 0.5%) of salts or complexes of the vitamin B 3 compound. Exemplary methods for minimizing or preventing the formation of undesirable salts and / or complexes include excluding substances that form substantially irreversible complexes or other undesirable complexes with the vitamin B 3 compound in the composition, pH adjustment, ionic strength adjustment, use of surfactants, and implementing formulation procedures in which the vitamin B 3 compound and the substances complexed therewith are in different phases.

[0053] Low pH buffer system

[0054] When providing a low-pH composition for topical administration to the skin, it is important to include a buffering system to help maintain the pH of the composition after it has been applied to the skin. On average, human skin pH is typically in the range of about 5.0 to 6.0. To maintain this pH, human skin has evolved a natural buffering system that resists pH changes. Thus, when a low-pH composition is applied to the skin, the skin's natural buffering system will attempt to adjust the pH of the composition to match the skin's natural pH. Without the addition of a buffering system, the low-pH composition may not provide the desired skin care benefits.

[0055] The low pH buffer system of the present disclosure includes an acid buffer. A variety of acids are known to be useful in skin care compositions. For example, alpha-hydroxy acids (e.g., citric acid, glycolic acid, malic acid, and lactic acid), beta-hydroxy acids (e.g., salicylic acid and propionic acid), and polyhydroxy acids (e.g., gluconic acid) are commonly used as exfoliants. However, some acids are stronger than others, and / or some individuals may be more sensitive to certain concentrations of acids than others. Both of these factors can increase the risk of skin irritation caused by low pH compositions containing acids. Some non-limiting examples of acids that may be suitable as the acid buffer of the present disclosure are lactic acid, gluconic acid, lactobionic acid, and / or maltobionic acid. Lactic acid and gluconic acid may be particularly suitable because they tend to be relatively mild to the skin (i.e., less likely to cause skin irritation) compared to other acids. However, lactic acid and gluconic acid are still strong enough to provide the desired low pH in the compositions of the present invention. Additionally, compositions containing lactic acid and / or gluconic acid can provide skin benefits and may provide additional skin benefits, such as improving the skin's natural moisturizing factor and / or stimulating collagen regeneration to help improve the visible signs of skin aging. The low pH compositions of the present disclosure may include from 0.5% to 5% of a suitable acid buffer. In some cases, the low pH composition may include from 0.75% to 4%, from 1% to 3%, or from 1.5% to 2.5% of the acid buffer. It should be understood that the acid buffer can be added in a form that is readily convertible to the desired acid. For example, glucono-delta-lactone and other gluconic acid precursors that are readily convertible to gluconic acid in the compositions of the present invention are considered to be gluconic acid for the purposes of the present invention.

[0056] The low pH buffer system of the present disclosure comprises a suitable salt buffer, which may depend on the selected acid buffer. For example, when the acid buffer is lactic acid, it may be desirable to use sodium lactate, and / or when the acid buffer is gluconic acid, it may be desirable to use sodium gluconate. Other non-limiting examples of salts that may be suitable for use herein include additional salt buffers selected from: calcium lactate gluconate, potassium lactate, zinc lactate, and potassium gluconate. The salt buffer may be present in any amount suitable to provide buffering capacity to maintain the desired low pH of the composition for at least 1 minute after application to the skin and for at least 1 minute after application (e.g., 5, 10, 15, 30, 60, or even 120 minutes or longer after application) to provide sufficient time for the active ingredient in the composition to penetrate the skin. In some cases, the salt buffer may be present in the low pH composition in an amount of 0.25% to 4% (e.g., 0.5% to 3%, 0.75% to 2%, or 1% to 1.75%). In some cases, the salt buffer may be present in a weight ratio of acid to salt of 1:10 to 10:1. It may be desirable to use the L-enantiomeric form of the acid and / or salt buffer, as it is the form that is naturally present in the body. Sodium lactate may be particularly suitable as a salt buffer, as it can also act as a humectant to help hydrate the skin. Of course, it should be understood that the compositions of the present invention may optionally contain other pH buffers known for use in skin care compositions.

[0057] Thickener

[0058] The low pH compositions of the present disclosure comprise a polymeric thickener that can tolerate a low pH electrolytic environment. That is, the thickener will not lose its ability to thicken or stabilize the composition at low pH in the presence of an acid-salt buffer system. It is known that some conventional neutralized thickeners degrade and / or lose their ability to properly thicken the composition at lower pHs and / or in the presence of acid-salt buffers (e.g., lactic acid / sodium lactate and gluconic acid / sodium gluconate). For example, some neutralized thickeners degrade in a low pH environment. On the other hand, fatty alcohol thickeners such as cetyl alcohol and stearyl alcohol are generally stable at low pH, but tend to impart an undesirable turbidity or opacity to the composition when in the form of serums, slurries, etc. It has also been found that certain anionic polymeric thickeners can provide suitable tolerance to a low pH environment, but cannot tolerate a buffer system formed by the combination of an acid and a salt. Thus, in some cases, the low pH compositions described herein may be free or substantially free of neutralized thickeners, fatty alcohol thickeners, and anionic thickeners. The thickener may be present in an amount of 0.0001% to 25% by weight of the composition (e.g., 0.001% to 20%, 0.01% to 10%, 0.5% to 7%, or 1% or 5%).

[0059] Other non-limiting examples of thickeners or water structuring agents that can be used alone or in combination herein include natural or synthetic gums, polysaccharides, carboxylic acid polymers, polyacrylamide polymers, sulfonated polymers, and copolymers thereof. Additional examples include modified gums, celluloses, and superabsorbent polymers. The term "superabsorbent polymer" should be understood to mean a polymer that in its dry state is capable of spontaneously absorbing at least 20 times its own weight of an aqueous fluid, particularly water and especially distilled water. Suitable polysaccharides include alkyl hydroxyalkyl cellulose ethers, such as hydroxypropyl methylcellulose stearoxy ether. This material is sold under the trade names SANGELOSE 60L and 90L by Daido Chemical Corp. Another suitable polysaccharide includes hydrophobically modified starch, such as modified potato starch. This material is sold under the trade name STRUCTURE SOLANACE by Nouryon. Another polymer includes a crosslinked polymer, the monomers of which are at least partially composed of acryloyldimethyltaurine monomers, such as, for example, sodium polyacryloyldimethyltaurate sold by Clariant under the trade name ARISTOFLEX SILK.

[0060] It has now been found that certain anionic polymer thickeners can provide suitable tolerance to low pH environments and impart desired feel and opacity characteristics to the composition. Thus, a particularly suitable example of an anionic thickener is polyacrylate cross-polymer-6, which is commercially available from Seppic, France, as SEPIMAX ZEN.

[0061] Viscosity-reducing oil

[0062] In some cases, when a low pH composition is applied to the target skin portion, the anionic polymer thickener can impart an undesired sticky feel. It has been found that adding certain oils (e.g., low molecular weight hydrocarbon oils or silicone oils) can reduce or prevent this sticky feel. Low molecular weight silicone oils may be particularly desirable because they tend to provide a smooth, velvety feel that consumers prefer, while hydrocarbon oils can sometimes feel greasy. The molecular weight of a silicone oil depends on the length of its silicone polymer chain, which is also directly proportional to the viscosity of the silicone oil. Thus, low molecular weight silicone oils suitable for use in the low pH compositions of the present invention have a kinematic viscosity of 100 cSt or less at 25 °C (e.g., 1 cSt to 90 cSt, 5 cSt to 50 cSt, or even 10 cSt to 30 cSt). Kinematic viscosity is a common way to classify silicone oils and can be obtained from material suppliers. A particularly suitable example of a low molecular weight silicone oil is 5 cSt polydimethylsiloxane fluid. As used herein, the term "polydimethylsiloxane" means a polydimethylsiloxane compound having the following formula:

[0063]

[0064] Second skin care composition

[0065] The second skin care composition for the present scheme is not particularly limited and can include a wide variety of skin care compositions, which contain vitamin B 3 compounds and are suitable for topical application to the skin. The second skin care composition can be provided in various product forms, including but not limited to solutions, suspensions, lotions, creams, gels, toners, bars, pen-shaped products, sprays, aerosols, ointments, cleansing liquid detergents (rinse-off or leave-on), and solid bars, foams, powders, mousses, shaving creams, wipes, strips, patches, hydrogels, film-forming products, facial and skin masks (with and without insoluble sheets), cosmetics such as foundation, eyeliner, and eyeshadow, etc. The composition form can conform to the specific dermatologically acceptable carrier selected (if present in the composition).

[0066] Dermatologically acceptable carrier

[0067] The low pH and second skin care compositions herein may contain a dermatologically acceptable carrier ("carrier"). The phrase "dermatologically acceptable carrier" means that the carrier is suitable for topical application to keratinized tissue, has good aesthetic properties, is compatible with the active substances in the composition, and does not cause any unreasonable safety or toxicity problems. In one embodiment, the carrier is present in an amount of about 50% to about 99%, about 60% to about 98%, about 70% to about 98%, or about 80% to about 95% by weight of the composition.

[0068] The carrier can be in various forms. In some cases, the solubility or dispersibility of components (such as extracts, sunscreen active substances, additional components) can determine the form and characteristics of the carrier. Non-limiting examples include simple solutions (such as aqueous or anhydrous), dispersions, emulsions, and solid forms (such as gels, bars, flowable solids, or amorphous materials). In some cases, the dermatologically acceptable carrier is in the form of an emulsion. The emulsion can have a continuous aqueous phase (such as water-in-oil or water-in-oil-in-water emulsion) or a continuous oil phase (such as oil-in-water or oil-in-water-in-oil emulsion). The oil phase of the present invention can include silicone oils, non-silicone oils (such as hydrocarbon oils, esters, ethers), and mixtures thereof. The aqueous phase generally contains water and water-soluble components (such as water-soluble humectants, conditioners, antimicrobial agents, wetting agents, and / or other skin care active substances). However, in some cases, the aqueous phase can contain components that are not water, including but not limited to water-soluble humectants, conditioners, antimicrobial agents, wetting agents, and / or other water-soluble skin care active substances. In some cases, the non-aqueous components of the composition include wetting agents such as glycerol and / or other polyols.

[0069] In some cases, the compositions herein are in the form of oil-in-water (“O / W”) emulsions that provide a mild and non-greasy sensory feel. Suitable O / W emulsions herein may comprise a continuous aqueous phase greater than 50% by weight of the composition, with the remainder being a dispersed oil phase. The aqueous phase may comprise from 1% to 99% water, based on the weight of the aqueous phase, and any water-soluble and / or water-miscible components. In these cases, the dispersed oil phase will generally be present at less than 30% by weight of the composition (e.g., 1% to 20%, 2% to 15%, 3% to 12%, 4% to 10%, or even 5% to 8%) to help avoid some of the undesirable sensory effects of an oily composition. The oil phase may include one or more volatile oils and / or non-volatile oils (e.g., vegetable oils, silicone oils, and / or hydrocarbon oils). Some non-limiting examples of oils suitable for use in the compositions of the present invention are disclosed in U.S. Patent 9,446,265 and U.S. Publication 2015 / 0196464.

[0070] The carrier may comprise one or more dermatologically acceptable hydrophilic diluents. As used herein, “diluent” includes materials into which a vitamin B 3 compound can be dispersed, dissolved, or otherwise incorporated. Hydrophilic diluents include water, organic hydrophilic diluents such as lower monohydric alcohols (e.g., C 1 -C 4 ) and low molecular weight diols and polyols, including propylene glycol, polyethylene glycol (e.g., molecular weight 200 g / mol to 600 g / mol), polypropylene glycol (e.g., molecular weight 425 g / mol to 2025 g / mol), glycerin, butylene glycol, 1,2,4-butanetriol, sorbitol esters, 1,2,6-hexanetriol, ethanol, isopropyl alcohol, sorbitol esters, butylene glycol, ethoxypropanol, ethoxylated ethers, propoxylated ethers, and combinations thereof.

[0071] Emulsifier

[0072] When the compositions herein are in the form of an emulsion (e.g., an oil-in-water emulsion), it may be desirable to include an emulsifier to stabilize the emulsion (i.e., prevent phase separation of the emulsion). The emulsifier may be present in the composition in an amount of 0.01% to 10% (e.g., 0.05% to 5%, or 0.1% to 2%). The emulsifier may be nonionic, anionic, or cationic. In some cases, the emulsifier may be a silicone emulsifier. Some non-limiting examples of emulsifiers suitable for use herein are disclosed in U.S. Patent 3,755,560; 4,421,769; and McCutcheon's Detergents and Emulsifiers, North American Edition, pages 317 - 324 (1986).

[0073] Some other non-limiting examples of emulsifiers that may be suitable for use herein include: ethers of polyethylene glycol and fatty alcohols, esters of polyethylene glycol and fatty acids, ethers of glycosylated polyethylene glycol and fatty acids, esters of glycosylated polyethylene glycol and fatty acids, ethers of C12-30 alcohols and glycerol or polyglycerol, esters of C12-30 fatty acids and glycerol or polyglycerol, ethers of alkylene oxide-modified C12-30 alcohols with glycerol or polyglycerol, ethers of C12-30 fatty alcohols with sucrose or glucose, esters of sucrose and C12-30 fatty acids, esters of pentaerythritol and C12-30 fatty acids, esters of sorbitol and / or sorbitan with C12-30 fatty acids, ethers of sorbitol and / or sorbitan with alkoxylated sorbitan, ethers of polyethylene glycol and cholesterol, esters of C12-30 fatty acids with alkoxylated ethers of sorbitol and / or sorbitan, and combinations thereof. A particularly useful class of emulsifiers is polyethylene glycol ethers of lauryl alcohol, such as lauryl polyoxyethylene ether-1 to lauryl polyoxyethylene ether-50 (e.g., lauryl polyoxyethylene ether-4). Other examples of emulsifiers include ethers of glycerol, polyglycerol, sucrose, glucose, or sorbitol; esters of glycerol, polyglycerol, sucrose, glucose, or sorbitol; and mixtures thereof. Other particularly useful classes of emulsifiers are alkyl esters of sorbitol and sorbitan, such as polysorbate 20, polysorbate 21, and polysorbate 40.

[0074] Silicone emulsifiers may be suitable for use herein. Linear or branched types of silicone emulsifiers may also be used. Particularly useful silicone emulsifiers include polyether-modified silicones such as KF-6011, KF-6012, KF-6013, KF-6015, KF-6015, KF-6017, KF-6043, KF-6028, and KF-6038, and polyglycerolated linear or branched silicone emulsifiers such as KF-6100, KF-6104, and KF-6105; all from Shin-Etsu. A particularly suitable emulsifier for use herein is PEG-11 methyl ether polydimethylsiloxane, which is available as KF-6011 from Shin-Etsu. Surprisingly, it has been found that the PEG-11 methyl ether polydimethylsiloxane emulsifier further reduces the tacky feel of anionic polymer thickeners, thereby improving the overall feel of low pH compositions. The emulsifier may be present in an amount of 0.1% to 10% (e.g., 1% to 5%, or 2% to 4%).

[0075] Other optional ingredients

[0076] The low pH and second skin care composition may optionally contain one or more additional ingredients commonly used in cosmetic compositions (e.g., colorants, skin care actives, anti-inflammatory agents, sunscreens, emulsifiers, buffers, rheology modifiers, combinations of these, etc.), provided that the additional ingredient does not adversely alter the skin health or appearance benefits provided by the compositions of the present invention. When incorporated into the composition, the additional ingredient should be suitable for contact with human skin tissue without undue toxicity, incompatibility, instability, allergic response, etc. Some non-limiting examples of additional actives include vitamins, minerals, peptides and peptide derivatives, glycosamines, sunscreens, sebum control agents, particles, flavonoid compounds, hair growth regulators, antioxidants and / or antioxidant precursors, preservatives, protease inhibitors, tyrosinase inhibitors, anti-inflammatory agents, humectants, exfoliants, skin brighteners, self-tanners, lubricants, anti-acne actives, anti-cellulite actives, chelating agents, anti-wrinkle actives, anti-atrophy actives, phytosterols and / or phytohormones, N-acyl amino acid compounds, anti-microbial agents and anti-fungal agents. Some non-limiting examples of skin care compositions and additional ingredients and / or skin care actives applicable herein are described in U.S. Publications 2002 / 0022040; 2003 / 0049212; 2004 / 0175347; 2006 / 0275237; 2007 / 0196344; 2008 / 0181956; 2008 / 0206373; 2010 / 00092408; 2008 / 0206373; 2010 / 0239510; 2010 / 0189669; 2010 / 0272667; 2011 / 0262025; 2011 / 0097286; US2012 / 0197016; 2012 / 0128683; 2012 / 0148515; 2012 / 0156146; and 2013 / 0022557; as well as U.S. Patents 5,939,082; 5,872,112; 6,492,326; 6,696,049; 6,524,598; 5,972,359; and 6,174,533.

[0077] When present, the optional ingredient(s) may be included in an amount of from 0.0001% to 50%; 0.001% to 20%; or even 0.01% to 10% (e.g., 50%, 40%, 30%, 20%, 10%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1%) by weight of the composition.

[0078] Method

[0079] Opacity test method

[0080] This method is used to determine the opacity of a product or material. The results are reported as a percentage, where the higher the percentage, the greater the opacity of the sample. Before measuring the opacity, the test composition to be tested is ground for 1 minute at 10,000 rpm using an Ultra-turrax T25 (from IKA, Germany) or an equivalent with an S 25N-25F dispersing tool (or equivalent), taking care not to introduce air into the sample. A sample is prepared by placing a sufficient amount of the composition in a suitable transmittance cell providing a 2 mm optical path (e.g., a CM-A130 rectangular cell from Konica Minolta or equivalent). The opacity of the sample is measured using a suitable spectrophotometer that can deliver the tristimulus values CIE XYZ under CIE D65 illumination conditions over the entire visible spectrum used for this method (e.g., a CM-3600A spectrophotometer available from Konica Minolta or equivalent). The spectrophotometer is set to deliver the tristimulus XYZ values defined by CIE 1931 with a 2° observer and a D65 light source. Two sets of tristimulus values are required to calculate the opacity - one with the 2 mm sample cell of the product in front of a white background and the other in front of a black background. Acceptable white backgrounds include the white portion of an opaque card (such as Opaque Card 2A type, Leneta Company, Inc, Mahwah, NJ, USA, or equivalent), and an acceptable black background is the black portion of an opaque card (such as Opaque Card 2A type, Leneta Company, Inc, Mahwah, NJ, USA, or equivalent). The opacity is determined by calculating the quotient of the Y tristimulus value using the black background divided by the Y tristimulus value using the white background and multiplying by 100%. The opacity is reported to the nearest integer percentage.

[0081] Rheology method

[0082] This method provides a way to measure the dynamic viscosity of a composition or material using a BROOKFIELD viscometer (e.g., model DV2T or equivalent) and a suitable spindle (e.g., RV4 or equivalent) according to the manufacturer's instructions. It should be understood that a person skilled in the art will be able to select an appropriate spindle based on the manufacturer's recommendations. After calibrating the viscometer, the spindle is immersed in a sufficient amount of the test sample (e.g., enough to submerge the spindle to the immersion mark on the spindle shaft). The speed of the spindle is set to 5 rpm, and then the viscometer is started. Allow the indicated viscosity reading to stabilize for a time (about 10 - 30 seconds). After the reading has stabilized, take 5 readings at 10-second intervals. The viscosity is calculated as the average of the 5 readings.

[0083] Example

[0084] Example 1 - Formulation

[0085] Table 1 provides examples of the low pH skin care compositions described herein. The compositions are prepared using conventional methods for preparing skin care compositions. Such methods generally involve mixing the ingredients to a relatively homogeneous state in one or more steps, with or without heating, cooling, application of vacuum, etc. Typically, an emulsion is prepared by first separately mixing the aqueous phase materials and the fatty phase materials and then, as appropriate, mixing the two phases to obtain the desired continuous phase. The compositions are preferably prepared to optimize stability (physical, chemical, light stability) and / or delivery of the active substance. Such optimization can include adjusting the pH (i.e., adjusting to less than 5), excluding substances that can complex with the active agent and thus have a negative impact on stability or delivery (e.g., excluding contaminated iron), using methods to prevent complex formation (e.g., appropriate dispersants or dual-compartment packaging), using appropriate light stability methods (e.g., incorporating sunscreens / sunblocks, using opaque packaging), etc.

[0086] The pH of the compositions tested in this example was measured using an Orion Model 525A pH meter (or equivalent) equipped with a flat surface electrode / probe (e.g., VWR Catalog No. 20, 89231-584). The probe of the pH meter was directly immersed into a pure sample of the composition.

[0087] Table 1

[0088]

[0089]

[0090] 1 KSG-16 available from Shin-Etsu

[0091] 2 CHRONOGEN YST available from Ashland, Inc.

[0092] 3 PROGELINE available from Lucas Meyer Cosmetics

[0093] 4 SEPIMAX ZEN available from Seppic

[0094] 5 KF-6011 available from Shin-Etsu

[0095] *Comparative Example

[0096] Table 1 (continued)

[0097]

[0098]

[0099] 6 ARISTOFLEX SILK available from Clariant

[0100] 7 ELDEW SL 205 available from Ajinomoto OmniChem

[0101] Table 1 (continued)

[0102]

[0103]

[0104] 8 TEGO RENEWHA LACTO available from Evonik

[0105] 9 TEGO RENEWHA MALTO available from Evonik

[0106] 10 Available from Jungbunzlauer

[0107] 11 PURAMEX Zn from Corbion

[0108] Example 2 - Improved Vitamin B 3 Skin Permeation of the Compound

[0109] This example demonstrates the ability of the present solution to improve the skin penetration of niacinamide. In this example, a low pH composition (Example I from Table 1) was applied to an ex vivo skin sample, followed by the application of a second skin care composition. The second skin composition used in this test comprised a variety of commercially available skin care compositions from Procter & Gamble Company. Each second skin care composition comprised 5% niacinamide. In the first test (summarized in Table 2A below), the skin samples were analyzed to determine the amount of niacinamide that penetrated through the stratum corneum into the epidermis. In the second test (summarized in Table 2B below), the skin samples were analyzed to determine the total amount of niacinamide that penetrated into and / or through the skin samples.

[0110] Skin penetration method (Franz cell)

[0111] In vitro skin penetration of active substances such as niacinamide from topically applied formulations can be determined using Franz diffusion cell assays (Franz, T. J. Percutaneous absorption. On the relevance of in vitro data. J. Invest. Dermatol. 64:190 - 195, 1975; Franz et al., The use of excised human skin to assess the bioequivalence of topical products. Skin Pharmacol. Physiol. 22:276 - 286, 2009). Franz diffusion cell assays are widely used in the skin care industry to evaluate skin penetration and dermal absorption safety assessments.

[0112] Skin samples are prepared from mid - thickness human cadaver skin thawed under environmental conditions. The skin samples are cut into appropriately sized pieces and mounted in a standard static Franz - type diffusion cell (0.79 cm 2 surface area) maintained at 37°C. Approximately 5 ml of receptor solution is placed in the receptor compartment at the bottom of each cell to collect any niacinamide that penetrates through the entire skin sample. The receptor solution is phosphate - buffered saline (PBS - pH 7.4) that contains 1% polysorbate - 20 and 0.02% sodium azide. The skin samples are equilibrated for two hours. Each treatment group has 6 replicates.

[0113] To prepare the test composition, aliquots of the test composition are doped with approximately 3 μCi of 14 ¹⁴C - niacinamide per 300 mg aliquot. The test composition aliquots are mixed and assayed in triplicate for total radioactivity using ULTIMA GOLD brand liquid scintillant (LSC) (available from PerkinElmer, Boston) or equivalent and a suitable liquid scintillation counter (e.g., TRI - CARB 2500TR brand liquid scintillation analyzer available from PerkinElmer).

[0114] 5 μL of the test composition is topically administered to the skin sample using a positive - displacement pipette. A spreading rod is used to gently spread the product over the skin surface (approx. 0.79 cm 2)。When testing the formulations of two or more products, there is a 3-minute interval between applications. At the end of the test (6 hours after dosing), the receptor solution is collected and the surface of each skin sample is wiped twice with Whatman filter paper soaked in PBS / Tween 20 and once with Whatman filter paper soaked in 70% / 30% ethanol / water to remove the unabsorbed (residual) product. The epidermis is separated from the dermis by dissection, and then the epidermis and dermis portions are dissolved overnight at 60 °C in 0.50 - 1.25 mL of SOLUENE-350 (obtainable from PerkinElmer). As described above, liquid scintillation counting is used to quantify the skin penetration of niacinamide. Scintillation counting is performed on the epidermis samples, dermis samples, and receptor solution. The amount of epidermal skin penetration is the total fluorescence measured from the epidermis samples (including the stratum corneum). Total penetration is the sum of the fluorescence measured from the epidermis samples, dermis samples, and receptor compartment. Skin penetration data can be expressed as % of the dose and / or μg / cm 2 。

[0115] The results of the skin penetration tests conducted in this example are summarized in Tables 2A and 2B and shown in Figure 1 and Figure 2 。The expected amount of niacinamide penetration is determined by applying Fick's law of diffusion to the total concentration of niacinamide applied to the target skin portion. As can be seen in Tables 2A and 2B, this formulation provides an unexpected increase in niacinamide penetration in each case. In some cases, as shown in Figure 1 and 2 the figures, this formulation even provides additional skin penetration results that are typically only expected from compositions having the same niacinamide concentration and thus the same osmotic thermodynamic potential. However, as can be seen in the OLAY REGENERIST CELLSCIENCE anti-aging cream product in Table 2B, not all compositions will unexpectedly increase the skin penetration of niacinamide, even when applied as a formulation of the low-pH composition of the present invention.

[0116] Table 2A: Niacinamide penetration into the epidermis (μg / cm 2 )

[0117]

[0118] * p < 0.05 relative to the penetration of the second composition alone

[0119] Table 2B: Total niacinamide penetration into the skin (μg / cm 2 )

[0120]

[0121] * p < 0.05 relative to the penetration of the second composition alone

[0122] Example 3 – Thermodynamic potential

[0123] This example qualitatively shows the reason why applying the skin care product according to the present solution results in a lower skin penetration outcome. In basic terms, vitamin B 3 The thermodynamic potential for penetration from the skin care composition into the skin is proportional to the concentration of the vitamin B 3 compound in the composition. In other words, the thermodynamic potential of the vitamin B 3 compound can be expressed as the ratio of the vitamin B 3 concentration to the product mass. And when two compositions with different concentrations of the vitamin B 3 compound are mixed on the skin during the solution, there is a dilution effect, so the thermodynamic potential of the mixed composition is reduced relative to the higher concentration composition. This effect is summarized in Table 3 below, which depends on the skin penetration of the test compositions measured in Example 2. As shown in Table 3, the skin penetration of niacinamide applied in the solution is unexpectedly high.

[0124] Table 3

[0125]

[0126] Example 4 - Opacity

[0127] This example demonstrates the desired opacity characteristics of the low-pH composition of the present invention. An opacity between 15 and 75 is generally desired. If the opacity is below 15, the composition looks like water, and consumers may question its efficacy. However, if the opacity is greater than 75, then consumers may consider the composition viscous, sticky, and / or non-penetrating to the skin. In this example, compositions J, M, N, P, Q, R, S, and T were tested. Additionally, the opacity of a conventional skin care composition (C1) was also tested. The conventional composition was Example 1 of U.S. Patent 5,968,528 to Deckner et al. The results of this test are summarized in Table 4. As can be seen in Table 4, compositions that are completely oil-free (i.e., compositions J and R) do not provide sufficient opacity, and compositions that are not customized to balance the amounts of oil and thickener, skin care active substances, and / or buffer systems may be too opaque, as demonstrated by composition C1.

[0128] Table 4

[0129] Composition J R M N P Q S T C1 Opacity 6 6 37 66 31 58 33 30 84

[0130] Example 5 - Low irritation

[0131] This example demonstrates the low irritation potential of the low-pH composition of the present invention. The low-pH composition was tested in clinical studies, cell-based in vitro assays, and human in vivo studies to determine the relative irritation potential of the composition.

[0132] Clinical study

[0133] As part of the clinical study described in Example 3 above, test subjects were required to fill out a questionnaire that rated the level of irritation associated with the test product applied to their skin. The questionnaire asked test subjects to rate their test product as "non-irritating to the skin". The questionnaire provided 7 possible answers: 1) Strongly Agree; 2) Agree; 3) Slightly Agree; 4) Don't Know; 5) Slightly Disagree; 6) Disagree; and 7) Strongly Disagree. The test compositions used in this example were Compositions G and I of Table 1 and the vehicle control of Example 3. The results of the test at Week 4 and Week 8 are summarized in Table 5 below. "Top 3" refers to the percentage of test subjects who answered "Strongly Agree", "Agree", and "Slightly Agree".

[0134] Table 5

[0135] Week Treatment Before 3 4 Vehicle control 97％ 4 Composition I 98％ 4 Composition G 97％ 8 Vehicle control 98％ 8 Composition I 100％ 8 Composition G 100％

[0136] At Week 4, 98% of the test subjects agreed that the inventive composition was non-irritating to the skin, while 97% of the test subjects agreed that the vehicle control was non-irritating to the skin. At Week 8, 100% of the test subjects agreed that the test composition was non-irritating to the skin, compared to 98% of the test subjects who agreed that the vehicle control was non-irritating to the skin. Thus, the results of this test indicate that the low pH compositions of the present invention can improve the appearance of the skin without irritating the skin of the user.

[0137] In vitro study

[0138] The ability of the in vitro portion of the test composition of this example to activate the well-known TRPV1 sensory receptor in commercially available HEK293 cells. TRP receptors (e.g., TRPA1, TRPV1, and TRPM8) are sensory receptors known for their involvement in transmitting thermal sensations (i.e., heat and cold) to the central nervous system. TRPV1 is believed to also be involved in triggering cutaneous sensory stimuli such as itching, burning, pain, pricking, stinging, and inflammation. Cell lines expressing the specific human TRPV1 receptor have previously been used to evaluate the ability of materials or compositions to activate TRPV1, particularly for evaluating the burning, pricking, taste, and / or pain-relieving effects of various consumer product formulations. In this example, HEK293 cells were pre-loaded with Fluo-4 AM (a calcium-binding dye), and a FLIPR TETRA brand cell screening system (available from Molecular Devices, LLC) or equivalent was used to treat with control substances and test compositions in a high-throughput manner. After activation of the TRPV1 ion channel, calcium ions enter the cell and bind to the Fluo-4 dye, generating a fluorescent signal that allows quantification of the response. To reduce the effects of non-specific calcium mobilization unrelated to TRPV1 activation, the formulation response was measured in the presence and absence of a specific TRPV1 inhibitor / antagonist compound. In the presence of the specific antagonist, the positive signal of TRPV1 receptor activation by the formulation will disappear or decrease, thereby increasing the accuracy of data collection attributed to formulation-dependent TRPV1 activation.

[0139] TRPV1 assay

[0140] To initiate the assay, HEK293 cells were grown in DMEM medium containing 10% FBS, high glucose, L-glutamine, phenol red, 100 μg / ml G418, and sodium pyruvate at 33 °C and 5% CO 2 2 for 4 - 5 days (80% - 90% confluent) (see, e.g., Sadofsky, L.R. et al. Unique Responses are Observed in Transient Receptor Potential Ankyrin 1 and Vanilloid1(TRPA1 and TRPV1)Co-Expressing Cells.Cells 2014, 3, 616 - 626). The second-generation cells were removed from the tissue culture vessel together with PBS, and the isolated cells were spun in a centrifuge at low speed (800 - 1000 rpm) for 3 min to form a pellet. The PBS medium was removed, and the cell pellet was resuspended in 4 mL of growth medium. 50 μg of Fluo-4 AM calcium dye dissolved in 25 μL of Pluronic F-127 was added, and then the cells were incubated for 1 hour at room temperature with gentle shaking. The cells were washed once with 45 mL of assay buffer (1×HBSS, 20 mM HEPES) by low-speed centrifugation (800 - 1000 rpm) for 3 minutes, and then resuspended in 10 mL of assay buffer. 100 μL aliquots (about 15×10 4 cells) were dispensed into each well of a 96-well black flat-bottom plate. The plate was allowed to stand at room temperature for 30 minutes, and then baseline fluorescence was recorded using a cell screening system (e.g., FLIPR TETRA or equivalent) at λ 激发 488 nm and λ 发射 514 nm. Capsaicin (350 nM) was used as an agonist control for each plate, and ionomycin (2 μM) was used as a positive control.

[0141] The test samples were prepared as 12X (10.8% formulation) stock solutions in assay buffer (w / v) and allowed to stand at room temperature for 1 hour. The test samples were then centrifuged at 14,000 rpm for 3 minutes. The aqueous phase was removed from the centrifuged samples and placed in a suitable tube, and mixed 1:1 in assay buffer to form a 6X stock solution. A TRPV1 antagonist composition was prepared by mixing the isolated aqueous phase 1:1 with a 12X stock solution of capsazepine (final concentration 25 μM). The 6X samples were diluted 1:3 with assay buffer or a 6X stock solution of the TRPV1 antagonist capsazepine (25 μM). 20 μL of the diluted composition was added in triplicate to the wells of a 96-well plate, with a final dilution of 0.3% formulation.

[0142] The maximum fluorescence value in each well was recorded until the peak agonist control reaction time (usually 40 - 50 seconds). The values of the replicate wells were averaged and then converted to a percentage of the capsaicin agonist control reaction. Each test sample reaction was recorded as the difference between (average test sample reaction) – (average test sample reaction + antagonist). Reactions below zero were reported as “no response”. Compositions M, N, and Q of Table 1 were tested in this example. Compositions shown in Tables 6A and 6B below were also tested. The results of the tests are summarized in Table 6C and shown in Figure 3, in addition, it shows that the lactic acid / sodium lactate buffer system of the inventive composition exhibits significantly less TRPV1 activation than the comparative low pH compositions. Specifically, the inventive composition exhibits less than 10% TRPV1 activation relative to the agonist control.

[0143] Table 6A

[0144]

[0145]

[0146] 1 SYMDIOL 68 available from Symrise

[0147] 2 PURAC HIPURE 90 available from Corbion

[0148] 3 PURASAL S HQ-60 available from Corbion

[0149] 4 SEPIMAX ZEN available from Seppic

[0150] 5 KF-6011P available from Shin-Etsu

[0151] Table 6B

[0152]

[0153]

[0154] 1 PURAC HIPURE 90 available from Corbion

[0155] 2 PURASAL S HQ-60 available from Corbion

[0156] 3 Available from Jungbunzlauer

[0157] 4 SEPIMAX ZEN available from Seppic 5 KF-6011P available from Shin-Etsu

[0158] Table 6C

[0159]

[0160] In vivo study

[0161] The in vivo part of this example shows the low irritation potential of the inventive composition relative to a low-pH formulation in comparison using different buffer systems. This study was a single-product blinded test using female test subjects aged 25 - 54 years. The test subjects were required to apply approximately 0.5 g (i.e., 1 pump) of the test composition to their entire face twice a day (in the morning and evening). The compositions tested in this study are provided in Table 6A above. After 1 week of use, the test subjects were asked whether the test composition irritated the skin. The results of the in vivo study are summarized in Table 7 below. As can be seen in Table 7, the data indicate that the inventive example is less irritating to the skin compared to two comparative examples.

[0162] Table 7

[0163] The present invention 1 The present invention 2 Comparison 1 Comparison 2 Do not irritate the skin 84.0％ 86.3％ 77％ 49.1％

[0164] Example / Combination

[0165] 1. A method for improving the skin penetration of a vitamin B 3 compound, comprising:

[0166] Identifying a target skin part for a desired skin health or appearance beneficial effect;

[0167] Applying a low-pH skin care composition to the target skin part, wherein the low-pH skin care composition comprises a first concentration of a vitamin B 3 compound; and

[0168] Subsequently applying a second skin care composition to the target skin part, wherein the second skin care composition comprises a second concentration of a vitamin B 3 compound, and the second concentration is higher than the first concentration.

[0169] 2. The method according to paragraph A, wherein the low-pH composition has a pH between about 2.0 and about 5.0, preferably about 2.5 to about 4.5, and more preferably about 3.0 to about 4.3.

[0170] 3. The method according to any of the preceding paragraphs, wherein the second skin care composition has a pH of about 5.0 to about 8.0.

[0171] 4. The method according to any of the preceding paragraphs, wherein the vitamin B 3 compound is selected from the group consisting of niacinamide, niacin, nicotinol, derivatives of these substances, and combinations thereof.

[0172] 5. The method according to paragraph D, wherein the vitamin B 3 compound is nicotinamide.

[0173] 6. The method according to paragraph D, wherein the low-pH composition comprises from about 0.01% to about 3% of the vitamin B 3 compound.

[0174] 7. The method according to paragraph D, wherein the second skin care composition comprises from about 2% to about 10% of the vitamin B 3 compound.

[0175] 8. The method according to any one of the preceding paragraphs, wherein the low-pH buffer system comprises an acid buffer selected from lactic acid, gluconic acid, lactobionic acid and maltobionic acid and a salt buffer selected from sodium lactate, sodium gluconate, calcium gluconolactate and potassium gluconate.

[0176] 9. The method according to any one of the preceding paragraphs, wherein the weight percentage ratio of the vitamin B 3 compound in the low-pH composition to the vitamin B 3 compound in the second skin care composition is from about 1:10 to about 3:4, preferably from about 1:5 to about 1:2.

[0177] 10. The method according to any one of the preceding paragraphs, wherein the low-pH composition comprises:

[0178] a) from about 0.1% to 5% of a pH buffer system comprising an acid buffer and a salt buffer;

[0179] b) from about 0.1% to 5% of a polymeric thickener comprising a low-pH tolerant thickener; and

[0180] c) from about 0.1% to 10% of a viscosity-reducing oil having a viscosity of 100 cSt or less at 25 °C.

[0181] 11. The method according to paragraph J, wherein the viscosity-reducing oil is a silicone oil, preferably polydimethylsiloxane.

[0182] 12. The method according to any one of the preceding paragraphs, wherein the low-pH composition further comprises from about 0.01% to about 1% of a silicone emulsifier.

[0183] 13. A method according to any of the preceding paragraphs, wherein at least one of the first skin care composition and the second skin care composition comprises an additional skin care active agent selected from the group consisting of vitamins, minerals, peptides, glycosamines, sunscreens, sebum control agents, flavonoid compounds, antioxidants, protease inhibitors, tyrosinase inhibitors, anti-inflammatory agents, moisturizers, exfoliants, skin brighteners, anti-acne agents, anti-wrinkle agents, phytosterols, N-acyl amino acid compounds, anti-microbial agents, anti-fungal agents, and combinations thereof.

[0184] 14. A method according to any of the preceding paragraphs, wherein the skin care composition has an opacity of from about 15 to about 75, preferably from about 35 to about 60, according to an opacity test.

[0185] 15. A method according to any of the preceding paragraphs, wherein the low pH composition exhibits less than about 10%, preferably less than about 5%, TRPV1 activation according to a TRPV1 assay.

[0186] 16. A method according to any of the preceding paragraphs, wherein the low pH composition is a skin care serum product having a viscosity of from about 1 cP to about 30,000 cP, preferably from about 1000 cP to about 15,000 cP, at 25 °C.

[0187] 17. A method according to any of the preceding paragraphs, wherein application of the low pH skin care composition and the second skin care composition during treatment does not result in skin irritation of the target skin portion.

[0188] The dimensions and values disclosed herein are not to be understood as being strictly limited to the exact numerical values recited. Instead, each such dimension is intended to mean the recited value and a range functionally equivalent thereto. For example, a dimension disclosed as "40 mm" is intended to mean "about 40 mm".

[0189] Unless expressly excluded or otherwise limited, each document cited herein, including any cross-referenced or related patent or patent application and any patent application or patent to which this application claims priority or for which it claims benefit, is hereby incorporated by reference in its entirety. The citation of any document is not an admission that it is prior art with respect to any invention disclosed or claimed herein or that it alone or in any combination with any one or more other references teaches, suggests, or discloses any such invention. Further, when any meaning or definition of a term in this invention conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to the term in this invention shall govern.

[0190] While specific embodiments of the present invention have been illustrated and described, it will be apparent to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. Accordingly, it is intended to cover all such changes and modifications that fall within the scope of the present invention in the appended claims.

Claims

1. A method for improving the skin penetration of vitamin B 3 compounds Comprising: Identifying a target skin part for desired skin health or appearance beneficial effects; Apply a low-pH skin care composition to the target skin portion, wherein the low-pH skin care composition comprises a first concentration of vitamin B 3 compound, wherein the pH of the low-pH skin care composition has a pH between 2.0 and 5.0; And Thereafter, a second skin care composition is applied to the target skin portion, wherein the second skin care composition comprises a second concentration of vitamin B 3 compound, and the second concentration is higher than the first concentration; wherein the vitamin B 3 compound is nicotinamide; wherein the low-pH skin care composition comprises 0.01% to 3% by weight of vitamin B 3 compound, and the second skin care composition comprises 2% to 10% by weight of vitamin B 3 compound; and wherein the method is for non-therapeutic purposes.

2. The method according to claim 1, wherein the low pH skin care composition has a pH between 2.5 and 4.

5.

3. The method according to claim 1, wherein the low pH skin care composition has a pH between 3.0 and 4.

3.

4. The method according to claim 1, wherein the second skin care composition has a pH of 5.0 to 8.

0.

5. The method according to claim 1, wherein the low pH skin care composition comprises a buffer system, and the buffer system comprises an acid buffer selected from lactic acid, gluconic acid, lactobionic acid and maltobionic acid and a salt buffer selected from sodium lactate, sodium gluconate, calcium gluconolactate and potassium gluconate.

6. The method according to claim 1, wherein the weight percentage ratio of the vitamin B 3 compound in the low pH skin care composition to the vitamin B 3 compound in the second skin care composition is from 1:10 to 3:

4.

7. The method according to claim 1, wherein the weight percentage ratio of the vitamin B 3 compound in the low-pH skin care composition to the vitamin B 3 compound in the second skin care composition is from 1:5 to 1:

2.

8. The method according to claim 1, wherein the low pH skin care composition comprises: a. A pH buffer system containing an acid buffer and a salt buffer in an amount of 0.1% to 5%; b. A polymer thickener containing a low pH tolerance thickener in an amount of 0.1% to 5%; and c. A viscosity-reducing oil in an amount of 0.1% to 10%, and the viscosity-reducing oil has a viscosity of 100 cSt or less at 25°C.

9. The method according to claim 8, wherein the viscosity-reducing oil has a viscosity of 10 cSt or less at 25°C.

10. The method according to claim 8, wherein the viscosity-reducing oil is a silicone oil.

11. The method according to claim 8, wherein the viscosity-reducing oil is polydimethylsiloxane.

12. The method according to claim 1, wherein the low pH skin care composition further comprises 0.01% to 1% of a silicone emulsifier.

13. The method according to claim 1, wherein at least one of the low pH skin care composition and the second skin care composition comprises an additional skin care active substance, and the additional skin care active substance is selected from the group consisting of vitamins, minerals, peptides, glycosamines, sunscreens, sebum control agents, flavonoid compounds, antioxidants, protease inhibitors, tyrosinase inhibitors, anti-inflammatory agents, moisturizers, exfoliants, skin brighteners, anti-acne agents, anti-wrinkle agents, phytosterols, N-acyl amino acid compounds, anti-microbial agents, and combinations thereof.

14. The method according to claim 13, wherein the anti-microbial agent comprises an anti-fungal agent.

15. The method according to claim 1, wherein according to the opacity test, the low pH skin care composition has an opacity of 15 to 75.

16. The method according to claim 1, wherein according to the opacity test, the low pH skin care composition has an opacity of 35 to 60.

17. The method according to claim 1, wherein according to the TRPV1 assay, the low pH skin care composition exhibits less than 10% TRPV1 activation.

18. The method according to claim 1, wherein, as measured by TRPV1, the low-pH skin care composition exhibits less than 5% TRPV1 activation.

19. The method according to claim 1, wherein the low-pH skin care composition is a skin care essence product having a viscosity of 1 cP to 30,000 cP at 25°C.

20. The method according to claim 1, wherein the low-pH skin care composition is a skin care essence product having a viscosity of 1000 cP to 15,000 cP at 25°C.

21. The method according to claim 1, wherein applying the low-pH skin care composition and the second skin care composition during treatment does not cause skin irritation to the target skin portion.

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