HK40061605A - Skin treatment methods and compositions for transdermal delivery of active agents - Google Patents

Description

Skin treatment methods and compositions for transdermal delivery of active agents

RELATED APPLICATIONS

This application claims priority from U.S. provisional patent application No. 62/959,874, filed on 10/1/2020, which is incorporated herein by reference in its entirety.

Technical Field

The present application relates to the field of dermatological compositions and skin treatment methods with at least one retinoid and/or other active agent and delivery systems for transdermal delivery thereof. Certain disclosed embodiments provide effective, mild activating solvent systems for topical application to the skin, including dermatological compositions and methods with retinol and their activation and delivery systems, and methods for their formulation, preparation and use.

Background

The active agents are used for the treatment of the skin in a variety of different dermatological conditions, such as psoriasis, photoaging, age spots, apparent aging of the skin due to external and internal causes, skin wrinkles, acne, pigmentation and skin cancer. The active agents are typically a prescription active agent and an over-the-counter active agent. The solvents used in dermatological formulations with skin treatment actives may be strong solvents, such as acetone, or mild (i.e., gentle) solvents. However, strong solvents are known to cause effects in skin conditions requiring additional treatment, including disruption of the skin barrier, and may interfere with patient compliance with skin treatment regimens. On the other hand, mild solvents are considered ineffective for the delivery of active agents in transdermal and dermal applications. Furthermore, with the current trend towards the widespread use of dermatological formulations in skin care, there is a continuing need for topical formulations of active agents for various skin treatments.

Retinoids are useful in the treatment of a variety of dermatological conditions, including inflammatory diseases and conditions characterized by increased cell turnover, such as psoriasis, photoaging, age spots, skin wrinkles, enlarged pores, oily skin, skin showing premature aging, acne, and skin cancer.

However, retinoids, especially retinol, are unstable and easily oxidized in the presence of air and in the presence of ingredients commonly used in cosmetic formulations. This is a serious problem when applied as a thin layer over a relatively large skin surface area, and also when the shelf-life efficacy of retinol containing products is concerned.

Retinol is also difficult to effectively release and force into the skin from prior art delivery systems, resulting in a greatly reduced delivery efficiency even with the use of relatively high concentrations of retinol in the formulation. Thus, although the first formulation may contain a higher concentration of the retinoid or retinol than the second formulation, the latter formulation may be more efficient in terms of delivery of the retinoid or retinol if it provides enhanced release and transdermal penetration of the active agent retinoid or retinol than the former.

Retinol may also irritate the skin, preventing continued use by those in need of treatment with retinol-containing formulations, thereby reducing (or even eliminating) the therapeutic effect. Useful retinoid and retinol formulations include solvent-based systems, ointments, water-based formulations, emulsions, gels, and lotions, all of which can vary in stability and efficiency. Thus, retinoid and retinol preparations are not fully utilized in skin care procedures because they tend to cause irritation.

Accordingly, there is a need in the art for topical formulations and delivery systems that can provide retinoids and/or other active agents to those in need thereof that can alleviate and improve one or more of the exemplary conditions described above, as well as other conditions recognized in the field of dermatology and cosmetic skin care procedures.

The present disclosure provides formulations and delivery systems for retinol and other members of the retinol family, as well as for other skin care actives (such as other skin care actives known in the skin care formulation art). Certain embodiments maintain product stability, exhibit low irritation, and/or provide increased release and delivery efficiency of an active agent (e.g., retinol or another member of the retinol family and/or other active agents).

Disclosure of Invention

In certain embodiments, the present disclosure provides skin care therapeutic formulations, more particularly, retinol formulations, having active agents and transdermal delivery and skin activation and solvent systems. The skin care formulations exhibit product stability, low irritation, and improved delivery efficiency of formulated active agents. In particular, the present disclosure provides delivery systems that exhibit product stability, low irritation, and improved delivery efficiency of formulated retinol.

Without wishing to be bound by theory, the inventors believe that certain skin care formulations disclosed herein provide surprising and unexpected results, as clinical studies conducted on prescription skin treatment actives show, which may be attributed to the solvent combination of certain embodiments of the present disclosure. The results of the clinical study were stronger than expected. In this study, low dose, consumer, home-returnable, cosmetic retinol formulations and novel solvent combinations were used, including novel solvents that would function contrary to convention. Since retinol is insoluble in this new solvent, the inventors have found that a special step preparation process enables it to function. Thus, the inventors were able to obtain certain retinol formulations that performed better than the prescribed drug tretinoin. As discussed further below in clinical studies using the Ortho's Retin-a brand, the inventors obtained comparable or better efficacy than the prescribed active agent in the tested embodiments, while scoring better in terms of irritation and consumer preference.

In certain embodiments, the present disclosure provides topical formulations having one or more skin treatment active agents (e.g., a retinoid, such as retinol) and an activating solvent system. The solvent system may comprise one or more of the following: isoprene glycol, isosorbide dimethyl ether, or a nonionic surfactant. The formulation may further comprise one or more of the following: antioxidants, xanthines, humectants, and emollients. In one embodiment, the formulation further comprises an antioxidant.

The skin treatment active agent may be one or more of the following: retinoids, steroids, skin depigmenting agents (lightening agents), hydroquinone, acne medications, salicylic acid, kojic acid, resorcinol, hexylresorcinol, benzoyl peroxide, sulfur, anti-aging agents, peptides, growth factors, alpha-hydroxy acids, enzymes, DNA repair enzymes, vitamins, antipruritics, cooling agents, menthol, analgesics, essential oils, anti-inflammatory agents, anti-itch agents, hydrating agents, penetrating agents, natural moisturizing factors, urea, emollients, sealants, amino acids, scrubs, skin conditioners, cleansers, sebum reducers, anti-infective agents, hair restoration agents, oxidative active agents, polar and non-polar skin treatment agents, herbal active agents, bakuchiol, therapeutic natural oils, essential oils. In one embodiment, the skin treatment active agent comprises retinol and/or derivatives thereof. In one embodiment, the skin treatment active comprises retinol.

The nonionic surfactant may be one or more of the following: ethoxylates, fatty ethoxylates, propoxylates, block copolymers, poloxamers, polyglycerol esters, polyglycerol emulsifiers, sorbitan, dipolar agents, phenolic nonionic surfactants.

The nonionic surfactant can be polysorbate 80, and the antioxidant can be one or more of: green tea polyphenols, Glycyrrhrizae radix extract, resveratrol, silymarin, curcumin, caffeine, astaxanthin, flavone, flavonoid, flavanol, tocopherol, ascorbic acid, coenzyme Q10, ergothioneine, glutathione, ectoin, bisabolol, and fructus Phyllanthi.

In certain embodiments, the formulation further comprises polysorbate 20.

In certain embodiments, the present disclosure relates to methods for treating dermatological conditions comprising topically applying to an affected area a therapeutically effective amount of a topical formulation having a skin treatment active as disclosed herein. In certain embodiments, the formulation comprises an activating solvent system comprising isoprene glycol, isosorbide dimethyl ether, and a nonionic surfactant.

The affected region may be one or more of the following: human skin, scalp, hair or nails. In one aspect disclosed herein, the skin is human skin. In other aspects disclosed herein, the skin is that of a companion animal, a domestic animal, or a commercial animal.

The disclosed activated solvent systems may also include one or more solubilizers, rheology modifiers, emulsifiers, and/or dispersing aids. In one aspect of this embodiment, the solubilizing agent/emulsifier is a nonionic solubilizing agent/emulsifier.

The disclosed formulations may also comprise at least one source of a retinoid. In one aspect of this embodiment, the retinoid may be retinol, retinal, retinol esters (including, for example, palmitate and stearate esters of retinol), retinoic acid, tretinoin, or synthetic retinoids (such as adapalene, bexarotene, tazarotene, or combinations of two or more thereof). In one aspect of this embodiment, the retinoid is retinol. In another aspect, the retinoid is all-trans retinol.

The disclosed formulations may also include one or more antioxidants. In one aspect of this embodiment, the antioxidant is a polyphenol. In a more specific aspect of this embodiment, the antioxidant comprises a polyphenol isolate of camellia japonica. In yet another aspect, the antioxidant comprises 90% or 95% polyphenol isolate of camellia japonica.

The disclosed formulations may also contain a xanthine-related compound, a polymeric derivative thereof, or a mixture of xanthine-related materials, which may be used as an antioxidant or a stimulator of antioxidant activity. In a particular aspect, the xanthine-related compound is caffeine.

In certain embodiments, the disclosed formulations may further comprise bakuchiol.

The disclosed formulations may also include one or more emollients. In one aspect of this embodiment, the softening agent is an ester or an oil. In various aspects of this embodiment, the softening agent may comprise one or more of the following: shea butter, cocoa butter, mineral oil, lanolin, petrolatum, paraffin, beeswax, squalene, cetyl alcohol, olive oil, tri-iso-caprylic glyceride, coconut oil, jojoba oil, sesame oil, almond oil, or other vegetable oils and combinations of two or more thereof.

In certain embodiments, the present disclosure may relate to methods for preparing the topical formulations described herein. The method can include forming a first mixture of an antioxidant system and an activating solvent system comprising isoprene glycol, isosorbide dimethyl ether, and a nonionic surfactant; separately combining an active agent (e.g., retinol) with isoprene glycol and isosorbide dimethyl ether to form an active agent mixture; and combining the first mixture with the active agent mixture. In certain embodiments, the process is carried out under an inert atmosphere.

Drawings

The drawings described below are for illustration purposes only and are not necessarily drawn to scale. The drawings are not intended to limit the scope of the disclosure in any way. Wherever possible, the same or similar reference numbers will be used throughout the drawings to refer to the same or like parts.

Figure 1 shows a researcher week 4 efficacy chart of mean clinical scores in smoothness, softness, brightness and radiance of skin treated with a formulation according to certain embodiments described herein compared to a comparative tretinoin formulation.

Figure 2 shows a investigator week 8 efficacy profile of the mean clinical score in dryness and visual smoothness of skin treated with a formulation according to certain embodiments described herein, compared to a comparative tretinoin formulation.

Figure 3 shows a table of subjects' 8 week efficacy of mean clinical scores in dryness and visual smoothness of skin treated with a formulation according to certain embodiments described herein compared to a comparative tretinoin formulation.

Figure 4 shows a table of subject 4 week efficacy of mean clinical scores in terms of overall appearance, color difference, crow's feet, softness, and visual smoothness of skin treated with a formulation according to certain embodiments described herein compared to a comparative tretinoin formulation.

Figure 5 shows a table of subject average tolerance scores for the average clinical scores for swelling, redness, burning, stinging, and itching of skin treated with a formulation according to certain embodiments described herein compared to a comparative tretinoin formulation.

Fig. 6A-6D show histology of skin treated with formulations according to certain embodiments described herein at week 12 (fig. 6B and 6D) compared to baseline (fig. 6A and 6C).

Detailed Description

The present disclosure provides skin care formulations, delivery systems, and methods of use thereof for treating, ameliorating, and improving dermatological conditions amenable to treatment with retinoids, including retinol and other skin treatment actives. Suitable conditions include, but are not limited to, inflammatory skin diseases and skin conditions characterized by increased cellular turnover, such as psoriasis, photoaging, appearance of a full-blown cream (weather-skin appearance), yellowing, loss of elasticity, loss of collagen-rich appearance and/or youth, redness, dryness, age spots, skin wrinkles, acne, rosacea, ichthyosis, and skin cancer. The disclosed formulations may also be used to improve one or more aesthetic criteria, including, but not limited to, overt skin aging, skin tone, appearance of a full blown cream, yellowing, loss of elasticity, redness, dryness, age spots, skin wrinkles, skin smoothness, brightness, perceived improvement in shine, and skin pores becoming less pronounced.

As used herein, the term "treatment" with respect to a skin condition generally means administration to provide a pharmacokinetic effect, regardless of the result. In certain embodiments, "treating" means "having a positive effect on" a skin condition and includes reducing, ameliorating and/or improving at least one symptom of a skin condition, reducing, ameliorating and/or improving the severity of a skin condition, slowing, arresting or inhibiting the progression of a skin condition, or sensing an improvement or benefit as a result of the treatment. It may also indicate that comparable or better treatment results than prescription drugs are achieved with over-the-counter products. Thus, treatment as used herein does not require a complete cure for the condition. In certain embodiments, the formulations or delivery systems disclosed herein can reduce the severity of a skin condition, reduce the severity of symptoms associated therewith, provide an improvement in the life treatment of a patient, or delay, prevent, inhibit the onset of, or provide a sensory benefit to one or more symptoms of a skin condition. As used herein, these terms also encompass aesthetic improvements to the skin when applying the disclosed active agent-containing formulations.

As used herein, the term "application" with respect to a disclosed topical formulation or method of using a disclosed topical formulation refers to any manner of applying a topical formulation to the skin of a patient that delivers the formulation to the skin surface of the patient in medical or cosmetic practice. Application, wiping, spreading, spraying of the disclosed topical formulations onto the skin of a patient, with or without the aid of suitable devices, is all encompassed within the scope of the term "applying" as used herein. The term "topical" with respect to applying or applying the disclosed formulation means applying or applying to the skin.

As used herein, the phrase "effective amount" refers to an amount of an agent or component thereof effective to alleviate or improve the skin condition as described above, including a range of effects, from detectable local improvement in the area of topical application to substantial alleviation of symptoms to improvement of one or more aesthetic criteria, including but not limited to, improvement in the perception of free radical damage due to sunlight (UVB, UVA, visible light), HEV (blue) light, Infrared (IR), pollution, irritants, allergens, or various environmental toxins, significant skin aging, radiation damage, sun or uv light damage, skin tone, appearance of a saturated weather cream, yellowing, appearance of fine lines, rough skin, sagging skin, tight skin, dryness, age spots, skin wrinkles, skin smoothness, brightness, luster, and skin pores becoming less pronounced, pigmentation, scarring, skin surface irregularities, skin surface, skin roughness, rosacea, acne, psoriasis, skin rejuvenation and rejuvenation processes, redness, ichthyosis, severe photodamage, lack of tactile smoothness, lack of visual smoothness, lack of softness, lack of brightness, lack of radiance, skin texture, facial fine lines, fishtail lines, color differences, wrinkled skin texture, decreased skin elasticity, and other damaging skin conditions. The effective amount will vary with the particular condition or conditions being treated, the severity of the condition, the duration of the treatment, the particular ingredients of the composition being used, and other factors. In certain embodiments, the disclosed compositions and formulations provide methods for stabilizing and delivering active agents (e.g., retinoids, including retinol) to the skin in an effective manner. Certain disclosed retinoid compositions, formulations, delivery systems, and methods of use thereof can reduce, minimize, or eliminate commonly observed retinoid-induced skin disorders, including, inter alia, itching, severe skin exfoliation, skin barrier disruption, discomfort, extreme dryness, skin cracking, and sensitization. In certain embodiments, the disclosed compositions, formulations, delivery systems, and methods of use thereof also provide aesthetic improvements to skin, including but not limited to younger looking skin, skin exhibiting more uniform tone, skin with less pronounced pores, and skin judged by the user to be smoother, and/or improvements with respect to its frosty or aged appearance, yellowing, loss of elasticity, redness, dryness, age spots, and/or skin wrinkles.

In certain embodiments, the activation and solvent systems disclosed herein not only maintain product stability, including stability of formulated active agents (e.g., retinoids) as well as antioxidants, but also provide better active agent efficiency. Thus, in certain embodiments, the inventors have surprisingly found that certain disclosed formulations are effective compared to typical household skin care formulations, and comparable to prescription actives. Thus, certain disclosed retinoid formulations and methods of use thereof, as compared to prescription strength actives, themselves effectively function in skin care treatments at over-the-counter strength, as discussed in more detail below. In certain embodiments, the formulation causes reduced, minimal or no skin irritation and other possible side effects commonly associated with the formulation, particularly in daily, long-term use.

The antioxidant may be a polyphenol, which is isolated from a plant, chemically synthesized; antioxidants can also be semisynthetic compounds prepared by modification of natural polyphenols or mixtures of polyphenols. In certain embodiments disclosed herein, the antioxidant comprises "green tea polyphenols" isolated and purified from leaves of a tea plant. These antioxidants formulated and delivered herein can provide antioxidant or anti-inflammatory activity, and can also provide skin smoothing, protecting, anti-irritation, or repair activity. The inventors have unexpectedly discovered that, in certain embodiments, the presence of an antioxidant, e.g., a polyphenol, in the retinoid formulations disclosed herein in the manner disclosed herein provides better tolerance to the retinoid formulation, i.e., reduces and/or eliminates irritation or redness resulting from use of the formulation (such as, for example, over-the-counter products used daily).

In certain embodiments, the present disclosure provides formulations comprising one or more retinoids (including retinol) that can be used in the disclosed delivery systems. Certain disclosed formulations can provide retinoid stability, low irritation, or effective release of the active agent retinoid/retinol when applied to the skin. In one aspect disclosed herein, the skin is human skin. In other aspects disclosed herein, the skin is that of a companion animal, a domestic animal, or a commercial animal.

The inventors further believe, without wishing to be bound by theory, that the unexpected results associated with certain embodiments of the retinoid/retinol formulations are obtained by the synergistic working of the activation and solvent systems herein, i.e., the activation and solvent systems act resulting in controlled release of the retinoid active agent. Thus, certain embodiments of the disclosed formulations release the active agent with maximum, optimal strength and release rate with minimal or no irritation to the skin.

The disclosed formulations may also comprise at least one source of a retinoid. In one aspect of this embodiment, the retinoid may be retinol, retinoic acid, retinal, esters of retinol or retinoic acid (including, for example, palmitate, acetate, propionate, butyrate, hexanoate, heptanoate, octanoate, and stearate of retinol or retinoic acid) or synthetic retinoids (such as, but not limited to adapalene, bexarotene, tazarotene, or combinations of two or more thereof). Retinoids or flavonols are oily substances that are solubilized by the formulations disclosed herein. In one aspect of this embodiment, the retinoid is retinol. In another aspect, the retinoid is all-trans retinol (i.e., tretinoin). In one embodiment, retinol and/or its derivatives are the only active agent in the formulation. In another embodiment, retinol and/or its derivatives in combination with another additional active agent (e.g., bakuchiol) is the only active agent in the formulations described herein, although the application does not limit the number of active agents.

In particular embodiments, the formulations and delivery systems disclosed herein comprise from about 0.01 wt% to about 1.0 wt% retinol and/or one or more derivatives thereof, based on the total weight of the formulation. In various aspects of these embodiments, the formulations and delivery systems disclosed herein comprise retinol and/or one or more derivatives thereof in the following amounts, based on the total weight of the formulation: about 0.02 wt% to about 1.0 wt%, about 0.03 wt% to about 1.0 wt%, about 0.04 wt% to about 1.0 wt%, about 0.05 wt% to about 1.0 wt%, about 0.06 wt% to about 1.0 wt%, about 0.07 wt% to about 1.0 wt%, about 0.08 wt% to about 1.0 wt%, about 0.09 wt% to about 1.0 wt%, about 0.1 wt% to about 1.0 wt%, about 0.2 wt% to about 1.0 wt%, about 0.3 wt% to about 1.0 wt%, about 0.4 wt% to about 1.0 wt%, or about 0.5 wt% to about 1.0 wt%. Such formulations and delivery systems may be, for example, those used in consumer products.

In particular aspects of these embodiments, the formulations and delivery systems disclosed herein comprise retinol and/or one or more derivatives thereof in the following amounts, based on the total weight of the formulation: about 0.1 wt%, about 0.2 wt%, 0.3 wt%, 0.5 wt%, 0.75 wt%, or 1.0 wt%.

In particular embodiments, the formulations and delivery systems disclosed herein comprise about 1.0 wt% to 50 wt% retinol and/or one or more derivatives thereof. Such formulations and delivery systems may be, for example, those used by physicians in office procedures.

Retinoids are some of the most effective anti-aging ingredients used in Over The Counter (OTC) cosmeceutical moisturizers. These OTC retinoids include retinol esters, retinol and retinal, which are interconvertible. Retinol esters can be hydrolyzed in keratinocytes to retinol, which can be oxidized to retinal and subsequently oxidized again to retinoic acid, also known as retinoic acid. The anti-aging activity of retinoids can be summarized as:

retinoic acid, retinal, retinol ester

Unfortunately, the tolerance ranking is just the opposite:

retinol ester > retinol-retinal > > retinoic acid

The concomitant irritation, particularly with retinoic acid and retinal, is believed to be due to an overload of the retinoic acid-associated pathway in the skin with a supraphysiological amount of exogenous retinoic acid. Thus, the poor tolerability of retinoids limits their use.

In certain embodiments, the derivative of retinol may include one or more of the following: retinal, retinol ester, or retinoic acid (retinoic acid). In certain embodiments, the formulations and delivery systems described herein may include retinoic acid (retinoic acid) in the following amounts, based on the total weight of retinol and its derivatives in the formulations and delivery systems described herein: less than about 50 wt%, less than about 40 wt%, less than about 30 wt%, less than about 20 wt%, less than about 15 wt%, less than about 10 wt%, less than about 8 wt%, less than about 5 wt%, less than about 3 wt%, less than about 1 wt%, or substantially none (e.g., 0 wt%).

Without wishing to be bound by theory, the inventors believe that the increased delivery efficiency of the active agent retinoid (e.g., retinol and/or derivatives thereof) and the significant reduction in irritation observed when based on the retinoid formulations disclosed herein, in certain embodiments, allows for formulations and applications with significantly higher concentrations of retinoid (e.g., retinol and/or derivatives thereof) than previously used. Thus, certain disclosed retinoid formulations and delivery systems provide effective skin care treatments at over-the-counter intensity, while also being both mildly and well tolerated by consumers.

Without wishing to be bound by theory, the inventors believe that in certain embodiments, the retinoids, retinol and/or all-trans retinol of the formulations and delivery systems disclosed herein contribute to one or more of the following: increase skin cell turnover, support collagen production in the skin, and lighten pigmented areas in the skin. Thus, the inventors further believe, without being limited by theory, that such beneficial skin activity in certain embodiments may be the result of different genes turned on by the retinoid/retinol formulations disclosed herein.

Similarly, the inventors believe that in certain embodiments formulated and delivered herein, the pure and active form of vitamin a, i.e., all-trans retinol, provides one or more of the following: effective topical treatment, low incidence of irritation, support of the skin barrier, or increased cellular turnover in the skin. This may result in one or more of the following: reduction of the appearance of fine lines, wrinkles or age spots, and improvement of skin texture or complexion, or promotion of a collagen-rich appearance. As used herein, "pure" refers to a potency or activity measured as a percentage of the content of the referenced component or agent. In certain embodiments, the retinol contained in the retinoid/retinol formulations or delivery systems described herein comprises retinol in the following amounts, based on the total weight of retinol and its derivatives in the formulations and delivery systems described herein: at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98 wt%, at least about 99 wt%, or at least about 99.5 wt%.

In certain embodiments, retinol may degrade into a non-bioactive form when exposed to light and air, which may reduce its efficacy. Without being construed as limiting, it is believed that the efficacy of retinol in treating the skin conditions described herein depends on its oxidative stability and/or the delivery system in which it is formulated.

In certain embodiments, the formulations and/or delivery systems disclosed herein form an anhydrous microemulsion in which the retinol and/or derivatives thereof are broken up into a dispersed phase and the solvent system is in a continuous phase. In certain embodiments, the microemulsion nature of the formulation is believed to contribute to the stability of retinol. As used herein, the term "anhydrous microemulsion" refers to a microemulsion comprising water in the following amounts, based on the total weight of the formulation: less than about 5 wt% water, less than about 4 wt% water, less than about 3 wt% water, less than about 2 wt% water, less than about 1 wt% water, less than about 0.5 wt% water, or anhydrous (e.g., 0 wt%).

In certain embodiments, the solvent system comprises a polyol, which may be part of the continuous phase of the microemulsion. In certain embodiments, the solvent system comprises a glycol, which may be part of the continuous phase of the microemulsion. Exemplary diols may include, but are not limited to, one or more of the following: propylene glycol, butylene glycol, butynediol, pentylene glycol, hexylene glycol, octylene glycol, neopentyl glycol, 2-methyl-1, 3-propanediol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, dibutylene glycol, isoprene glycol, ethoxydiglycol, or combinations thereof. In one embodiment, the solvent system comprises isoprene glycol, which may be part of the continuous phase of the microemulsion. In one embodiment, the solvent system described herein comprises ethoxydiglycol. In one embodiment, the solvent system disclosed herein comprises isoprene glycol and ethoxydiglycol. In certain embodiments, the polyol (e.g., a diol such as isoprene glycol) also acts as a humectant by retaining moisture in the skin and creating a smooth film on the skin surface.

In certain embodiments, the formulations or delivery systems described herein may comprise glycols in amounts within the following ranges, based on the total weight of the formulation: any of about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, or about 50 wt%, to any of about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, or about 90 wt%, or any subrange or individual value therein. In certain embodiments, the formulations or delivery systems described herein may comprise glycols in amounts within the following ranges, based on the total weight of the formulation: any one of about 10 wt% to about 90 wt%, about 25 wt% to about 75 wt%, about 45 wt% to about 65 wt%, or about 50 wt% to about 60 wt%, or any subrange or individual value therein.

In certain embodiments, the formulations or delivery systems described herein may comprise an amount of isoprene glycol based on the total weight of the formulation within the following ranges: any of about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, or about 50 wt%, to any of about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, or about 90 wt%, or any subrange or single value therein. In certain embodiments, the formulations or delivery systems described herein may comprise an amount of isoprene glycol based on the total weight of the formulation within the following ranges: any one of about 10 wt% to about 90 wt%, about 25 wt% to about 75 wt%, about 45 wt% to about 65 wt%, or about 50 wt% to about 60 wt%, or any subrange or individual value therein.

In certain embodiments, the formulations or delivery systems described herein may comprise ethoxydiglycol in an amount within the following ranges, based on the total weight of the formulation: about 1 wt%, about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, or about 50 wt%, to any of about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, or about 80 wt%, or any subrange or single value therein. In certain embodiments, the formulations or delivery systems described herein may comprise ethoxydiglycol in an amount within the following ranges, based on the total weight of the formulation: any of about 1 wt% to about 80 wt%, about 1 wt% to about 10 wt%, about 1 wt% to about 5 wt%, or about 2 wt% to about 3 wt%, or any subrange or individual value therein.

In certain embodiments, the formulations or delivery systems described herein comprise isoprene glycol and ethoxydiglycol in a weight-to-weight ratio of: any of about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 10:1, or about 5:1, to any of about 1:5, about 1:10, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, or about 1:100, or any subrange or individual ratio therein. In certain embodiments, the formulations or delivery systems described herein have the following weight-to-weight ratios of isoprene glycol and ethoxydiglycol: about 50:1 to about 1:1, about 40:1 to about 10:1, or about 30:1 to about 20:1, or any subrange or individual ratio therein.

In certain embodiments, the solvent system of the formulations or delivery systems described herein further comprises isosorbide dimethyl ether. In certain embodiments, the formulations or delivery systems described herein may comprise isosorbide dimethyl ether (DMI) in an amount within the following ranges, based on the total weight of the formulation: any of about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, or about 50 wt%, to any of about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, or about 90 wt%, or any subrange or individual value therein. In certain embodiments, the formulations or delivery systems described herein comprise DMI in an amount within the following ranges, based on the total weight of the formulation: any one of about 5 wt% to about 90 wt%, about 15 wt% to about 60 wt%, about 20 wt% to about 40 wt%, or about 25 wt% to about 35 wt%, or any subrange or individual value therein.

In certain embodiments, the formulations or delivery systems described herein comprise a diol and a DMI in a weight-to-weight ratio of: any of about 20:1, about 15:1, about 10:1, about 8:1, about 5:1, about 3:1, or about 2:1, to any of about 1:2, about 1:3, about 1:5, about 1:8, about 1:10, about 1:15, or about 1:20, or any subrange or single ratio therein. In certain embodiments, the formulations or delivery systems described herein comprise a diol and a DMI in a weight-to-weight ratio of: about 20:1 to about 1:1, about 10:1 to about 1:1, or about 3:1 to about 1:1, or any subrange or individual ratio therein.

In certain embodiments, the solvent system of the formulations or delivery systems described herein further comprises a surfactant, such as a nonionic surfactant. Exemplary suitable nonionic surfactants include, but are not limited to, one or more of the following: ethoxylates, fatty ethoxylates, propoxylates, block copolymers, poloxamers, polyglycerol esters, polyglycerol emulsifiers, sorbitan, dipolar agents, phenolic nonionic surfactants, or combinations thereof. In certain embodiments, the nonionic surfactant in the formulations described herein comprises polysorbate 80.

In certain embodiments, the formulations or delivery systems described herein can include surfactants (e.g., nonionic surfactants) in amounts within the following ranges, based on the total weight of the formulation: about 1 wt%, about 3 wt%, about 5 wt%, about 8 wt%, about 10 wt%, about 15 wt%, or about 20 wt% to about 25 wt%, about 30 wt%, about 35 wt%, or about 40 wt%, or any subrange or individual value therein. In certain embodiments, the formulations or delivery systems described herein comprise a surfactant (e.g., a nonionic surfactant) in an amount within the following ranges, based on the total weight of the formulation: any one of about 1 wt% to about 40 wt%, about 3 wt% to about 15 wt%, about 6 wt% to about 10 wt%, or about 7 wt% to about 9 wt%, or any subrange or individual value therein.

In certain embodiments, the formulations or delivery systems described herein may include polysorbate 80 in an amount within the following ranges, based on the total weight of the formulation: about 1 wt%, about 3 wt%, about 5 wt%, about 8 wt%, about 10 wt%, about 15 wt%, or about 20 wt% to about 25 wt%, about 30 wt%, about 35 wt%, or about 40 wt%, or any subrange or individual value therein. In certain embodiments, the formulations or delivery systems described herein comprise polysorbate 80 in an amount within the following ranges, based on the total weight of the formulation: any one of about 1 wt% to about 40 wt%, about 3 wt% to about 15 wt%, about 6 wt% to about 10 wt%, or about 7 wt% to about 9 wt%, or any subrange or individual value therein.

In certain embodiments, the formulations or delivery systems described herein comprise a glycol (e.g., isoprene glycol and/or ethoxydiglycol) and a surfactant (e.g., polysorbate 80) in the following weight-to-weight ratios: about 20:1, about 15:1, or any of about 10:1, to about 8:1, about 5:1, about 3:1, or any of about 1:1, or any subrange or single ratio therein. In certain embodiments, the formulations or delivery systems described herein comprise a glycol and a surfactant having the following weight-to-weight ratios: about 20:1 to about 1:1, about 10:1 to about 1:1, or about 5:1 to about 1:1, or any subrange or individual ratio therein.

The disclosed formulations also comprise one or more solubilizing and/or emulsifying agents and/or dispersing agents. In one aspect of this embodiment, the solubilizing/emulsifying/dispersing agent is a nonionic solubilizing/emulsifying/dispersing agent.

In certain embodiments, the formulations described herein further comprise bakuchiol. Without being construed as limiting, it is believed that in certain embodiments, bakuchiol enhances retinol. The bakuchiol is derived from seed of Psoralea corylifolia, and is a novel dermatological ingredient with antioxidant, anti-inflammatory and antibacterial properties. It is not a retinoid and, in certain embodiments, remains photostable. It is believed to have retinol-like functionality through the regulation of retinol-like gene expression that induces the upregulation of I, III and type IV collagen and extracellular matrix synthase.

One of the challenges associated with retinol formulations is to pre-form retinol and allow it to penetrate the skin without causing irritation. In certain embodiments, the solvent system described herein helps to enhance the penetration of retinol into the skin, which is further enhanced by bakuchiol, thereby achieving the benefits of tretinoin without concomitant irritation. In certain aspects, it is believed that bakuchiol can be used as a cosolvent for retinol because of their similarity in chemical structure.

In certain embodiments, the formulations described herein can include a retinoid (e.g., retinol) and bakuchiol, e.g., with any of the delivery systems described herein and/or with any of the excipients described herein.

In certain embodiments, the formulations described herein may comprise bakuchiol in an amount within the following ranges, based on the total weight of the formulation: 0 wt% or more, about 0.1 wt%, about 0.3 wt%, about 0.5 wt%, about 0.7 wt%, or about 1 wt%, to any of about 3 wt%, about 5 wt%, about 7 wt%, about 10 wt%, about 15 wt%, or about 20 wt%, or any subrange or individual value therein. In certain embodiments, the formulations described herein may comprise bakuchiol in an amount within the following ranges, based on the total weight of the formulation: more than 0 wt% to about 20 wt%, from about 0.1 wt% to about 3 wt%, from about 0.5 wt% to about 2 wt%, or any subrange or individual value therein.

In certain embodiments, the weight-to-weight ratio of retinol to bakuchiol is within the following range: about 10:1 to about 1:10, about 8:1 to about 1:8, about 5:1 to about 1:5, about 3:1 to about 1:3, or about 2:1 to about 1:2, or any subrange or individual ratio therein.

In certain embodiments, the formulations described herein further comprise polysorbate 20, which may be complexed with and/or solubilize retinol. In certain embodiments, the formulations described herein may comprise polysorbate in amounts within the following ranges, based on the total weight of the formulation: 0 wt% or more, about 0.01 wt%, about 0.1 wt%, about 0.3 wt%, about 0.5 wt%, about 0.7 wt%, or about 1 wt%, to any one of about 3 wt%, about 5 wt%, about 7 wt%, about 10 wt%, about 15 wt%, about 20 wt%, or about 30 wt%, or any subrange or individual value therein. In certain embodiments, the formulations described herein may comprise bakuchiol in an amount within the following ranges, based on the total weight of the formulation: more than 0.01 wt% to about 30 wt%, from about 0.1 wt% to about 3 wt%, from about 0.2 wt% to about 0.5 wt%, or any subrange or individual value therein.

In certain embodiments, the weight-to-weight ratio of retinol to polysorbate 20 is within the following range: about 10:1 to about 1:10, about 8:1 to about 1:8, about 5:1 to about 1:5, about 3:1 to about 1:3, about 2:1 to about 1:2, or about 1:1, or any subrange or individual ratio therein.

In certain embodiments, the formulations described herein provide for the effective delivery of retinol, which may be attributed to one or more components of a unique solvent system, for example, a polyol (e.g., a glycol such as isoprene glycol and/or ethoxydiglycol), DMI, a surfactant (e.g., polysorbate 80), bakuchiol, or a combination thereof. In one embodiment, the efficacy of the solvent system is enhanced by including one or more of the following: isoprene glycol, DMI, polysorbate 80, bakuchiol, or a combination thereof.

In certain embodiments, the formulations described herein further comprise an antioxidant system, such as a plant anti-inflammatory agent, to reduce irritation. In certain embodiments, the formulations described herein include, but are not limited to, one or more of the following: tea polyphenols (green tea), black tea extract, glycyrrhiza glabra (glycyrrhiza glabra) root extract, or combinations thereof.

Antioxidants, particularly green tea polyphenols, and retinol, are generally considered to be notoriously difficult to stabilize because they are susceptible to oxidation and/or degradation by oxygen, moisture, light, trace metals, and other components often contained in reagents. This is particularly true for topical formulations which present a large surface area when spread on the skin, thus promoting air oxidation of sensitive ingredients of the applied agent, and/or when a stable long-term shelf life (e.g. 2 years) of the formulation is sought. Surprisingly and unexpectedly, certain disclosed formulations overcome these formulations and provide a stable, non-or minimally irritating, or effective system for topical application to the skin.

The antioxidant contained in the disclosed retinoid formulations may include tea (green tea) polyphenols. In a particular embodiment, a purified extract of tea (green tea) polyphenols is included in the formulation. The present disclosure contemplates polyphenols that may be in purities ranging from trace amounts obtained from, for example, green tea extracts to 100% pure polyphenols. Although any tea (green tea) preparation of polyphenols may be formulated in various embodiments, in particular aspects of the present embodiments a purified preparation of 90% or 95% of the polyphenols of tea (green tea) may be formulated. In various other formulations, the amount of polyphenol antioxidant added is inversely related to its purity.

The antioxidants included in the disclosed retinoid formulations may include tea (green tea) polyphenols, which may be a mixture of multiple polyphenol species. Suitable green tea polyphenols include, but are not limited to, catechins such as epigallocatechin gallate (EGCG), Epigallocatechin (EGC), epicatechin gallate (ECG), and Epicatechin (EC), cis and trans isomers thereof, salts thereof, equivalent derivatives thereof, and combinations thereof. In a particular aspect, the major component of the formulated polyphenol antioxidant is epigallocatechin gallate (EGCG).

In certain embodiments, the formulations described herein comprise an antioxidant system comprising any of the green tea polyphenols described herein in combination with at least one additional antioxidant (such as, but not limited to, black tea extract and/or licorice extract).

In one embodiment, the additional antioxidant in the antioxidant system may be selected from the group consisting of cinnamic acid, ferulic acid, caffeic acid, p-coumaric acid, sinapic acid, cis and trans isomers thereof, salts thereof, equivalent derivatives thereof, and combinations thereof. In another embodiment, the additional antioxidants in the antioxidant system (and in the topical composition in general) are free or substantially free of cinnamic acid, ferulic acid, caffeic acid, p-coumaric acid, sinapic acid, their cis and trans isomers, salts thereof, equivalent derivatives thereof, and combinations thereof.

In certain embodiments, the additional antioxidant in the antioxidant system may be selected from the group consisting of gallic acid, delphinidin, luteolin, quercetin, anthocyanins, taxifolin, kaempferol, malvidin, hesperidin, pelargonidin, apigenin, naringenin, chrysin, ergothioneine, glutathione, emblica, its cis and trans isomers, salts thereof, equivalent derivatives thereof, and combinations thereof.

In certain embodiments, the additional antioxidant in the antioxidant system may be selected from apigenin, ergothioneine, glutathione, emblic leafflower fruit, cis and trans isomers thereof, salts thereof, equivalent derivatives thereof, and combinations thereof.

The disclosed formulations may also contain xanthine-related compounds, polymeric derivatives thereof, or mixtures of xanthine-related materials that can be used as antioxidants or stimulators of antioxidant activity. In a particular aspect, the xanthine-related compound is caffeine. In another particular aspect, the caffeine of the disclosed formulations and delivery systems is pure, ultra-pure, or USP grade caffeine.

The disclosed formulations may also include one or more humectants and/or moisturizers. The disclosed formulations may also include one or more emollients. In one aspect of this embodiment, the softening agent can be an ester, an oil, or a silicone. In various aspects of this embodiment, the softening agent may comprise one or more of the following: shea butter, cocoa butter, mineral oil, lanolin, petrolatum, paraffin, beeswax, squalene, cetyl alcohol, olive oil, tri-iso-caprylic glyceride, coconut oil, jojoba oil, sesame oil, almond oil or other vegetable oils, omega-6 fatty acids, ceramides, primrose oil, grape seed oil, ceramides, and combinations of two or more thereof.

Each antioxidant in the antioxidant system may be present individually or cumulatively at the following concentrations, based on the total weight of the formulation: more than 0 wt.%, about 0.001 wt.%, about 0.01 wt.%, about 0.05 wt.%, about 0.1 wt.%, about 0.15 wt.%, about 0.2 wt.%, about 0.25 wt.%, about 0.3 wt.%, about 0.35 wt.%, or about 0.4 wt.%, to about 0.45 wt.%, about 0.5 wt.%, about 0.55 wt.%, about 0.6 wt.%, about 0.65 wt.%, about 0.7 wt.%, about 0.75 wt.%, about 0.8 wt.%, about 0.85 wt.%, about 0.9 wt.%, about 0.95 wt.%, about 1 wt.%, about 1.5 wt.%, about 2 wt.%, about 3 wt.%, about 4 wt.%, about 5 wt.%, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, about 10 wt.%, about 15 wt.%, or about 20 wt.%, any single one or sub-range therein.

In certain embodiments, the antioxidant system comprises black tea extract present in an amount within the following ranges, based on the total weight of the formulation: 0 wt.% or more to about 20 wt.%, about 0.001 wt.% to about 5 wt.%, or about 0.001 wt.% to about 0.5 wt.%, or any subrange or individual value therein.

In certain embodiments, the antioxidant system comprises licorice extract present in the formulation in an amount within the following range, based on the total weight of the formulation: 0 wt.% or more to about 20 wt.%, about 0.001 wt.% to about 5 wt.%, or about 0.001 wt.% to about 0.5 wt.%, or any subrange or individual value therein.

In certain embodiments, the antioxidant system comprises green tea polyphenols in an amount within the following ranges, based on the total weight of the formulation: about 0.1 wt.% to about 15 wt.%, about 0.1 wt.% to about 5 wt.%, or about 0.5 wt.% to about 2 wt.%, or any subrange or individual value therein.

In certain embodiments, the antioxidant system comprises a xanthine (e.g., caffeine) in an amount within the following ranges, based on the total weight of the formulation: about 0.01 wt.% to about 10 wt.%, about 0.1 wt.% to about 5 wt.%, or about 0.5 wt.% to about 2.5 wt.%, or any subrange or individual value therein.

In certain embodiments, the antioxidant system comprises, consists of, or consists essentially of: any of the green tea polyphenols described herein in combination with any of the xanthines (e.g. caffeine), black tea extract and licorice extract at (individual or cumulative) concentrations based on the total weight of the formulation: more than 0 wt.%, about 0.001 wt.%, about 0.01 wt.%, about 0.05 wt.%, about 0.1 wt.%, about 0.15 wt.%, about 0.2 wt.%, about 0.25 wt.%, about 0.3 wt.%, about 0.35 wt.%, or about 0.4 wt.%, to any one of about 0.45 wt.%, about 0.5 wt.%, about 0.55 wt.%, about 0.6 wt.%, about 0.65 wt.%, about 0.7 wt.%, about 0.75 wt.%, about 0.8 wt.%, about 0.85 wt.%, about 0.9 wt.%, about 0.95 wt.%, about 1 wt.%, about 1.5 wt.%, about 2 wt.%, about 3 wt.%, about 4 wt.%, about 5 wt.%, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, about 10 wt.%, about 15 wt.%, or any single one or sub-range thereof.

In certain embodiments, the weight-to-weight ratio of green tea polyphenols to the cumulative one or more additional antioxidants (e.g., xanthines (e.g., caffeine), black tea extract, and licorice extract) is within the following range: about 10:1 to about 1:10, about 8:1 to about 1:8, about 5:1 to about 1:5, about 3:1 to about 1:3, about 2:1 to about 1:2, or about 1: 1.

The inventors have noted that certain embodiments not only provide for robust antioxidant reduction of Reactive Oxygen Species (ROS), but that they also surprisingly provide for a reduction of irritation typically associated with retinol applications. This reduction in irritation observed in certain embodiments is significantly superior to other formulations. Inclusion of these materials in certain disclosed formulations can enhance patient compliance. As noted in the tests presented below, patients adhered to the treatment regimen because they were not or minimally stimulated. Thus, while irritation is a major problem for topical retinol applications, no or minimal irritation is observed when tested identically with certain retinoids disclosed herein.

In a further embodiment, the all-trans retinol of the above formulation may be replaced or supplemented by one or more of the following retinoids at the indicated weight percent (% w/w) levels: retinal (0.01% -1%), retinol ester (0.01% -5%), retinoic acid (0.01% -0.2%), synthetic retinoids, such as adapalene (0.02-0.5%), tazarotene (0.01% -0.2%).

In still further embodiments, the all-trans retinol of the above formulations may be replaced or supplemented by one or more of the following retinoids at the indicated (% w/w) levels: retinal (0.05-0.10%), retinol esters (0.1-2%), retinoic acid (0.02% -0.15%), synthetic retinoids, e.g., adapalene (0.1-0.3%), tazarotene (0.05% -0.1%).

In certain embodiments, the dosage of the formulations of the present disclosure to be applied to the skin is within the following range: 0.01g to 5g, 0.02g to 4g, 0.05g to 3g, 0.1g to 2g, 0.2g to 1 g. In one aspect of these embodiments, the dosage of the formulation of the present disclosure to be applied to the skin may be 0.4 g. The actual dosage applied will depend on the condition to be treated, the particular regimen to be followed, and the personal preferences of the user, among other things. For example, different dosages may be used for spot treatments, multi-spot treatments, full or partial face treatments, body part (e.g., neck, hand, etc.) treatments, and the like.

In certain embodiments, the formulation comprises at least one additional cosmetically acceptable excipient. Exemplary cosmetically acceptable excipients include, but are not limited to, epidermal penetration enhancers, solvents, mild surfactants, oil bodies, emulsifiers, pearlizing waxes, consistency regulators, thickeners, rheology modifiers, suspending agents, chelating agents, preservatives, superfatting agents, stabilizers, polymers, silicone or siloxane compounds (e.g., octyl methyl silicone, PEG/PPG-18/18 dimethyl silicone), fats, waxes, lecithins, phospholipids, uv light protection factors, bioactive ingredients, additional antioxidants, deodorants, antiperspirants, antidandruff agents, film formers, bulking agents, insect repellents, self tanning agents, tyrosinase inhibitors, hydrotropes, solubilizing agents, essential oils, dyes, zinc oxide, fatty alcohols, fatty acid esters, adjuvants, natural or synthetic triglycerides (including glycerides and derivatives), Hydrocarbon oils, superfatting agents, polymers, bioactive ingredients, hydrotropes, bacteriostats, colorants, ultraviolet screening agents, agents that absorb ultraviolet light and provide photoprotection to the skin, or combinations thereof.

Additional cosmetically acceptable excipients

In certain embodiments, the cosmetically acceptable excipient comprises a natural gum (e.g., a natural plant gum). Suitable natural gums include, but are not limited to, guar gum, carob gum, konjac gum, xanthan gum, sclerotium gum, gum arabic, cellulose gum (modified or unmodified), or combinations thereof.

In certain embodiments, the cosmetically acceptable vehicle comprises an emulsifier. Suitable emulsifiers include, but are not limited to, PEG-30 dipolyhydroxystearate, PEG-4 dilaurate, PEG-8 glycolate, PEG-40 sorbitan monooleate, PEG-7 glyceryl cocoate, PEG-2 amygdaline, PEG-25 hydrogenated castor oil, glyceryl stearate (and) PEG-100 stearate, PEG-7 olivate, PEG-8 oleate, PEG-8 laurate, PEG-60 amygdaline, PEG-20 methylgluconate, PEG-40 stearate, PEG-100 stearate, PEG-80 sorbitan laurate, steareth-2, steareth-12, oleyl-2, cetyl polyether-2, laureth-4, oleyl-10, Oleyl-10/polyethylene glycol 10 oleyl ether, ceteth-10, steareth-20, ceteth-20, oleyl-20, steareth-21, ceteth-20, laureth-23, steareth-100, glyceryl stearate citrate, glyceryl stearate SE (self emulsifying), stearic acid, stearate, polyglycerol-3-methylglucose distearate or a combination thereof.

Other suitable emulsifiers are phosphoric esters and salts thereof, e.g. cetyl phosphate (C:)A) Cetyl diethanolamine phosphate (C)DEA), potassium cetyl phosphate (K) Sodium cetylstearyl sulfate, sodium glyceryl oleate phosphate, hydrogenated vegetable glyceryl phosphates and mixtures thereof. Other suitable emulsifiers are sorbitan oleate, sorbitan sesquioleate, sorbitan isostearate, sorbitan trioleate, cetearyl glucoside, lauryl glucoside, decyl glucoside, sodium stearyl glutamate, sucrose polystearate and hydrated polyisobutene. Furthermore, one or more synthetic polymers may be used as emulsifiers. For example, PVP eicosene copolymer, acrylates/C_10-30Alkyl acrylate crosspolymers, acrylate/steareth-20 methacrylate copolymers, PEG-22/dodecanediol copolymers, PEG-45/dodecanediol copolymers and mixtures thereof.

In certain embodiments, the cosmetically acceptable vehicle comprises a chelating agent. Suitable chelating agents include, but are not limited to, disodium Ethylenediaminetetraacetate (EDTA), diethylenetriaminepentaacetic acid (DTPA), N- (hydroxyethyl) -ethylenediaminetetraacetic acid (HEDTA), and nitrilotriacetic acid (NTA).

In certain embodiments, the cosmetically acceptable vehicle comprises additional antioxidants, such as certain forms of vitamin E. Suitable forms of vitamin E that may be included in the topical composition may be selected from alpha, beta, delta, and gamma-tocopherols and alpha, beta, delta, and gamma-tocotrienols and combinations thereof.

In certain embodiments, the cosmetically acceptable vehicle in the topical composition comprises a preservative. Suitable preservatives include, for example, phenoxyethanol, paraben solutions, pentanediol and sorbic acid, and also under the trade reference namesSilver complexes are known and other classes of substances (i.e. suitable preservatives) are listed in appendix 6 of parts a and B of the cosmetic legislation.

In certain embodiments, the cosmetically acceptable vehicle comprises an essential oil. Suitable essential oils comprise a mixture of natural and synthetic fragrances. Natural fragrances are from flowers (lily, lavender, rose, jasmine, orange blossom, ylang), stems and leaves (geranium, patchouli, jatropha), fruits (fennel, caraway, cumin, juniper berry), fruit peels (bergamot, lemon, orange), roots (nutmeg, angelica, celery, cardamom, aucklandia, iris, agilawood), wood (pine, sandalwood, guaiac, fir, rosewood), herbs and herbs (tarragon, lemon grass, sage, thyme), needles and twigs (spruce, fir, pine, short pine), resins and balsams (white rosin, elemi, benzoin, myrrh, frankincense, red myrrh extracts Linalyl acetate, dimethyl benzyl carbene acetate, phenethyl acetate, linalyl benzoate, benzyl formate, ethyl tolyl glycinate, allyl cyclohexyl propionate, styrallyl propionate and benzyl salicylate. Ethers include, for example, benzyl ethyl ether, aldehydes include, for example, linear alkyl acetals having 8 to 18 carbon atoms, citral, citronellal, citronelloyloxyacetal, cyclamenal, hydroxycitronellal, lily aldehyde and taraxylaldehyde, ketones include, for example, ionone, α -isomethylionone and methyl cedrone, alcohols include anethole, citronellol, eugenol, isoeugenol, geraniol, linalool, phenethyl alcohol and terpineol, and hydrocarbons include mainly terpenes and balsams.

Relatively low volatility essential oils which are used primarily as fragrance ingredients are also suitable for use as essential oils, such as sage oil, chamomile oil, clove oil, lemon balm oil, peppermint oil, cinnamon leaf oil, linden flower oil, juniper berry oil, vetiver oil, frankincense oil, white rosin oil, opium (labolanum) oil and lavender oil. Other suitable oils include bergamot oil, dihydrolauryl alcohol, lily aldehyde, chrysal, citronellol, phenylethyl alcohol, alpha-hexyl cinnamaldehyde, geraniol, benzyl acetone, cyclamen aldehyde, linalool, robinol, ambroxol, indole, cnidium ketone, sapphia, lemon oil, citrus oil, orange oil, allyl glycolate, cyclopentanal, vanillin oil, sage oil, beta-damascenone, geranium oil bourbon, cyclohexyl salicylate, Vertofix coeur, amberlone, Fixolide NP, evernyl, iraldein-gamma, phenylacetic acid, geranyl acetate, benzyl acetate, rose bengal, romil, irotyl, and floramat, alone or in combination.

In certain embodiments, the cosmetically acceptable vehicle comprises an essential oil selected from lavender oil, bergamot oil, eucalyptus oil, chamomile oil, cajeput oil, or combinations thereof. In one embodiment, the cosmetically acceptable vehicle comprises lavender oil, chamomile oil, or a combination thereof.

In certain embodiments, the essential oils (each essential oil alone or all essential oils cumulatively in the topical composition) are present in the topical composition in an amount such that, based on the total weight of the topical composition: 0 wt.% or more to about 5 wt.%, from 0 wt.% or more to about 1 wt.%, or about 0.01 wt.% to about 0.3 wt.%.

In certain embodiments, the pH of the topical composition is in the following range: any of about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, or about 2.9, to any of about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, or about 4.0. In certain embodiments, the pH of the topical composition is from about 2.0 to about 4.0, from about 2.5 to about 3.5, or from about 2.7 to about 3.3.

The formulations described herein may be formulated in any dermatologically acceptable form, such as a serum, lotion, cream, foam, spray, ointment, gel, lotion, or as a pad or roll-on application formulation, which may contain ingredients that physically or cosmetically improve, modify, or stabilize the composition.

Formulations according to the present disclosure may further comprise one or more additional cosmetically acceptable excipients as described below.

Fatty alcohols

Guerbet alcohols based on fatty alcohols having from 6 to 18 carbon atoms, preferably from 8 to 10 carbon atoms, including cetyl alcohol, stearyl alcohol, cetearyl alcohol, oleyl alcohol, octyldodecanol, C₁₂-C₁₅Alcohol benzoates, acetylated lanolin alcohols, and the like.

Fatty acid esters

Straight chain C₆-C₂₄Fatty acids and straight chains C₃-C₂₄Esters of alcohols, branches C₆-C₁₃Carboxylic acids with straight chains C₆-C₂₄Esters of fatty alcohols, straight-chain C₆-C₂₄Esters of fatty acids with branched alcohols, in particular 2-ethylhexanol, hydroxycarboxylic acids with straight-chain or branched C₆-C₂₂Esters of fatty alcohols (in particular dioctyl malate), esters of straight-chain and/or branched fatty acids with polyhydric alcohols (for example propylene glycol, dimer diol or trimer triol) and/or Guerbet alcohols, for example esters of acids and alcohols such as isopropanol, hexanol, octanoic acid, 2-ethylhexanoic acid, decanoic acid, lauric acid, isotridecanoic acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, isostearic acid, oleic acid, elaidic acid, parsley acid, linoleic acid, linolenic acid, eleostearic acid, arachidic acid, gadoleic acid (gadoleic acid), behenic acid and erucic acid and technical-grade mixtures thereof (for example obtained in the pressure removal of natural fats in the reduction of aldehydes from the oxidative synthesis of Roelen's, or in the two places of unsaturated fatty acids), such as isopropanol, hexanol, octanol, 2-ethylhexanol, decanol, lauryl alcohol, Isotridecyl alcohol, myristyl alcohol, cetyl alcohol, palmitoyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, elaidyl alcohol, parsley alcohol (petroselinyl alcohol), linoleyl alcohol, linolenyl alcohol, tungenyl alcohol, arachidyl alcohol, gadoleyl alcohol (gadoleyl alcohol), behenyl alcohol, erucyl alcohol (erucyl alcohol), bronsted alcohol (brassidyl alcohol) and technical mixtures thereof (for example, in the oil-and-fat based technical methyl ester or high pressure hydrogenation from the Roelen's oxidative synthesis, and as a monomeric fraction of the dimerisation of unsaturated fatty alcohols).

Examples of such ester oils are isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl isostearate, isopropyl oleate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, isononyl isononanoate, 2-ethylhexyl palmitate, 2-hexyl laurate, 2-hexyl stearate, 2-octyl laurate palmitate, oleyl oleate, oleyl erucate, erucyl alcohol, cetearyl octanoate, cetyl palmitate, cetyl stearate, cetyl oleate, cetyl behenate, cetyl acetate, myristyl myristate, myristyl behenate, myristyl oleate, myristyl stearate, myristyl palmitate, myristyl lactate, propylene glycol dicaprylate/caprate, isopropyl laurate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, isononyl isononanoate, 2-ethylhexyl palmitate, cetyl oleate, 2-hexyl laurate, 2-octyl palmitate, cetyl oleate, myristyl palmitate, myristyl myristate, myristyl lactate, propylene glycol dicaprylate/caprate, caprylate, propylene glycol dicaprate, caprylate, caprylic acid ester, cetyl palmitate, cetyl oleate, cetyl palmitate, glyceryl myristate, and mixtures thereof, and mixtures of various esters, Stearyl heptanoate, diisostearyl malate, octyl hydroxystearate, and the like.

Other adjuvants

Dihexyl-2, 6-naphthalenedicarboxylate, di-n-butyl adipate, di-2-ethylhexyl succinate and di-isotridecyl lactate, and glycol esters such as ethylene glycol dioleate, ethylene glycol diisotridecanoate, propylene glycol di (2-ethylhexanoate), propylene glycol diisostearate, propylene glycol dipelargonate, butylene glycol diisostearate and neopentyl glycol dicaprylate. C₆-C₂₄Esters of aliphatic alcohols and/or Guerbet alcohols with saturated and/or unsaturated aromatic carboxylic acids, in particular benzoic acid, C₂-C₁₂Esters of dicarboxylic acids with straight-chain or branched alcohols having 1 to 22 carbon atoms or polyols having 2 to 10 carbon atoms and 2-6 hydroxyl groups.

Natural or synthetic triglycerides, including glycerides and derivatives

Based on C₆-C₁₈Diglycerides or triglycerides of fatty acids, modified by reaction with other alcohols (caprylic/capric triglycerides, wheat germ glycerides, etc.). Polyglycerol esters (polyglycerol-n, such as polyglycerol-4 decanoate, polyglycerol-2 isostearate, etc.) or castor oil, hydrogenated vegetable oil, sweet almond oil, wheat germ oil, sesame oil, hydrogenated cottonseed oil, coconut oil, avocado oil, corn oil, hydrogenated castor oil, shea butter, cocoa butter, soybean oil, mink oil, sunflower seed oil, safflower oil, macadamia nut oil, olive oil, hydrogenated tallow, almond oil, hazelnut oil, borage oil, etc.

Waxes include esters of long chain acids and alcohols, as well as compounds with waxy properties, such as carnauba wax, beeswax (white or yellow), lanolin wax, candelilla wax, white wax (ozokerite), japan wax, paraffin wax, microcrystalline wax, ceresin, cetyl esters wax, synthetic beeswax, and the like. Also hydrophilic waxes, such as cetostearyl alcohol or partial glycerides.

Pearly wax:

alkyl glycol esters, especially ethylene glycol distearate; fatty acid alkanolamides, in particular coconut oil fatty acid diethanolamide; partial glycerides, in particular stearic acid monoglyceride; esters of polyvalent unsubstituted or hydroxy-substituted carboxylic acids with fatty alcohols having from 6 to 22 carbon atoms, especially the long-chain esters of tartaric acid; fatty substances, such as fatty alcohols, fatty ketones, fatty aldehydes, fatty ethers and fatty carbonates, which have a total of at least 24 carbon atoms, in particular lauryl and distearyl ether; fatty acids, such as stearic, hydroxystearic or behenic acid, ring-opening products of olefinic epoxy compounds having 12 to 22 carbon atoms with fatty alcohols having 12 to 22 carbon atoms and/or polyols having 2 to 15 carbon atoms and 2 to 10 hydroxyl groups, and mixtures thereof.

Hydrocarbon oil:

mineral oil (light or heavy), petrolatum (yellow or white), microcrystalline wax, paraffin and isoparaffinic compounds, hydrogenated isoparaffinic molecules (such as polydecene and polybutene), hydrogenated polyisobutene, squalane, isohexadecane, isododecane and other substances from the plant and animal kingdom.

Silicone or siloxane (organic substituted polysiloxane)

Dimethylpolysiloxanes, methylphenylpolysiloxanes, cyclic silicones, and amino-, fatty acid-, alcohol-, polyether-, epoxy-, fluorine-, glycoside-and/or alkyl-modified silicone compounds, which may be in liquid or resin form at room temperature. Linear polysiloxanes, dimethicone (Dow conning 200 fluid, Rhodia Mirasil DM), dimethicone carbinol, cyclic silicone fluid, cyclopentasiloxane volatiles (Dow Corning345 fluid), phenyl trimethicone (Dow Corning 556 fluid). Also suitable are simethicones, which are mixtures of dimethylsilicones having an average chain length of 200 to 300 dimethylsiloxane units with hydrosilicates. In addition, a detailed investigation of suitable volatile silicones by Todd et al can also be found in cosm. toil.91, 27 (1976).

Emulsifier

Any conventionally available emulsifier can be used in the composition. The emulsifier system may include, for example: carboxylic acids and salts thereof: alkaline soaps of sodium, potassium and ammonium, metal soaps of calcium or magnesium, organic based soaps (e.g. lauric, palmitic, stearic and oleic acids, etc.). Alkyl phosphates or phosphonates, acid phosphates, diethanolamine phosphate, potassium cetyl phosphate. Ethoxylated carboxylic acids or polyethylene glycol esters, PEG-n acrylates. Linear fatty alcohols having from 8 to 22 carbon atoms, from 2 to 30mol of ethylene oxide and/or from 0 to 5mol of propylene oxide being branched with fatty acids having from 12 to 22 carbon atoms and with alkylphenols having from 8 to 15 carbon atoms in the alkyl radical. Fatty alcohol polyglycol ethers, such as laureth-n, ceteth-n, steareth-n, oleyl-n. Fatty acid polyglycol ethers, such as stearic acid PEG-n, oleic acid PEG-n, and coconut acid PEG-n. Monoglycerides and polyol esters. C of 1-30mol of addition product of ethylene oxide and polyhydric alcohol₁₂-C₂₂Fatty acid monoesters and diesters. Fatty acids and polyglycerol esters, such as glycerol monostearate, diisostearyl-polyglycerol-3-diisostearate, triglycerol diisostearate, polyglycerol-2-sesquiisostearate or polyglycerol dimer acid ester. Mixtures of compounds from a plurality of these substance classes are also suitable. Fatty acid polyglycol esters such as diethylene glycol monostearate, fatty acid and polyethylene glycol esters, esters of fatty acid and sucrose such as sucrose esters, esters of glycerol and sucrose such as sucrose glycerides. Sorbitol and sorbitan, sorbitan mono-and diesters of saturated and unsaturated fatty acids having from 6 to 22 carbon atoms and ethylene oxide addition products. Polysorbate-n series, sorbitan esters such as sesquiisostearate, sorbitan, PEG- (6) -isostearate sorbitan, PEG- (10) -sorbitan laurate, and PEG-17-dioleate sorbitan. Glucose derivative, C₈-C₂₂Alkyl monoglycosides and oligosaccharide glycosides and ethoxylated analogues, with glucose being preferred as the sugar component. O/W emulsifiers, e.g. methyl glucose polyether-20 times half stearate, sorbitan stearate/sucrose cocoate, methyl glucose sesquistearateAcid esters, cetearyl alcohol/cetearyl glucoside. W/O emulsifiers, such as methyl glucose dioleate/methyl glucose isostearate. Sulfates and sulfonated derivatives, dialkyl sulfosuccinates, dioctyl succinate, alkyl lauryl sulfonates, linear sulfonated paraffins, sulfonated tetrapropylene sulfonates, sodium lauryl sulfate, ammonium lauryl sulfate and ethanolamine, lauryl ether sulfates, laureth sulfates, sulfosuccinates, acetoisothioesters (acetyl isothionates), alkanolamide sulfates, taurine, methyltaurine, imidazole sulfates. Polysiloxane/polyalkyl/polyether copolymers and derivatives, dimethyl silicone, copolyols, silicone-polyoxyethylene copolymers, silicone-ethylene glycol copolymers. Propoxylated or POE-n ethers (Meroxapols), poloxamers or poly (oxyethylene) m-block-poly (oxypropylene) n-block (oxyethylene). Zwitterionic surfactants carry at least one quaternary ammonium group and at least one carboxylate and/or sulfonate group in the molecule. Particularly suitable zwitterionic surfactants are betaines, for example N-alkyl-N, N-dimethylammonium glycinate, cocoalkyldimethylammonium glycinate, N-acylaminopropyl-N, N-dimethylammonium glycinate, cocoacylaminopropyl-dimethylammonium glycinate and 2-alkyl-3-carboxymethyl-3-hydroxyethylimidazoline, each having 8 to 18 carbon atoms in the alkyl or acyl group, and also cocoacylaminoethylhydroxyethylcarboxymethyl glycinate, N-alkylbetaines, N-alkylaminobetaines. Alkyl imidazolines, alkyl peptides, lipoamino acids, self-emulsifying bases and compounds as described in K.F. DePolo, A short textbook of cosmetology (short text for cosmetics) Chapter 8, tables 8-7, page 250-251.

Nonionic bases such as PEG-6 beeswax (and) PEG-6 stearate (and) polyglycerol-2-isostearate, glyceryl stearate (and) PEG-100 stearate, PEG-5 glyceryl stearate, sorbitan oleate (and) polyglycerol-3 ricinoleate, sorbitan stearate and sucrose cocoate, glyceryl stearate and laureth-23, cetearyl alcohol and ceteth-20, cetearyl alcohol and polysorbate 60 and PEG-150 and stearate-20, cetearyl alcohol and cetearyl polyglucoside, cetearyl alcohol and ceteareth-20, cetearyl alcohol and PEG-40 castor oil and sodium cetearyl sulfate, stearyl alcohol and steareth-7 and steareth-10, cetostearyl and ceteth-7 and 10, glyceryl stearate and PEG-75 stearate, propylene glycol ceteth-3 acetate, propylene glycol isocetyl-3 acetate, cetostearyl and ceteth-12 and oleyl-12, PEG-6 stearate and PEG-32 stearate, PEG-6 stearate and ceteth-20 and steareth-20, PEG-6 stearate and ceteth-20 and glyceryl stearate and steareth-20, glyceryl stearate and ceteth-20.

Anionic basic bases such as PEG-2 stearate SE, glyceryl stearate SE, propylene glycol stearate. Anionic acid bases, such as cetearyl alcohol and sodium cetearyl sulphate, cetearyl alcohol and sodium lauryl sulphate, trimonol polyether-4 phosphate and ethylene glycol stearate and PEG-2 stearate, glyceryl stearate and sodium lauryl sulphate. Cationic acid bases such as cetearyl alcohol and cetyl ammonium bromide.

Auxiliaries and additives

Cosmetic sunscreen compositions, such as creams, gels, lotions, alcoholic and water/alcoholic solutions, emulsions, wax/fat compositions, stick formulations, powders or ointments, may also comprise the following as further adjuvants and additives: for example, mild surfactants, superfatting agents, consistency regulators, thickeners, polymers, stabilizers, bioactive ingredients, swelling agents, other ultraviolet light protection factors, antioxidants, hydrotropes, preservatives, self-tanning agents, solubilizers, essential oils, colorants, bacteriostats, and the like.

Super fatting agent

Suitable substances for use as superfatting agents are, for example, lanolin and lecithin and also polyethoxylated or acetylated lanolin and lecithin derivatives, polyol fatty acid esters, monoglycerides and fatty acid alkanolamides, the latter simultaneously acting as foam stabilizers.

Surface active agent

Examples of suitable mild surfactants (i.e. surfactants which are particularly well tolerated by the skin) include fatty alcohol polyglycol ether sulphates, monoglycerides sulphates, monoalkyl and/or dialkyl sulphosuccinates, fatty acid isothiocyanates, fatty acid sarcosinates, fatty acid taurates, fatty acid glutamates, alpha-olefin sulphonates, ether carboxylic acids, alkyl oligoglucosides, fatty acid glucosides, alkylamidobetaines and/or protein fatty acid condensation products, the latter preferably being based on wheat protein.

Consistency regulators/thickeners and rheology modifiers

Silicon dioxide, magnesium silicate, aluminium silicate, polysaccharides or derivatives thereof (e.g. hyaluronic acid, xanthan gum, guar gum, agar, alginate, carrageenan, gellan gum, pectin) or modified celluloses (e.g. hydroxycellulose, hypromellose). In addition, polyacrylates or homopolymers of reticulated acrylic acid and polyacrylamide, carbomers (carbomer 980, 981, 1382, ETD 2001, ETD2020, ULTREZ type 10) or the SALCARE series, such as SALCARE SC80 (steareth propyl ether/acrylate copolymer), SALCARE SC81 (acrylate copolymer), Salcare SC91 and Salcare AST (sodium acrylate copolymer/PPG-1 trideceth-6), SEPIGEL 305 (polyacrylamide/laureth-7), SIMULGEL NS and SIMULGEL EG (hydroxyethyl acrylate/sodium dimethyltaurate acrylate copolymer), STABILEN 30 (acrylate/vinyl isodecanoate crosspolymer), PEMULEN TR-1 (acrylate/C10-30 alkyl acrylate crosspolymer), LUVIGEL EM (sodium acrylate copolymer), ACULYN 28 (acrylate/beheneth-25 methacrylate copolymer), and the like.

Polymer and method of making same

As anionic, zwitterionic, amphiphilic and nonionic polymers, the following can be taken into account: for example, vinyl acetate/crotonic acid copolymers, vinylpyrrolidone/vinyl acrylate copolymers, vinyl acetate/butyl maleate/isobornyl acrylate copolymers, methyl vinyl ether/maleic anhydride copolymers and esters thereof, uncrosslinked polyacrylic acid and polyacrylic acid crosslinked with a polyol, acrylamidopropyl trimethylammonium chloride/acrylate copolymers, octylacrylamide/methyl methacrylate-t-butylaminoethyl methacrylate/2-hydroxypropyl methacrylate copolymers, polyvinylpyrrolidone, vinylpyrrolidone/vinyl acetate copolymers, vinylpyrrolidone/dimethylaminoethyl methacrylate/vinylcaprolactam terpolymers, and optionally derivatized cellulose ethers and silicones. Furthermore, the polymers described in EP1093796 (pages 3 to 8, paragraphs 17 to 68) can be used.

Bioactive ingredients

Bioactive ingredients are understood to mean, for example, tocopherol acetate, tocopherol palmitate, deoxyribonucleic acid, retinol, bisabolol, allantoin, phytantriol, panthenol, AHA acids, amino acids, ceramides, pseudoceramides, essential oils, plant extracts and vitamin complexes.

Antioxidant agent

In addition to the primary photoprotective substances, it is also possible to use secondary photoprotective substances of the antioxidant type which interrupt the photochemical reaction chain triggered by the penetration of ultraviolet radiation through the skin or hair. Typical examples of such antioxidants are amino acids (e.g. glycine, histidine, tyrosine, tryptophan) and derivatives thereof, imidazole (e.g. urocanic acid) and derivatives thereof, peptides (e.g. D, L-carnosine, D-carnosine, L-carnosine and derivatives thereof (e.g. anserine), carotenoids, carotenes, lycopene and derivatives thereof, chlorogenic acid and derivatives thereof, lipoic acid and derivatives thereof (e.g. dihydrolipoic acid), aurothioglucose, propylthiouracil and other thiols (e.g. thioredoxin, glutathione, cysteine, cystine, cysteamine and its glycosyl, N-acetyl, methyl, ethyl, propyl, pentyl, butyl, lauryl, palmitoyl, oleyl, linoleic acid, cholesterol and glycerides) and salts thereof, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and its derivatives (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts) and sulfoximine compounds (e.g., thionine sulfoximine, homocysteine sulfoximine, thionine sulfone, penta-, hexa-, heptathionine sulfoximine), and (metal) chelators (e.g., hydroxy fatty acids, palmitic acid, lactoferrin), hydroxy acids (e.g., citric acid, lactic acid, malic acid), humic acids, bile extracts, bilirubin, biliverdin, EDTA, EDDS, EGTA and derivatives thereof, unsaturated fatty acids and derivatives thereof (e.g., linolenic acid, linoleic acid, oleic acid), folic acid and derivatives thereof, ubiquinone and ubiquinol and derivatives thereof, vitamin C and derivatives (e.g., ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbyl acetate), tocopherols and derivatives (e.g., vitamin E acetate), vitamin a and derivatives (e.g., vitamin a palmitate) and coniferyl benzoate of benzoin resin, rutinic acid and its derivatives, glycosyl rutin, ferulic acid, furfuryl glucitol, carnosine, butyl hydroxytoluene, butyl hydroxyanisole, nordihydroguaiaretic acid, trihydroxybutyl propane, uric acid and its derivatives, mannose and its derivatives, superoxide dismutase, N- [3- (3, 5-di-tert-butyl-4-hydroxyphenyl) propionyl ] sulfanilic acid (and salts thereof, e.g., disodium salt), selenium and its derivatives (e.g., selenomethionine), stilbene and its derivatives (e.g., stilbene oxide, trans-stilbene oxide) and derivatives (salts, esters, ethers, sugars, nucleotides, nucleosides, peptides, and lipids) suitable for use in accordance with the present invention. HALS ("hindered amine light stabilizers") compounds may also be mentioned.

Hydrophilic agent

To improve the flow properties, it is also possible to use hydrotropes such as ethoxylated or non-ethoxylated monoalcohols, diols or polyols with a low number of carbon atoms or ethers thereof (e.g. ethanol, isopropanol, 1, 2-dipropylene glycol, propylene glycol, glycerol, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol monobutyl ether, diethylene glycol monomethyl ether; diethylene glycol monoethyl ether, diethylene glycol monobutyl ether and the like). The polyols considered for this purpose preferably have from 2 to 15 carbon atoms and at least two hydroxyl groups. The polyols may also contain further functional groups, in particular amino groups, and/or may be modified with nitrogen. A typical example is as follows: glycerol, alkyl glycols, such as ethylene glycol, diethylene glycol, propylene glycol, butylene glycol, hexylene glycol and polyethylene glycols having an average molecular weight of from 100 to 1000 daltons; industrial oligoglycerol mixtures having an inherent degree of condensation of from 1.5 to 10, for example industrial diglycerol mixtures having a diglycerol content of from 40% to 50% by weight; methanol compounds such as, in particular, trimethylolethane, trimethylolpropane, trimethylolbutane, pentaerythritol and dipentaerythritol; lower alkyl glycosides, especially those having 1 to 8 carbon atoms in the alkyl group, such as methyl and butyl glucoside; sugar alcohols having 5 to 12 carbon atoms, such as sorbitol or mannitol; sugars having 5 to 12 carbon atoms, such as glucose or sucrose; amino sugars, such as glucosamine; diethanolamine, for example diethanolamine or 2-amino-1, 3-propanediol.

Preservative and bacteriostatic agent

Suitable preservatives include, for example, methyl, ethyl, propyl, butyl, benzalkonium chloride, 2-bromo-2-nitropropane-1, 3-diol, dehydroacetic acid, diazolidinyl urea, 2-dichlorobenzyl alcohol, DMDM hydantoin, formaldehyde solution, methyldibromopentanil, phenoxyethanol, sodium hydroxymethylglycinate, imidazolidinyl urea, triclosan, and other substance classes listed in the following references: DePolo-A short textbook of cosmetics, chapter 7, tables 7-2, 7-3, 7-4 and 7-5, page 210, 219.

Bacteriostatic agent

Typical examples of bacteriostatic agents are preservatives having a specific action on gram-positive bacteria, such as 2,4,4 ' -trichloro-2 ' -hydroxydiphenyl ether, chlorhexidine (1, 6-bis (4-chlorophenyl-biguanidino) hexane) or TCC (3,4,4 ' -trichloroformanilide). A large number of aromatic substances and etheric oils also have antibacterial properties. Typical examples are eugenol, menthol and thymol, the active ingredients in clove oil, peppermint oil and thyme oil. The natural deodorant of interest is the terpene alcohol farnesol (3,7, 11-trimethyl-2, 6, 10-dodecatrien-1-ol), which is present in lyme flower oil. Glyceryl monolaurate has also been shown to be a bacteriostatic agent.

Coloring agent

Substances which are suitable and permissible for cosmetic purposes can be used as colorants, for example as compiled in the publication "Kosmetische Farbemittel" on pages 81 to 106 of Farbstoffkommision der Deutschen Forschungsgeseeinschaft, Verlag Chemie, Weinheim, 1984.

Ultraviolet screening agent

Suitable sunscreens will include a series of organic uv screeners selected from the group consisting of: 1(+/-) -1,7, 7-trimethyl-3- [ (4-methylphenyl) methylene ] bicyclo- [2.2.1] heptan-2-one; p-methylbenzylidenecamphor, 1,7, 7-trimethyl-3- (phenylmethylene) bicyclo [2.2.1] heptan-2-one; benzylidene camphor, (2-hydroxy-4-methoxyphenyl) (4-methylphenyl) methanone, 2, 4-dihydroxybenzophenone, 2,2 ', 4,4 ' -tetrahydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid, 2,2 ' -dihydroxy-4, 4 ' -dimethoxybenzophenone, 2,2 ' -dihydroxy-4-methoxybenzophenone, α - (2-oxobornylidene-3-yl) toluene-4-sulfonic acid and salts thereof, 1- [4- (1, 1-dimethylethyl) phenyl ] -3- (4-methoxyphenyl) propane-1, 3-dione, N, N, N-trimethyl-4- [ (4,7, 7-trimethyl-3-oxobicyclo [2,2,1] -heptylidene-2-yl) methyl ] aniline methylsulfate, 3,3, 5-trimethylcyclohexyl-2-hydroxybenzoate, isoamyl p-methoxycinnamate, menthyl anthranilate, 2-ethylhexyl 2-cyano-3, 3-diphenylacrylate, 2-ethylhexyl 4- (dimethylamino) benzoate, 2-ethylhexyl 4-methoxycinnamate, 2-ethylhexyl salicylate, benzoic acid, 4, 4' - (1,3, 5-triazine-2, 4, 6-triyltrimethyleneamino) tri-, tris (2-ethylhexyl) ester, 4-aminobenzoic acid, benzoic acid, 4-amino-, ethyl ester, polymer with ethylene oxide, 2-phenyl-1H-benzimidazole-5-sulfonic acid, 2-acrylamide, N- [ [4- [ (4,7, 7-trimethyl-3-oxobicyclo [2.2.1] hepten-2-yl) methyl ] phenyl ] methyl ] -, homopolymer. Triethanolamine salicylate, 3,3 '- (1, 4-phenylenedimethyl) bis [7, 7-dimethyl-2-oxo-bicyclo [2.2.1] heptane-1-methanesulfonic acid ], titanium dioxide, 2, 2' -methylene-bis- [6- (2H-benzotriazol-2-yl) -4- (1,1,3, 3-tetramethylbutyl) -phenol ], bis-ethylhexyloxyphenol methoxyphenyl triazine, 1H-benzimidazole-4, 6-disulfonic acid, 2,2 '- (1, 4-phenylene) bis-, disodium salt, benzoic acid, 4, 4' - [ [6- [ [4- [ [ (1, 1-dimethylethyl) amino ] carbonyl ] -phenyl ] amino ]1,3, 5-triazin-2, 4-diyl ] diimino ] di-, phenol, 2- (2H-benzotriazol-2-yl) -4-methyl-6- [ 2-methyl-3- [1,3,3, 3-tetramethyl-1- [ (trimethylsilyl) oxy ] disiloxanyl ] propyl ] -, dimethylsilicone diethylbenzylidene malonate, benzenesulfonic acid, 3- (2H-benzotriazol-2-yl) -4-hydroxy-5- (1-methylpropyl) -, monosodium salt, benzoic acid, 2- [4- (diethylamino) -2-hydroxybenzoyl ] -, hexyl ester, 1-dodecylammonium, salts of N- [3- [ [4- (dimethylamino) benzoyl ] amino ] -propyl ] N, N-dimethyl-, with 4-methylbenzenesulfonic acid (1:1), 1-propanaminium, N, N, N-trimethyl-3- [ (1-oxo-3-phenyl-2-propenyl) amino ] -, chloride, 1H-benzimidazole-4, 6-disulfonic acid, 2, 2' - (1, 4-phenylene) di-, 1,3, 5-triazine, 2,4, 6-tris (4-methoxyphenyl) -, 1,3, 5-triazine, 2,4, 6-tris [4- [ (2-ethylhexyl) oxy ] phenyl ] -, 1-propanaminium, 3- [ [3- [3- (2H-benzotriazol-2-yl) -5- (1, 1-dimethylethyl) -4-hydroxyphenyl ] -1-oxopropyl ] amino ] -N, N-diethyl-N-methyl-, methylsulfate (salt), 2-propenoic acid, 3- (1H-imidazol-4-yl) -, benzoic acid, 2-hydroxy-, [4- (1-methylethyl) phenyl ] methyl ester, 1,2, 3-propanetriol, 1- (4-aminobenzoate), phenylacetic acid, 3, 4-dimethoxy-alpha-oxo-, 2-propenoic acid, 2-cyano-3, 3-diphenyl-, ethyl ester, benzoic acid, p-menth-3-yl ester, 2,2 '-bis (1, 4-phenylene) -1H-benzimidazole-4, 6-disulfonic acid monosodium salt or phenylbenzimidazole disodium tetrasulfonate, 1,3, 5-triazine-2, 4, 6-triamine and N, N' -bis [4- [5- (1, 1-dimethylpropyl) -2-benzoxazolyl ] phenyl ] -N "- (2-ethylhexyl).

Agent for absorbing UV light and/or providing photoprotection to the skin

Suitable agents that absorb ultraviolet light and/or provide photoprotection to the skin and/or optionally provide sunless tanning include compounds of formula I:

wherein:

each R¹Independently H, (C)₁-C₆) Alkyl, (C)₃-C₇) Carbocyclic ring or R_aC (═ O) -, two R⁴The radicals together form- (C)₃-C₈) Alkyl-radical, - (C)₂-C₆) alkyl-Y- (C)₂-C₆) Alkyl-radical or- (C)₁-C₆) alkyl-Y' - (C)₁-C₆) An alkyl-group; or

Each R⁴Independently H, (C)₁-C₆) Alkyl, (C)₃-C₇) Carbocyclic ring or R_aC (═ O) -, two R¹The radicals together form- (C)₃-C₈) Alkyl-radical, - (C)₂-C₆) alkyl-Y- (C)₂-C₆) Alkyl-radical or- (C)₁-C₆) alkyl-Y' - (C)₁-C₆) An alkyl-group; or

Two R⁴The radicals together form- (C)₃-C₈) Alkyl-radical, - (C)₂-C₆) alkyl-Y- (C)₂-C₆) Alkyl radical or- (C)₁-C₆) alkyl-Y' - (C)₁-C₆) Alkyl-group, two R¹The radicals together form- (C)₃-C₈) Alkyl-radical, - (C)₂-C₆) alkyl-Y- (C)₂-C₆) Alkyl-radical or- (C)₁-C₆) alkyl-Y' - (C)₁-C₆) An alkyl-group;

the dotted bond labeled "a" is absent and the dotted bond labeled "b" is a double bond; or all the dotted bonds are single bonds;

R²is H, (C)₁-C₆) Alkyl or aryl, wherein the aryl is optionally substituted with one or more Z¹Substituted by groups;

R³is H, (C)₁-C₆) Alkyl or aryl, wherein the aryl is optionally substituted with one or more Z¹Substituted by groups;

y is O, S, NH, NR_cP, P (═ O) or POH;

y' is Si (R)_b)₂or-Si (R)_b)₂—O—Si(R_b)₂—；

Each R_aIndependently is (C)₁-C₆) Alkyl, (C)₃-C₇) Carbocyclic or aryl, wherein the aryl is optionally substituted with one or more Z¹Substituted by groups;

each R_bIndependently is (C)₁-C₆) Alkyl, (C)₃-C₇) Carbocyclic or aryl, wherein the aryl is optionally substituted with one or more Z¹Substituted by groups;

each R_cIndependently is R_gOr C optionally substituted with one or more groups independently selected from₁-C₁₈Saturated or unsaturated carbon chain: oxo (═ O), hydroxy, mercapto, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) Alkanoyloxy, NR_dR_eA carboxyl group and an aryl group, wherein R is_cAny aryl of (a) is optionally substituted by one or more R_fSubstitution;

each R_dAnd R_eIndependently selected from H, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkanoyl, phenyl, benzyl and R_g；

Each R_fIndependently selected from (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) Alkanoyloxy, -C (═ O) -phenyl and-C (═ O) CH₂C (═ O) -phenyl, wherein any phenyl is optionally substituted with one or more groups selected from: (C)₁-C₆) Alkyl, — SO₃H and (C)₁-C₆) An alkoxy group;

each R_gIs that

Each Z¹Independently selected from (C)₁-C₆) Alkyl, halogen, — CN, — OR_n1、—NR_q1R_r1、—NR_n1COR_p1、—NR_n1CO₂R_p1、NO₂、—C(O)R_n1、—C(O)OR_n1and-C (O) NR_q1R_r1Wherein Z is¹Any of (C)₁-C₆) Alkyl is optionally substituted with one or more (e.g., 1,2,3, 4, 5, or 6) halogens;

each R_n1Independently selected from H and (C)₁-C₆) Alkyl radical, wherein R_n1Any of (C)₁-C₆) Alkyl is optionally substituted with one or more, e.g., 1,2,3, 4, 5, or 6) halogens;

each R_p1Independently is (C)₁-C₆) An alkyl group; and

R_q1and R_r1Each independently selected from H and (C)₁-C₆) Alkyl, or R_q1And R_r1Together with the nitrogen to which they are attached form piperidine, pyrrolidine, morpholine, azetidine, thiomorpholine, piperazine or 4-methylpiperazine;

or a salt thereof.

Specific groups of compounds and specific compounds of formula I that can be incorporated into the topical compositions described herein, as well as methods of making such compounds, are described in U.S. patent nos. 9, 403, 778 and 9,987,211, which are incorporated herein by reference in their entirety.

Suitable agents that absorb ultraviolet light and/or provide photoprotection to the skin and/or optionally provide sunless tanning may include compounds of formula II:

or a salt thereof, wherein:

R¹is H, (C)₁-C₆) Alkyl, (C)₃-C₇) Carbocyclic ring or R_aC(═O)—；

R²Is H, (C)₁-C₆) Alkyl or aryl, wherein the aryl is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹Substituted by groups;

R⁴is H, (C)₁-C₁₀) Alkyl, aryl, heteroaryl, and heteroaryl,(C₃-C₇) Carbocyclic ring or R_aC(═O)—；

R_aIs (C)₁-C₆) Alkyl, (C)₃-C₇) Carbocyclic or aryl, wherein the aryl is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹Substituted by groups;

each Z¹Independently selected from (C)₁-C₆) Alkyl, halogen, — CN, — OR_n1、—NR_q1R_r1、—NR_n1COR_p1、—NR_n1CO₂R_p1、NO₂、—C(O)R_n1、—C(O)OR_n1and-C (O) NR_q1R_r1Wherein Z is¹Any of (C)₁-C₆) Alkyl is optionally substituted with one or more (e.g., 1,2,3, 4, 5, or 6) halogens;

each R_n1Independently selected from H and (C)₁-C₆) Alkyl radical, wherein R_n1Any of (C)₁-C₆) Alkyl is optionally substituted with one or more (e.g., 1,2,3, 4, 5, or 6) halogens;

each R_p1Independently is (C)₁-C₆) An alkyl group; and

R_q1and R_r1Each independently selected from H and (C)₁-C₆) Alkyl, or R_q1And R_r1Together with the nitrogen to which they are attached form piperidine, pyrrolidine, morpholine, azetidine, thiomorpholine, piperazine or 4-methylpiperazine.

Specific groups of compounds and specific compounds of formula II that can be added to the topical compositions described herein, as well as methods of making such compounds, are described in U.S. patent 9,987,211, which is incorporated herein by reference in its entirety.

Suitable agents that absorb ultraviolet light and/or provide photoprotection to the skin and/or optionally provide sunless tanning may include compounds of formula III:

wherein:

each R¹Independently H, (C)₁-C₆) Alkyl, (C)₃-C₇) Carbocyclic ring or R_aC (═ O; or two R¹The radicals together form- (C)₃-C₈) Alkyl-radical, - (C)₂-C₆) alkyl-Y- (C)₂-C₆) Alkyl-radical or- (C)₁-C₆) alkyl-Y' - (C)₁-C₆) An alkyl-group; or

The dotted bond labeled "a" is absent and the dotted bond labeled "b" is a double bond; or all of the dotted bonds are single bonds;

R²is H, (C)₁-C₆) Alkyl or aryl, wherein the aryl is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹Substituted by groups;

R³is H, (C)₁-C₆) Alkyl or aryl, wherein the aryl is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹Substituted by groups;

R⁴is hydroxy, carboxy, (C)₁-C₆) Alkoxycarbonyl, — OPO₃H₂、—OR_cor-NR_dR_e(ii) a And R is⁵Is H; or R⁴And R⁵Taken together are oxo;

y is O, S, NH, P (═ O) or POH;

y' is Si (R)_b)₂or-Si (R)_b)₂—O—Si(R_b)₂—；

Each R_aIndependently is (C)₁-C₆) Alkyl, (C)₃-C₇) Carbocyclic or aryl, wherein the aryl is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹Substituted by groups;

each R_bIndependently is (C)₁-C₆) Alkyl, (C)₃-C₇) Carbocyclic or aryl, wherein the aryl is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹Substituted by groups;

R_cis R_fOr C optionally substituted with one or more substituent groups independently selected from₁-C₂₀Saturated or C₂-C₂₀Unsaturated carbon chain: oxo (═ O), hydroxy, mercapto, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) Alkanoyloxy, NR_dR_eA carboxyl group and an aryl group, wherein the aryl group is optionally substituted with one or more (e.g., 1,2,3, 4 or 5) Z¹Substituted by groups;

R_dis H, (C)₁-C₆) Alkyl or (C)₁-C₆) An alkanoyl group;

R_eis H or C optionally substituted with one or more substituent groups independently selected from₁-C₂₀Saturated or C₂-C₂₀Unsaturated carbon chain: oxo (═ O), hydroxy, mercapto, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Alkoxycarbonyl, (C)₁-C₆) Alkanoyloxy, NR_dR_eA carboxyl group and an aryl group, wherein the aryl group is optionally substituted with one or more (e.g., 1,2,3, 4 or 5) Z¹Substituted by groups;

each R_fThe method comprises the following steps:

each Z¹Independently selected from (C)₁-C₆) Alkyl, halogen, — CN, — OR_n1、—NR_q1R_r1、—NR_n1COR_p1、—NR_n1CO₂R_p1、NO₂、—C(O)R_n1、—C(O)OR_n1and-C (O) NR_q1R_r1Wherein Z is¹Any of (C)₁-C₆) Alkyl is optionally substituted with one or more (e.g., 1,2,3, 4, 5, or 6) halogens;

each R_n1Independently selected from H and (C)₁-C₆) Alkyl radical ofIn R_n1Any of (C)₁-C₆) Alkyl is optionally substituted with one or more (e.g., 1,2,3, 4, 5, or 6) halogens;

each R_p1Independently is (C)₁-C₆) An alkyl group; and

R_q1and R_r1Each independently selected from H and (C)₁-C₆) Alkyl, or R_q1And R_r1Together with the nitrogen to which they are attached form piperidine, pyrrolidine, morpholine, azetidine, thiomorpholine, piperazine or 4-methylpiperazine;

or a salt thereof.

Specific groups of compounds and specific compounds of formula III that can be added to the topical compositions described herein, as well as methods of making such compounds, are described in U.S. patent 9,364,406 and U.S. patent 9,987,211, which are incorporated herein by reference in their entirety.

Sunscreen agent

The formulations disclosed herein may include sunscreens such as avobenzone, etidron, methyl anthranilate, oxybenzone, dioxybenzone, sulfoisobenzone, cinnamate, homosalate, octocrylene, and oxisalate. Such compositions may comprise organic uv filters, so-called hydrophilic or lipophilic sun protection filters, which are effective in the UVA and/or UVB and (/ or IR and/or VIS (absorbers), in particular these substances may be selected from cinnamic acid derivatives, salicylic acid derivatives, camphor derivatives, triazine derivatives, beta-diphenylacrylate derivatives, p-aminobenzoic acid derivatives, and polymeric and silicone filters, which are described in WO93/04665 further examples of organic filters are shown in patent application EP-a 0487404, particularly suitable combinations are p-aminobenzoic acid and its derivatives PABA, ethyl dihydroxypropyl PABA, ethyl hexyl dimethyl PABA, for example those sold under the name "caesoll 507" by ISP, glycerol PABA, PEG-25PABA, for example, BASF sold under the name "Uvinul P25".

Other uv filter ingredients that may be added to the topical compositions disclosed herein include:

salicylic acid ester: homosalate sold by Merck under the name Eusolex HMS; for example ethylhexyl salicylate sold by Symrise under the name "Neo Heliopan OS"; dipropylene glycol salicylate, such as diethylene glycol salicylate sold by Scher under the name "dispsal", such as TEA salicylate sold by Symrise under the name "Neo Heliopan TS".

Beta, beta-diphenylacrylate derivatives: for example Merck to "Octocrylene sold under the name OCR "; "Uvinul N539" from BASF, octocrylene sold by BASF under the name "Uvinul N35".

Benzophenone derivatives: benzophenone-1, for example sold under the name "Uvinul 400"; benzophenone-2, for example sold under the name "Uvinul D50"; benzophenone-3 or oxybenzone, for example sold under the name "Uvinul M40"; benzophenone-4, for example sold under the name "Uvinul MS 40"; benzophenone-9, for example BASF sold under the name "Uvinul DS-49", benzophenone-5, benzophenone-6, for example Norquay sold under the name "Helisorb 11", benzophenone-8, for example American Cyanamid sold under the name "Spectra-Sorb UV-24", benzophenone-12 n-hexyl 2- (4-diethylamino-2-hydroxybenzoyl) benzoate or 2-hydroxy-4-methoxybenzophenone sold under the name "Merck", Darmstadt4360 under the name of Suki Kagaku Kogyo.

Benzylidene camphor derivatives: 3-benzylidene camphor, such as Chimex sold under the name "Mexoryl SD"; 4-methylbenzylidenecamphor, such as sold by Merck under the name "Eusolex 6300"; benzylidene camphorsulfonic acids such as Chimex sold under the name "Mexoryl SL"; camphorzamethammonium sulfate, such as Chimex sold under the name "Mexoryl SO"; p-xylylene dicamphor sulfonic acid, such as Chimex sold under the name "Mexoryl SX"; polyacrylamidomethylbenzylidenecamphor, Chimex, is sold under the name "Mexoryl SW".

Phenylbenzimidazole derivatives: phenylbenzimidazole sulfonic acids, such as Merck, are sold under the name Eusolex 232, and phenyldibenzoimidazole tetrasulfonic acid disodium salt, such as Symrise, is sold under the name Neo Heliopan AP.

Phenyl benzotriazole derivatives: cresol trozole trisiloxane, such as Rhodia Chimie sold under the name "Silatrizole"; methylenebis (benzotriazolyl) tetramethylbutylphenol in solid form, such as sold under the name "MIXXIM BB/100" by Fairmount Chemical, or in micronized form as an aqueous dispersion, such as sold under the name "Tinosorb M" by BASF.

Triazine derivatives: ethylhexyl triazone, such as BASF sold under the name "Uvinul T150"; diethylhexyl butamido triazone, such as Sigma 3V sold under the name "Uvasorb HEB"; 2,4, 6-tris (diisobutyl 4' -aminobenzylidenemalonate) -s-triazine or 2,4, 6-tris (diphenyl) -1,3, 5-triazine, BASF sold as Tinosorb A2B; 2, 2' - [6- (4-methoxyphenyl) -1,3, 5-triazine-2, 4-diyl ] bis [5- (2-ethylhexyl) oxy ] phenol, BASF sold as Tinosorb S; n2, N4-bis [4- [5- (1, 1-dimethylpropyl) -2-benzoxazolyl ] phenyl ] -N-6- (2-ethylhexyl) -1,3, 5-triazine-2, 4, 6-triamine, Sigma 3V sold as Uvasorb K2A.

Anthranilic acid (anthranine) derivatives: menthyl anthranilates, such as Symrise, are sold under the name "Neo Heliopan MA".

Imidazole derivatives: dimethoxybenzylidene dioxoimidazolidine propionic acid ethylhexyl ester.

Benzylidene malonate derivatives: polyorganosiloxanes containing functional benzylidene malonate groups, such as, for example, silicone-15, such as, for example, Hoffmann LaRoche, sold under the name "Parsol SLX".

4, 4-diarylbutadiene derivatives: 1, 1-dicarboxy (2, 2' -dimethylpropyl) -4, 4-diphenylbutadiene.

Benzoxazole derivatives: 2, 4-bis [5- (1-dimethylpropyl) benzoxazol-2-yl (4-phenyl) imino ] -6- (2-ethylhexyl) imino-1, 3, 5-triazine, for example Sigma 3V sold under the name Uvasorb K2A; and mixtures comprising the same.

Suitable organic uv-protective substances may preferably be selected from: ethylhexyl salicylate, phenyl benzimidazolesulfonate, benzophenone-3, benzophenone-4, benzophenone-5, 2- (4-diethylamino-2-hydroxybenzoyl) n-hexyl benzoate, 4-methylbenzylidene camphor, p-xylylene dicamphor sulfonic acid, disodium phenyldibenzoimidazole tetrasulfonic acid, methylenebis (benzotriazolyl) tetramethylbutylphenol, ethylhexyl triazone, diethylhexylbutamido triazone, cresotriazole trisiloxane, polysilicone-15, 1, 1-dicarboxyl (2, 2' -dimethylpropyl) -4, 4-diphenylbutadiene, 2, 4-bis [5-1 (dimethylpropyl) benzoxazol-2-yl (4-phenyl) imino ] -6- (2-ethylhexyl) imino-1, 3, 5-triazines and mixtures thereof.

The compositions of the present invention may also comprise other uv filters, so-called particulate uv filters. These combinations with particulate uv filters may be powders, but also as dispersions or pastes. In one embodiment, the inorganic ultraviolet filter is titanium dioxide, such as, for example, coated titanium dioxide (e.g., coated titanium dioxide)T-2000，T-AQUA，T-AVO，T-OLEO); zinc oxide (e.g., Sachtotec); iron oxide; or ceria and/or zirconia. Furthermore, combinations with pigmentary titanium dioxide or zinc oxide are also possible, wherein the particle size of these pigments is greater than or equal to 200nm, for exampleFG orFFPharma。

The compositions of the invention may comprise inorganic UV filters which have been treated by conventional methods, as described, for example, in Cosmetics & Toiletries, 1990, 105, 53-64. One or more of the following post-treatment components may be: amino acids, beeswax, fatty acids, fatty acid alcohols, anionic surfactants, lecithin, phospholipids, sodium, potassium, zinc, iron or aluminum salts of fatty acids, polyethylene glycols, silicones, proteins (in particular collagen or elastin), alkanolamines, silica, alumina, other metal oxides, phosphates (for example sodium hexametaphosphate), or glycerol.

In one embodiment, the particulate uv filter used in the composition of the invention is:

untreated titanium Dioxide, such as the product Microtitanium Dioxide MT500B from Tayca; the titanium dioxide P25 from Degussa,

micronized titanium Dioxide after-treatment with alumina and silica, for example, the product "titanium Dioxide MT 100 SA" from Tayca; or the product "Tioveil Fin" by Uniqema,

micronized titanium Dioxide after post-treatment with aluminium oxide and/or stearic acid/aluminium laurate, for example Microtitanium Dioxide MT 100T from Tayca, Eusolex T-2000 from Merck,

micronized titanium Dioxide after-treatment with iron oxide and/or iron stearate, for example, the product "Microtitanium Dioxide MT 100F" from Tayca,

micronized titanium Dioxide post-treated with a post-treatment of silica, alumina and silicone, for example, the product of Tayca, "micronized Dioxide MT 100 SAS",

micronized titanium Dioxide after-treatment with sodium hexametaphosphate, for example the product "Microtitanium Dioxide MT 150W" from Tayca.

The treated micronized titanium dioxide used in combination may also be post-treated with:

octyl trimethoxysilane; for example, Tego Sun T805, a product of Evonik Goldschmidt GmbH,

silica; such as, for example, the DSM product Parsol T-X,

alumina and stearic acid; for example, the product UV-Titan M160 from Sachtleben,

aluminum and glycerin; for example, the product UV-Titan from Sachtleben,

aluminum and silicone oils, for example, the product UV-Titan M262 from Sachtleben,

sodium hexametaphosphate and polyvinylpyrrolidone,

polydimethylsiloxanes, for example, the product 70250Cardre UF TiO2SI3 "from Cardre,

polydimethylhydrosiloxanes, such as, for example, the product Microtitanium Dioxide USP Grade hydrophibic "from Color Techniques.

In a particular embodiment, the composition of the invention comprises untreated zinc oxide, such as, for example, product Z-Cote from BASF (Sunsmart), Nanox from Elementis. In another particular embodiment, the composition of the invention may comprise zinc oxide that has been post-treated, such as the following:

toshibi's "Zinc Oxide CS-5" (ZnO post-treated with polymethylhydrosiloxane);

nanogard Zinc Oxide FN from Nanophase Technologies;

"SPD-Z1" by Shin-Etsu (ZnO post-treated with silicone grafted acrylic polymer dispersed in cyclomethicone);

"Escalol Z100" by ISP (alumina post-treated with ZnO dispersed in ethylhexyl methoxycinnamate/dimethicone copolymer mixture); and

fuji Pigment, "Fuji ZNO-SMS-10" (ZnO post-treated with silica and polymethylsilsesquioxane).

In another particular embodiment, the composition of the invention may comprise an untreated particulate cerium oxide pigment, such as "Colloidal cerium oxide" from Rhone Poulenc. In another particular embodiment, the composition of the invention may comprise untreated and/or post-treated iron oxide, Nanogar from Arnaud.

By way of example, mixtures of various metal oxides can be employed, such as, for example, titanium dioxide and cerium oxide with or without aftertreatment, such as, for example, Sunveil a, a product from Ikeda. Furthermore, mixtures of aluminum oxide, silicon dioxide and titanium dioxide after-treated with silicone, zinc oxide mixtures (e.g.product UV-Titan M261 from Sachtleben) can also be used in combination with the UV protection agents according to the invention.

Application method

In some embodiments, the present disclosure relates to methods of treating the effects of free radical induced damage of the skin of a subject. Free radical induced damage may include free radical damage from sunlight (UVB, UVA, visible light), HEV (blue) light, Infrared (IR), pollution, irritants, allergens, or various environmental toxins that are destructive to the skin (e.g., by hydrolyzing elastin fibers in the skin or de-synthesizing collagen in the lower dermal layer of the skin). Exemplary free radical-induced damage that can be treated, prevented, minimized, reduced, or alleviated after application of an effective amount of any of the topical compositions described herein to the skin of a subject includes, but is not limited to, severe photodamage, lack of tactile smoothness, lack of visual smoothness, lack of softness, lack of brightness, lack of radiance, skin texture, skin wrinkles, facial fine lines, fishtail lines, color shading, dry skin texture, appearance of fine lines, rough skin, sagging skin, tight skin, poor skin elasticity, age spots, pigmentation, scars, irregularities in the skin surface, rosacea, acne, psoriasis, reduced skin regeneration and renewal processes, appearance of saturated menstrual efflorescence, yellowing, redness, dryness, ichthyosis, and other damaged skin conditions.

In certain embodiments, the present disclosure relates to a method of treating the skin of a subject by administering to the skin of the subject an effective amount of any of the formulations described herein, wherein the skin exhibits improved tactile smoothness after administration of the formulation for a time period of from about 1 week to about 16 weeks, from about 2 weeks to about 14 weeks, from about 4 weeks to about 12 weeks, about 4 weeks, about 8 weeks, about 12 weeks, or any single value or subrange therein.

In certain embodiments, the present disclosure relates to a method of treating the skin of a subject by administering to the skin of the subject an effective amount of any of the formulations described herein, wherein the skin exhibits improved softness after administration of the formulation for a period of time from about 1 week to about 16 weeks, from about 2 weeks to about 14 weeks, from about 4 weeks to about 12 weeks, about 4 weeks, about 8 weeks, about 12 weeks, or any single value or subrange therein.

In certain embodiments, the present disclosure relates to a method of treating the skin of a subject by administering to the skin of the subject an effective amount of any of the formulations described herein, wherein the skin exhibits improved brightness after a time of about 1 week to about 16 weeks, about 2 weeks to about 14 weeks, about 4 weeks to about 12 weeks, about 4 weeks, about 8 weeks, about 12 weeks, or any single value or subrange therein of administration of the formulation.

In certain embodiments, the present disclosure relates to a method of treating the skin of a subject by administering to the skin of a subject an effective amount of any of the formulations described herein, wherein the skin exhibits improved radiance after a period of time of from about 1 week to about 16 weeks, from about 2 weeks to about 14 weeks, from about 4 weeks to about 12 weeks, about 4 weeks, about 8 weeks, about 12 weeks, or any single value or subrange therein, of administration of the formulation.

In certain embodiments, the present disclosure relates to a method of treating the skin of a subject by administering to the skin of the subject an effective amount of any of the formulations described herein, wherein the skin exhibits improved visual smoothness after administration of the formulation for a time period of from about 1 week to about 16 weeks, from about 2 weeks to about 14 weeks, from about 4 weeks to about 12 weeks, about 4 weeks, about 8 weeks, about 12 weeks, or any single value or subrange therein.

In certain embodiments, the present disclosure relates to a method of treating the skin of a subject by administering to the skin of the subject an effective amount of any of the formulations described herein, wherein the skin exhibits improved firmness conditions after administration of the formulation for a period of time from about 1 week to about 16 weeks, from about 2 weeks to about 14 weeks, from about 4 weeks to about 12 weeks, about 4 weeks, about 8 weeks, about 12 weeks, or any single value or subrange therein.

In certain embodiments, the present disclosure relates to a method of treating the skin of a subject by administering to the skin of a subject an effective amount of any of the formulations described herein, wherein the skin exhibits improved skin texture after a period of time of from about 1 week to about 16 weeks, from about 2 weeks to about 14 weeks, from about 4 weeks to about 12 weeks, about 4 weeks, about 8 weeks, about 12 weeks, or any single value or subrange therein of administration of the formulation.

In certain embodiments, the present disclosure relates to a method of treating the skin of a subject by administering to the skin of the subject an effective amount of any of the formulations described herein, wherein the skin exhibits an improved overall photoaging appearance after a period of time of from about 1 week to about 16 weeks, from about 2 weeks to about 14 weeks, from about 4 weeks to about 12 weeks, about 4 weeks, about 8 weeks, about 12 weeks, or any single value or subrange therein of administration of the formulation.

In certain embodiments, the present disclosure relates to a method of treating the skin of a subject by administering to the skin of a subject an effective amount of any of the formulations described herein, wherein the skin exhibits reduced dryness after a period of time of from about 1 week to about 16 weeks, from about 2 weeks to about 14 weeks, from about 4 weeks to about 12 weeks, about 4 weeks, about 8 weeks, about 12 weeks, or any single value or subrange therein of administration of the formulation.

In certain embodiments, the present disclosure relates to a method of treating the skin of a subject by administering to the skin of the subject an effective amount of any of the formulations described herein, wherein the skin exhibits reduced barrier damage (e.g., as indicated by a lower increase in transepidermal water loss) compared to the increase in transepidermal water loss exhibited by administration of the comparative formulation after administration of the formulation for a time of about 1 week to about 16 weeks, about 2 weeks to about 14 weeks, about 4 weeks to about 12 weeks, about 4 weeks, about 8 weeks, about 12 weeks, or any single value or subrange therein. Although in certain embodiments the use of retinoid-based treatment may show some increase in transepidermal water loss (TEWL), the skin treated with any of the formulations described herein at a given treatment time point (e.g., about 4 weeks, about 8 weeks, about 12 weeks, etc.) may show an increase in TEWL that is less than about 100%, less than about 95%, less than about 90%, or less than about 88%. The TEWL increase may be measured in comparison to a baseline measurement taken at 0 time prior to starting treatment.

In certain embodiments, the present disclosure relates to a method of treating skin of a subject by administering to the skin of the subject an effective amount of any of the formulations described herein, wherein the skin exhibits improved crow's feet after a time of about 1 week to about 16 weeks, about 2 weeks to about 14 weeks, about 4 weeks to about 12 weeks, about 4 weeks, about 8 weeks, about 12 weeks, or any single value or subrange therein of administration of the formulation.

In certain embodiments, the present disclosure relates to a method of treating the skin of a subject by administering to the skin of a subject an effective amount of any of the formulations described herein, wherein the skin exhibits an improved color difference after a time of administration of the formulation for about 1 week to about 16 weeks, about 2 weeks to about 14 weeks, about 4 weeks to about 12 weeks, about 4 weeks, about 8 weeks, about 12 weeks, or any single value or subrange therein.

In certain embodiments, the present disclosure relates to a method of treating the skin of a subject by administering to the skin of the subject an effective amount of any of the formulations described herein, wherein after administration of the formulation for a time of about 1 week to about 16 weeks, about 2 weeks to about 14 weeks, about 4 weeks to about 12 weeks, about 4 weeks, about 8 weeks, about 12 weeks, or any single value or subrange therein, the skin exhibits an improvement in one or more of the following: tactile smoothness, softness, brightness, luster, visual smoothness, firmness, skin texture, overall photoaged appearance, dryness, crow's feet, or color difference, and wherein the subject experiences enhanced tolerance (e.g., in one or more of: itch, stinging, burning, redness or swelling) as compared to an efficacy-equivalent tretinoin formulation. The tretinoin formulation with comparable efficacy was the following formulation: after administration of the formulation for a period of about 1 week to about 16 weeks, about 2 weeks to about 14 weeks, about 4 weeks to about 12 weeks, about 4 weeks, about 8 weeks, about 12 weeks, or any single value or subrange therein, the formulation exhibits similar improvements in one or more of the following (i.e., no statistically significant differences, as defined in the clinical studies described in the examples): tactile smoothness, softness, brightness, gloss, visual smoothness, firmness, skin texture, overall photo-aged appearance, dryness, crow's feet, or color difference.

In certain embodiments, the present disclosure relates to a method of treating the skin of a subject by administering to the skin of the subject an effective amount of any of the formulations described herein, wherein the skin exhibits an improvement in one or more of the following after administration of the formulation for a time of about 1 week to about 16 weeks, about 2 weeks to about 14 weeks, about 4 weeks to about 12 weeks, about 4 weeks, about 8 weeks, about 12 weeks, or any single value or subrange therein, as compared to an efficacy-equivalent tretinoin formulation: tactile smoothness, softness, brightness, luster, visual smoothness, firmness, skin texture, overall photoaged appearance, dryness, crow's feet, or color difference, and wherein the subject experiences reduced barrier damage (e.g., in transepidermal water loss) as compared to an efficacy-equivalent tretinoin formulation. The tretinoin formulation with comparable efficacy was the following formulation: after administration of the formulation for a period of about 1 week to about 16 weeks, about 2 weeks to about 14 weeks, about 4 weeks to about 12 weeks, about 4 weeks, about 8 weeks, about 12 weeks, or any single value or subrange therein, the formulation exhibits similar improvements in one or more of the following (i.e., no statistically significant differences, as defined in the clinical studies described in the examples): tactile smoothness, softness, brightness, gloss, visual smoothness, firmness, skin texture, overall photo-aged appearance, dryness, crow's feet, or color difference.

In certain embodiments, the present disclosure relates to a method of treating the skin of a subject by administering to the skin of the subject an effective amount of any of the formulations described herein, wherein the skin exhibits newly formed collagen after a period of time of from about 1 week to about 16 weeks, from about 2 weeks to about 14 weeks, from about 4 weeks to about 12 weeks, about 4 weeks, about 8 weeks, about 12 weeks, or any single value or subrange therein of administration of the formulation.

In certain embodiments, the present disclosure relates to a method of treating the skin of a subject by administering to the skin of a subject an effective amount of any of the formulations described herein, wherein the skin exhibits epidermal thickening after administration of the formulation for a time of about 1 week to about 16 weeks, about 2 weeks to about 14 weeks, about 4 weeks to about 12 weeks, about 4 weeks, about 8 weeks, about 12 weeks, or any single value or subrange therein. A given epidermal thickening for a given treatment time point (e.g., about 4 weeks, about 8 weeks, about 12 weeks, etc.) compared to baseline (e.g., 0 time prior to starting treatment) may be in the following range: any of about 10%, about 20%, about 30%, or about 40%, to any of about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, or about 200%. In certain embodiments, the epidermal thickening for a given treatment time point (e.g., about 4 weeks, about 8 weeks, about 12 weeks, etc.) may be at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50%.

In certain embodiments, the present disclosure relates to a method of treating the skin of a subject by administering to the skin of the subject an effective amount of any of the formulations described herein, wherein the skin exhibits greater epidermal thickening after administration of the formulation for a period of about 1 week to about 16 weeks, about 2 weeks to about 14 weeks, about 4 weeks to about 12 weeks, about 4 weeks, about 8 weeks, about 12 weeks, or any single value or subrange therein, as compared to an efficacy-equivalent tretinoin formulation. The tretinoin formulation with comparable efficacy was the following formulation: after administration of the formulation for a period of about 1 week to about 16 weeks, about 2 weeks to about 14 weeks, about 4 weeks to about 12 weeks, about 4 weeks, about 8 weeks, about 12 weeks, or any single value or subrange therein, the formulation exhibits similar improvements in one or more of the following (i.e., no statistically significant differences, as defined in the clinical studies described in the examples): tactile smoothness, softness, brightness, gloss, visual smoothness, firmness, skin texture, overall photo-aged appearance, dryness, crow's feet, or color difference.

In certain embodiments, the present disclosure relates to a treatment regimen method comprising administering to the skin of a subject who has undergone or will undergo a dermatological treatment course an effective amount of any of the formulations described herein. In certain embodiments, the methods described herein further comprise administering a dermatological treatment course after administering the topical composition and/or before administering the topical composition, depending on the treatment regimen. In certain embodiments, the topical compositions described herein help improve the outcome of dermatological procedures, for example, by accelerating healing, eliminating non-Reactive Oxygen Species (ROS), quenching Reactive Oxygen Species (ROS), inducing collagen elimination, or any combination thereof.

The effective amount will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the particular ingredients of the formulation used, and other factors. In certain embodiments, the formulations described herein are suitable for administration by frequent periodic application, e.g., once, twice, three times, or four times daily, e.g., for at least 1 day, at least 3 days, at least 5 days, at least 7 days, at least 10 days, at least 14 days, at least 21 days, at least 30 days, at least 8 weeks, at least 12 weeks, etc. Thus, in certain embodiments, the methods described herein further comprise periodically repeating the administration of the formulation.

In certain embodiments, the formulations described herein are suitable for administration before or after a course of treatment, e.g., before or after a dermatological course of treatment.

Preparation method

The present disclosure also relates to methods of making any of the formulations described herein. The formulations and delivery systems disclosed herein can be prepared under ambient conditions. In certain embodiments, the formulations disclosed herein can be prepared under an inert atmosphere. In a particular aspect of this embodiment, the inert atmosphere is an inert gas, such as, but not limited to, nitrogen, argon, or a combination thereof. In certain embodiments, the formulations disclosed herein are prepared under a dry inert atmosphere, which may include, consist essentially of, or consist of one or more dry inert gases, which may be in the form of, but not limited to, dry nitrogen, dry argon, or a combination thereof. In certain embodiments, the formulation is prepared under any of the dry inert atmospheres described herein to stabilize the formulation so that certain ingredients (e.g., retinol) do not separate and/or precipitate out.

In certain embodiments, methods of making the formulations described herein comprise methods having multiple steps, wherein the steps can be precisely resolved and/or correlated with corresponding conditions (e.g., temperature, mixing intensity, and duration) to solubilize various ingredients, stabilize the final formulation, and reduce and/or minimize and/or eliminate precipitation.

For example, a first amount of isoprene glycol (or another suitable polyol described herein) can be mixed with a first amount of polysorbate 80 (or another suitable surfactant described herein) and a xanthine (e.g., caffeine) to form a first mixture. The first mixture can be mixed, e.g., with a paddle mixer, at a first temperature (e.g., about 60 ℃ to about 120 ℃, about 70 ℃ to about 110 ℃, or about 80 ℃ to about 100 ℃) for a first time (e.g., about 15 minutes to about 90 minutes, about 30 minutes to about 60 minutes, or about 40 minutes to about 50 minutes) until the xanthine (e.g., caffeine) is dissolved, the first mixture is clear and free of lumps. Subsequently, in certain embodiments, the first mixture can be cooled to a second temperature (e.g., about 50 ℃ to about 110 ℃, about 60 ℃ to about 100 ℃, or about 70 ℃ to about 90 ℃).

In certain embodiments, a first amount of DMI and/or a first amount of ethoxydiglycol may be added to the first mixture at once to ultimately form a second mixture. After each ingredient is added, the mixture can be mixed for a second time (e.g., about 1 minute to about 30 minutes, about 5 minutes to about 25 minutes, or about 10 minutes to about 20 minutes) until the second mixture is homogeneous and free of lumps. Subsequently, in certain embodiments, the second mixture can be cooled to a third temperature (e.g., about 30 ℃ to about 90 ℃, about 40 ℃ to about 80 ℃, or about 50 ℃ to about 70 ℃).

In certain embodiments, in a first separate container, a second amount of isoprene glycol (or another suitable polyol as described herein) can be combined with tea (green tea) polyphenols to form a third mixture. In certain embodiments, a glycol is used to solubilize the tea (green tea) polyphenols, for example by forming a complex between the glycol and the tea (green tea) polyphenols. The third mixture may be mixed for a third time until the third mixture is homogeneous and free of lumps. Subsequently, in certain embodiments, the third mixture can be heated to a third temperature (e.g., about 30 ℃ to about 90 ℃, about 40 ℃ to about 80 ℃, or about 50 ℃ to about 70 ℃) that is substantially similar to the third temperature of the cooled second mixture. In certain embodiments, the third mixture may become clear when heated. In certain embodiments, the tea (green tea) polyphenols are not added directly to the second mixture, but are first dissolved in a separate container in order to more effectively dissolve the tea (green tea) polyphenols.

In certain embodiments, the third mixture may be added to the second mixture to form a fourth mixture.

In certain embodiments, in a second separate container, a concentrated form of retinol (which may be complexed with polysorbate 20 and/or solubilized with polysorbate 20) may be combined with various ingredients from the fourth mixture, such as with a second amount of polysorbate 80, a second amount of DMI, and a second amount of ethoxydiglycol to form a fifth mixture. In this way, and not to be construed as limiting, it is believed that by incorporating retinol into the various ingredients in the formulation, it will remain stable in the formulation and will not precipitate out. The fifth mixture may be mixed until it is homogeneous, lump-free, and clear.

In certain embodiments, the fifth mixture can be added to the fourth mixture at a fourth temperature (e.g., about 30 ℃ to about 70 ℃, about 40 ℃ to about 60 ℃, or about 45 ℃ to about 55 ℃) to form a sixth mixture.

In certain embodiments, bakuchiol and/or additional antioxidants (e.g., black tea extract and/or licorice extract) can be added at once to the sixth mixture to ultimately form the final formulation. After addition of each ingredient, the mixture can be mixed for a certain time (e.g., about 1 minute to about 15 minutes, about 3 minutes to about 10 minutes, or about 4 minutes to about 6 minutes) until the final formulation is homogeneous and free of lumps. Subsequently, in certain embodiments, the final formulation may be cooled to a final temperature (e.g., about 10 ℃ to about 50 ℃, about 20 ℃ to about 40 ℃, or about 25 ℃ to about 30 ℃).

As can be seen in the procedures described above, in certain embodiments, certain ingredients of the formulation are dissolved separately or added in two separate steps (e.g., a first amount is added in certain steps and a second amount is added in a different step) to give a uniform, lump-free and stable formulation. In certain embodiments, the procedure is done under controlled conditions to minimize or eliminate the introduction of water, air, or light into the process, thereby maintaining the stability of various ingredients (e.g., retinol and tea (green tea) polyphenols).

Illustrative embodiments

The following examples are intended to aid in the understanding of the present invention and, of course, should not be construed as specifically limiting the invention described and claimed herein. Such variations of the invention, including all equivalent substitutions now known or later developed within the purview of those skilled in the art and minor variations in formulation or experimental design, are to be considered within the scope of the invention encompassed herein.

Clinical study testing of skin care formulations was conducted using 0.25%, 0.5%, and 1.0% of the exemplary retinol formulations, where a group of users began using the disclosed formulations containing these doses of all-trans retinol, starting with the lowest dose and gradually increasing to the next highest dose one month after each use. The second group had the same treatment with tretinoin, a prescribed retinoid that is considered the gold standard for anti-aging retinoid treatment. Participants increased once a month (0.025%, 0.05% and 0.1%), and the groups using the retinol formulations disclosed herein in the examples below experienced excellent, surprising results, in many cases as good or better as the individuals in the group using tretinoin, and were less irritating.

The data obtained demonstrate the effectiveness of the disclosed topical retinoid-containing formulations for improving skin properties.

The disclosed formulations can be used alone and/or with auxiliary products (e.g., sunscreens, moisturizers, and cleansers) in a step-wise procedure as described above.

In exemplary embodiments of the formulations disclosed herein, the ingredients are: isoprene glycol, isosorbide dimethyl ether, polysorbate 80, ethoxy diglycol, caffeine, tea (green tea) polyphenol, retinol, polysorbate 20, bakuchiol, purified water, glycyrrhiza glabra (glycyrrhiza glabra) root extract, tea (black tea) leaf extract, and glycerin.

In the disclosed formulation, ethoxydiglycol is used in a customary manner according to the european cosmetic legislation, requiring it to be present at less than 2.6%. Isoprene glycol, isosorbide dimethyl ether, polysorbate 80 are significantly weaker, milder solvents for retinol and retinol derivatives (retinoids).

The formulations disclosed herein provide results comparable to the prescribed retinoids and remain within the cosmetic (non-pharmaceutical) dosage range of retinol, and thus can be used without limitation.

Exemplary compositions (all expressed as% w/w)

Example 1:

composition (I)	Concentration (wt%)
		Isoprenyl glycols	10-90％
Polysorbate 80	1-40％
		Caffeine	0.01-10％
Dimethyl isosorbide	5-90％
		Ethoxy diglycol	0-80％
Green tea polyphenols	0.1-15％
		Retinol	0.01-30％
Polysorbate 20	0-30％
		Bakuchiol	0-20％
Black tea extract	0-20％
		Glycyrrhiza uralensis extract	0-20％

Example 2:

example 3: 0.25% retinol

Composition (I)	Concentration (wt%)
		Isoprenyl glycols	The proper amount is 100 percent
Polysorbate 80	8.52％
		Caffeine	1.25％
Dimethyl isosorbide	30.00％
		Ethoxy diglycol	2.50％
Green tea polyphenols	1.25％
		Retinol	0.25％
Polysorbate 20	0.25％
		Bakuchiol	1.00％
Black tea extract	0.001％
		Glycyrrhiza uralensis extract	0.001％

Example 4: 0.5% retinol

Example 5: 1.0% retinol

Composition (I)	Concentration (wt%)
		Isoprenyl glycols	The proper amount is 100 percent
Polysorbate 80	8.52％
		Caffeine	1.25％
Dimethyl isosorbide	30.00％
		Ethoxy diglycol	2.50％
Green tea polyphenols	1.25％
		Retinol	1.00％
Polysorbate 20	1.00％
		Bakuchiol	1.00％
Black tea extract	0.001％
		Glycyrrhiza uralensis extract	0.001％

Clinical research

Method

A single-site, double-blind control study included 45 photoaged women aged 35-65 years with Fitzpatrick skin types I-IV, moderate wrinkles. Subjects who had used facial retinoids within 3 months prior to screening and/or alpha hydroxy acids within 1 month were excluded. Subjects were randomized 2:1 into the following groups:

group 1:30 subjects applied 0.25% retinal serum (e.g., the composition of example 3 above) for 4 weeks. On week 1, 0.25% retinal serum was used twice weekly, followed by overnight use on week 2, followed by nights use on weeks 3 and 4. Moisturizers (lipid repair cream), TOPIX Pharmaceuticals, inc., Amityville, NY) were placed on the retinal serum for each evening application and each morning.

Group 2: 15 subjects applied 0.025% tretinoin cream for 4 weeks. On week 1, the 0.025% tretinoin cream was used twice a week, then overnight on week 2, then overnight on weeks 3 and 4. On each application and each morning, a test moisturizer (Ceray Moisturizing Cream, L' Oreal, NY) was placed on retinoic acid Cream (Ortho Dermatologies, N.J.).

Dermatologist researchers and subjects evaluated the following facial efficacy parameters: overall severity of photodamage, dryness, lack of smoothness of touch, lack of smoothness of vision, lack of softness, lack of brightness, lack of gloss, lack of firmness, poor skin texture, fine facial lines, crow's feet, color difference, and dry cheek skin texture. All assessments were graded on a 5-point sequential scale (0 none, 1 minimal, 2 mild, 3 moderate, 4 severe). In addition, investigators and subjects evaluated overall clinical improvement compared to baseline at week 12 using a 5-part table (1 ═ significant improvement, 2 ═ moderate improvement, 3 ═ slight improvement, 4 ═ no change, 5 ═ worse). The investigator and subjects completed the assessment with reference to baseline images (anterior, right and left images) of the subjects.

Tolerance was graded according to the following parameters: itching, stinging, burning, redness, swelling. All assessments were performed on a 5-point sequential scale (0 none, 1 minimal, 2 mild, 3 moderate, 4 severe).

Compliance was enhanced using a weekly diary, requiring subjects to record product application and any comments on the weekly diary provided. Compliance text was sent at week 2, asking subjects to contact the study center when they experienced any difficulty in using the study product, and encouraging subjects to remain consistent with treatment, continuing to maintain a daily diary.

The visible light from the middle, right and left faces was used to take clinical pictures with a VISIA CR43 camera system (cantield Scientific, NJ) at each visit. Noninvasive assessment of barrier function was obtained from the left lateral face using an evaporator (cyberdem, Broomall, PA) in the form of a transepidermal water loss (TEWL) measurement.

Skin biopsies were obtained from 6 subjects of group 1 and 4 subjects of group 2. A 2mm skin biopsy was taken from the face in front of the right ear at baseline (visit 1) and a 2mm skin biopsy was taken from the face in front of the left ear at week 12 (visit 4). Histological evaluation included epidermal plumpness, stratum corneum densification, increased collagen, increased glycosaminoglycans (GAG), decreased melanin, improved vascularity and epidermal processes (vascurities and retetides), and decreased solar elastosis. These analyses were performed on formalin-fixed specimens using H & E, elastic staining and GAG staining (Garron Solomon, Tri-point Diagnostics, Morrisville, NC).

Statistics of

In addition to descriptive statistics (mean, standard deviation and percentage), researchers performed rank-off data analysis on paired comparisons at different time points within and between groups using Wilcoxon signed rank test and signed test. The change was considered significant when the p-value was less than or equal to 0.05.

Results

Of the 45 subjects, 43 successfully completed the study. Two out of 45 subjects were discontinued due to retinoid tolerance problems, one for each study group. This was unexpected because this study involved a rather aggressive retinol treatment (retinization) regimen. After cessation of retinoid treatment, all facial irritation immediately disappeared. Some adverse reactions occurred due to rapid facial retinol treatment (6 in group 1,4 in group 2). These are all expected to occur and all are addressed after changing the facial treatment regimen. No serious adverse events occurred during the study.

Retinol experience

All subjects were asked to score their experiences at the end of the 12 week study. Lower scores indicate better performance. The lipid-building cream (lipid repanning cream) used in the retinoid serum group was statistically superior to the currently available cream (P ═ 0.038) used in the retinoic acid group. Both groups of subjects reported improvements in confidence, beautiful skin and empowerment.

Efficacy of the investigator

The investigators rated facial skin appearance parameters using a 5-point sequential scale (0: none, 1: minimal, 2: mild, 3: moderate, 4: severe) at baseline (visit 1), week 4 (visit 2), week 8 (visit 3) and week 12 (visit 4). There were no statistically significant attributes between the two groups at any time point, indicating a balance between retinol serum and retinoic acid, according to the efficacy assessed by the investigator.

Longitudinal intra-group evaluation showed statistically significant improvement in tactile smoothness, softness, brightness, and gloss for both groups after 4 weeks of use, but greater significance for the retinol group (figure 1). In addition, retinol has statistical significance (P ═ 0.031) for improvement of visual smoothness, while retinoic acid has no statistical significance for improvement of visual smoothness. The improvement continued until week 8, and both groups showed statistical significance in terms of tactile smoothness, visual smoothness, softness, brightness, luster, firmness, skin texture, and overall photoaged appearance. Retinol showed a statistically very significant improvement in skin dryness (P <0.001), whereas tretinoin did not (figure 2). After 12 weeks of use, both products showed improvement, but the statistical significance of the retinol group was still higher.

Overall efficacy of the investigator

At week 12, the investigators rated the overall improvement in facial appearance using the following scale: 1 is a marked improvement, 2 is a moderate improvement, 3 is a slight improvement, 4 is unchanged, and 5 is worse. There was no statistically significant difference in the overall improvement of retinol serum and tretinoin (P ═ 0.778).

Tolerance of investigator

The investigators assessed tolerance by querying the subjects for itching, stinging, and burning sensations, as well as redness and swelling. There were no statistically significant differences between the retinol serum and tretinoin in any of the tolerance categories.

Subject efficacy

Subjects were evaluated for their skin appearance at baseline, week 4, week 8 and week 12 for various photodamage parameters using a 5-point sequential scale (0 ═ none, 1 ═ minimum, 2 ═ mild, 3 ═ moderate, 4 ═ severe). There were no statistically significant differences between the two groups at any time, except that the visual smoothness of the retinol serum was better at week 8 (P ═ 0.045, fig. 3).

In-group longitudinal assessment analysis showed that both retinol serum and retinoic acid users experienced improvement, however, retinol serum users had higher statistical significance at all time points. Specifically, statistically significant improvements were observed in visual smoothness (P ═ 0.003), softness (P ═ 0.006), fishtail (P ═ 0.001), color difference (P ═ 0.004), and overall photoaged appearance (P ═ 0.031) assessed at week 4 for subjects using retinol (fig. 4). At week 8, the softness of the retinol serum group was still significant (P <0.001), while the softness of the tretinoin group was not significant (fig. 3). Most parameters of both treatments showed statistical significance at week 12.

Overall efficacy of the subject

After 12 weeks of use, subjects were evaluated for overall clinical improvement relative to baseline examinations using a 5-subscale (1: significant improvement, 2: moderate improvement, 3: mild improvement, 4: no change, 5: worse). The subjects were evaluated with reference to a baseline image. There was no statistical difference between the two groups (P ═ 0.697). Both retinol serum and retinoic acid users report significant improvement in skin on average.

Subject tolerance

Subjects rated for tolerance according to itching, stinging, burning, redness and swelling, with lower ratings indicating less tolerance problems. At week 4, there was only a statistically significant difference in itching between the retinol serum and the retinoic acid users. The retinol serum group experienced less itching (P ═ 0.010; fig. 5).

Water loss through The Epidermis (TEWL)

TEWL (evaporatron, Cyberderm, Broomall, PA) measurements were performed at baseline, week 8 and week 12. Although TEWL increased with both retinol and tretinoin, no statistically significant difference was observed between the two groups at week 8 (P0.337) and week 12 (P0.604). Although the barrier damage caused by both products (P <0.001) was consistent with the use of retinoids, longitudinal intra-group comparisons showed less barrier damage at week 12 with retinol serum than with tretinoin treatment. At week 12, the TEWL increased 104% in the tretinoin group and 88% in the retinol serum group. The TEWL increase for retinol was 16% lower than for tretinoin.

Histology

Baseline histology was compared to week 12 histology. After 12 weeks of use, retinol serum subjects showed newly formed collagen and greater epidermal thickening compared to retinoic acid treated subjects.

Fig. 6A-6D show an increase in epidermal thickening of about 30% to about 50% compared to baseline. Figures 6A-6D show that collagen deposition is approximately 2 to 3 times that of baseline (initial and 12 weeks, same subject, retinol group).

Fig. 6A depicts the baseline sample at 100 x magnification, and fig. 6C depicts the baseline sample at 200 x magnification. Fig. 6B is a 100-fold magnification of the 12-week sample, and fig. 6D is a 200-fold magnification of the 12-week sample.

Discussion of the related Art

After 12 weeks of use, both the retinol serum and tretinoin showed a fair value at many investigators and subject evaluation endpoints, although on average, the retinol serum group was more significant. Subjects in the retinol serum group started treatment for 4 weeks, with the earliest assessment visit, the skin appeared smoother, less dry. Retinol serum subjects reported several aspects of facial improvement after 4 weeks of use, including smoother skin, softer skin, reduced fine lines and wrinkles around the eyes, improved skin tone uniformity, and overall reduction in photodamage. The improvement in skin softness continued for the subject retinol until week 8, whereas the improvement in skin softness did not occur until week 8 in the subject retinoic acid.

TEWL measurements mean that subjects using the retinol serum had 16% less water loss across the compromised barrier during the study. The presence of newly formed collagen and greater epidermal thickening also coincides with clinical and functional improvement after completion of the study.

Conclusion

The retinoid serum containing bakuchiol represents an effective replacement for the prescription of retinoic acid, providing rapid retinol treatment and appearance improvement in photodamaged skin.

For purposes of simplicity of explanation, the embodiments of the present method are depicted and described as a series of acts. However, acts in accordance with the present invention may occur in various orders and/or concurrently, and with other acts not presented and described herein. Moreover, not all illustrated acts may be required to implement a methodology in accordance with the disclosed subject matter. Further, those skilled in the art will understand and appreciate that the methodologies could alternatively be represented as a series of interrelated states via a state diagram or events.

In the previous descriptions, numerous specific details are set forth, such as specific materials, dimensions, process parameters, etc., in order to provide a thorough understanding of the present invention. The particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments. The word "example" or "exemplary" is used herein to mean serving as an example, instance, or illustration. Any aspect or design described herein as "exemplary" or "exemplary" is not necessarily to be construed as preferred or advantageous over other aspects or designs. Rather, the use of "example" or "exemplary" is intended to present concepts in a concrete fashion. As used herein, the term "or" means an inclusive "or" rather than an exclusive "or". That is, unless otherwise specified or clear from context, "X comprises a or B" means any of the natural inclusive permutations. That is, if X comprises A; x comprises B; or X includes both A and B, then "X includes A or B" is satisfied under either condition. In addition, the articles "a" and "an" as used in this application and the appended claims should generally be construed to mean "one or more" unless specified otherwise or clear from context to be directed to a singular form. Reference throughout this specification to "an embodiment," "certain embodiments," or "one embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "one embodiment," "some embodiments," or "an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment.

Reference in this specification to numerical ranges should not be construed as limiting, but rather should be construed to include outer limits of the ranges as well as each number and/or narrower range within the numerical range recited.

When referring to physical quantities, the term "about" should be understood to include measurement errors within 10%. For example, "about 100 ℃ C" is understood to mean "100. + -. 10 ℃.

The invention has been described with reference to specific exemplary embodiments thereof. The specification and drawings are, accordingly, to be regarded in an illustrative rather than a restrictive sense. Various modifications in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

Claims (26)

1. A topical formulation comprising a skin treatment active and an activating solvent system comprising isoprene glycol, dimethyl isosorbide and a non-ionic surfactant.

2. The formulation of claim 1, further comprising an antioxidant.

3. The formulation of any one of claims 1-2, wherein the skin therapeutically active agent comprises retinol.

4. The formulation of any one of claims 1-3, further comprising bakuchiol.

5. The formulation of any one of claims 1-4, wherein the non-ionic surfactant is one or more of: ethoxylates, fatty ethoxylates, propoxylates, block copolymers, poloxamers, polyglycerol esters, polyglycerol emulsifiers, sorbitan, dipolar agents, phenolic nonionic surfactants.

6. The formulation of any one of claims 1-5, wherein the non-ionic surfactant comprises polysorbate 80.

7. The formulation of any one of claims 1-6, further comprising polysorbate 20.

8. The formulation of any one of claims 2-7, wherein the antioxidant is one or more of: green tea polyphenols, Glycyrrhrizae radix extract, resveratrol, silymarin, curcumin, caffeine, astaxanthin, flavone, flavonoid, flavanol, tocopherol, ascorbic acid, coenzyme Q10, ergothioneine, glutathione, ectoin, bisabolol, and fructus Phyllanthi.

9. The formulation of any one of claims 2-8, wherein the antioxidant comprises camellia polyphenol.

10. The formulation of any one of claims 2-9, wherein the antioxidant comprises a xanthine, the xanthine being caffeine.

11. The formulation of any one of claims 1-10, comprising (% w/w):

about 10% to about 90% isoprene glycol;

about 1% to about 40% polysorbate 80;

from about 0.01% to about 10% caffeine;

about 5% to about 90% isosorbide dimethyl ether;

up to about 80% ethoxydiglycol;

from about 0.1% to about 15% camellia (green tea) polyphenols;

about 0.01% to about 30% retinol;

up to about 30% polysorbate 20;

up to about 20% bakuchiol;

up to about 20% black tea extract; and

up to about 20% licorice root extract.

12. The formulation of any one of claims 1-11, comprising (% w/w):

about 45% to about 65% isoprene glycol;

about 6% to about 10% polysorbate 80;

from about 0.5% to about 2.5% caffeine;

about 20% to about 40% isosorbide dimethyl ether;

about 1% to about 5% ethoxydiglycol;

from about 0.1% to about 5% camellia (green tea) polyphenols;

about 0.05% to about 1.5% retinol;

about 0.05% to about 2% polysorbate 20;

about 0.1% to about 3% bakuchiol;

about 0.001% to about 5% black tea extract; and

about 0.001% to about 5% licorice root extract.

13. The formulation of any one of claims 1-12, comprising (% w/w):

a suitable amount to 100% of isoprene glycol;

about 8% to about 9% polysorbate 80;

from about 1% to about 1.5% caffeine;

about 25% to about 35% isosorbide dimethyl ether;

about 2% to about 3% ethoxydiglycol;

from about 1% to about 1.5% camellia (green tea) polyphenols;

about 0.2% to about 1.2% retinol;

about 0.2% to about 1.2% polysorbate 20;

about 0.5% to about 1.5% bakuchiol;

about 0.001% to about 0.1% black tea extract; and

from about 0.001% to about 0.1% licorice extract.

14. A method for therapeutically treating a skin condition comprising topically applying to an affected area a therapeutically effective amount of a topical formulation comprising a skin treatment active agent and an activating solvent system comprising isoprene glycol, isosorbide dimethyl ether and a non-ionic surfactant.

15. The method of claim 14, wherein the affected area is one or more of human skin, scalp, hair, nails.

16. The method of any one of claims 14-15, wherein the active agent comprises retinol.

17. The method of any one of claims 14-16, wherein the non-ionic surfactant comprises polysorbate 80.

18. The method of any one of claims 14-17, wherein the formulation further comprises an antioxidant.

19. The method of any one of claims 14-18, wherein the formulation further comprises bakuchiol.

20. A method for preparing a topical formulation comprising:

forming a first mixture of an antioxidant system and an activating solvent system comprising isoprene glycol, dimethyl isosorbide and a nonionic surfactant;

separately combining retinol with isoprene glycol and isosorbide dimethyl ether to form a retinol mixture; and

combining the first mixture with the retinol mixture,

wherein the process is carried out under an inert atmosphere.

21. The topical formulation of any one of claims 1-13 or the topical formulation prepared by the method of claim 20, wherein skin treated with the formulation for at least 4 weeks exhibits at least about 30% epidermal thickening.

22. A topical formulation according to any one of claims 1 to 13 or prepared by the method of claim 20, wherein skin treated for at least 4 weeks with the formulation shows at least 2-fold more collagen deposition compared to baseline.

23. The topical formulation of any one of claims 1-13 or the topical formulation prepared by the method of claim 20, wherein skin treated with the formulation for at least 4 weeks exhibits less than about a 100% increase in transepidermal water loss compared to baseline.

24. The method of any one of claims 14-19, wherein skin treated with the formulation for at least 4 weeks exhibits at least about 30% epidermal thickening.

25. The method of any one of claims 14-19 or claim 24, wherein skin treated with the formulation for at least 4 weeks exhibits at least 2-fold more collagen deposition compared to baseline.

26. The method of any one of claims 14-19 or claim 24, wherein skin treated with the formulation for at least 4 weeks exhibits less than about a 100% increase in transepidermal water loss compared to baseline.