Compositions and methods for treating skin disorders

Abstract

This specification provides compositions and methods for treating skin disorders. In particular, this specification provides compositions that enhance retinoid-based skin treatment while preventing side effects.

Description

Technical Field

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 453,792, filed on Mar. 22, 2023, the entire content of which is incorporated herein by reference for all purposes.

[0002] Compositions and methods for treating skin disorders are provided herein. In particular, compositions for enhancing the treatment of skin with retinoids while preventing side effects are provided herein.

Background Art

[0003] Topical retinoids are used to treat a wide variety of skin diseases. For example, acne vulgaris is treated with all-trans retinoic acid (tretinoin), marketed under the well-known brand name Retin-A (Janssen Pharmaceuticals) and the lesser-known brand name Avita (Penederm); severe acne is treated with oral 13-cisretinoic acid (isotretinoin; marketed for oral administration under the brand name Accutaneoral). 9-cisretinoic acid (alitretinoin) is used topically to treat skin lesions of AIDS-associated Kaposi's sarcoma (Panretin brand gel, Ligand Pharmaceuticals) and systemically to treat chronic eczema and renal cancer. Synthetic retinoids approved for use against acne and psoriasis include adapalene (marketed under the brand name Differin) and tazarotene (marketed under the brand name Tazorac), respectively. Psoriasis is also treated with a trimethylmethoxyphenyl analog of ethyl retinoate (etretinate; marketed under the brand name Soriatane (acetretin), formerly marketed under Tegison (etretinate)). Retinoids are also used to treat other types of acne (e.g., cystic acne and rosacea) and various keratinization disorders, such as ichthyosis (e.g., ichthyosis lamellaris, ichthyosis vulgaris), pityriasis rubra pilaris, and Darier's disease. Retinoids are also used for chemotherapy and chemopreventive therapy for skin cancers and precancerous lesions (e.g., basal cell and squamous cell carcinoma and keratosinus acanthoma). Retinoids are also used to treat skin conditions such as warts, keratotic eczema of the hands and feet, and cutaneous sarcoidosis. In addition, retinoids are used to treat photoaged skin with formulations such as those marketed under the brand name Renova. Therefore, retinoids are widely used both topically and systemically (oral) for a wide variety of conditions.

[0004] Further uses of retinoids include preventing photoaging of human skin (e.g., U.S. Patent Nos. 5,837,224 and 6,130,254), preventing and reversing age-related aging of human skin, treating post-inflammatory hyperpigmentation in dark skin (e.g., U.S. Patent Nos. 5,750,570 and 6,017,960), preventing UV-induced loss of collagen biosynthesis, preventing UV-induced functional vitamin A deficiency, and preventing acne-related scarring and inflammation.

[0005] Anyone trained in the use of retinoids will recognize the toxicity issues, but common side effects of long-term retinoid use, such as erythema (redness), scaling, burning, and / or itching, are far more common and predictable. See, for example, JW Fluhr et al., "Tolerance profile of retinol, retinaldehyde and retinoic acid under maximized and long-term clinical conditions," Dermatology 1999;199 Supplement 1: pp. 57-60. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] U.S. Patent No. 5,837,224 [Patent Document 2] U.S. Patent No. 6,130,254 [Patent Document 3] U.S. Patent No. 5,750,570 [Patent Document 4] U.S. Patent No. 6,017,960 [Non-patent literature]

[0007] [Non-Patent Document 1] JW Fluhr et al., "Tolerance profile of retinol, retinaldehyde and retinoic acid under maximized and long-term clinical conditions," Dermatology 1999;199 Supplement 1:57-60. [Overview of the Initiative] [Problems that the invention aims to solve]

[0008] In light of the foregoing, it is beneficial to prevent exfoliation, desquamation, and dryness associated with topical and systemic (oral) retinoid therapy without significantly reducing the desired therapeutic effect. Furthermore, it is useful to provide this benefit without interfering with or making the retinoid treatment regimen difficult, thereby maintaining, if not improving, patient compliance with retinoid therapy. [Means for solving the problem]

[0009] (Summary of Disclosure) This specification provides compositions and methods for treating skin disorders. In particular, this specification provides compositions that enhance retinoid-based skin treatment while preventing side effects.

[0010] By combining retinoids, amphiregulin inhibitors (e.g., the root of Paeonia suffructicosa), and anti-inflammatory agents (e.g., Centipeda cunninghammii), this disclosure makes it possible to increase the concentration of retinoids, improve efficacy, and reduce side effects.

[0011] For example, in some embodiments, a composition is provided herein that comprises a) 0.075-0.20% (e.g., 0.075-0.1%, 0.075-0.15%, 0.15-0.2%, 0.075-0.20%, 0.1-0.15%, 0.1-0.2%, 0.1-0.2%, or 0.15%) (w / w) of a retinoid compound; b) an extract of the root of Peonia safruticosa; and c) an extract of Centipeda kunningami, which is formulated for topical administration. In some embodiments, the extract comprises 2 parts Centipeda kunningami to 1 part Peonia safruticosa (e.g., ±1%, 2%, 5%, 10%, 20%, 25%, etc.). In some embodiments, the extract or composition contains 0.01-3.0% (e.g., 0.1-3%, 1.0-3%, 1.5-3%, 0.5-3%, 0.5-2%, 0.5-2.5%, 0.5-1.5%, 1.0-3.0%, or 1.0-2.0%) (w / w) of Peonia safruticosa and 0.5-4% (e.g., 0.5-1%, 0.5-1.5%, 0.5-2%, 0.5-2.5%, 0.5-3%, 0.5-3.5%, 1-3%, 1-4%, 1.5-4%, 1.5-3%, 2.0-3.0%) (w / w) of Centipeda kunningami. In some embodiments, the extract or composition contains 1.33% Peonia safruticosa and 2.67% Centipeda kunningami. In some embodiments, the extract contains an organic solvent.

[0012] In some embodiments, Centipeda kunningami and / or Peonia safruticosa are extracted in water or an organic solvent (e.g., alcohol (e.g., ethanol) or diol (e.g., butylene glycol)). In some embodiments, after extraction, the extract is resuspended in a second solvent that is the same as or different from the initial extraction solvent. In some embodiments, the final extract contains one or more preservatives.

[0013] This disclosure is not limited to specific retinoid compounds. Examples include, but are not limited to, retinol. In some embodiments, the extract increases the efficacy of the retinoid and reduces side effects (e.g., skin irritation). In some embodiments, the extract inhibits the activity of amphiregulin and / or EGFR.

[0014] In some embodiments, the composition is a liquid, cream, lotion, gel, ointment, salve, or spray.

[0015] Further embodiments provide a method for treating or preventing a skin condition, comprising administering a composition described herein to a subject skin condition, wherein the composition treats or prevents one or more signs or symptoms of the subject skin condition.

[0016] This disclosure is not limited to specific skin conditions. Examples include, but are not limited to, acne, AIDS-associated Kaposi's sarcoma, eczema, psoriasis, keratinization disorders, skin cancer, warts, cutaneous sarcoidosis, or photoaging of the skin (e.g., wrinkles and / or sagging).

[0017] The compositions described may be applied at regular or irregular intervals (for example, as needed to reduce or prevent symptoms of a skin condition). In some embodiments, the compositions are applied at least daily (for example, once, twice, or more times a day). In some embodiments, the compositions are applied every two days, every three days, weekly, monthly, or at other intervals. For example, in some exemplary embodiments, the compositions are applied every other day for a week, and then once a day for a further period (for example, several days, several weeks, several months, several years, or indefinitely).

[0018] Further embodiments provide the use of the compositions described herein for treating or preventing a skin condition in a subject, or provide the compositions described herein for use in treating or preventing a skin condition in a subject.

[0019] Further embodiments are described herein.

Brief Description of the Drawings

[0020] [Figure 1] Shows the changes in visual evaluation after 12 consecutive weeks of application of the test and control products (mean ± SD, *p < 0.05 after application compared to baseline, †p < 0.05 for the test group compared to the control group). [Figure 2] Shows the changes in the average roughness Ra after 12 consecutive weeks of application of the test and control products (mean ± SD, *p < 0.05 after application compared to baseline, †p < 0.05 for the test group compared to the control group). [Figure 3] Shows the changes in the mean square roughness Rq after 12 consecutive weeks of application of the test and control products (mean ± SD, *p < 0.05 after application compared to baseline, †p < 0.05 for the test group compared to the control group). [Figure 4] Shows the changes in the maximum roughness (depth) Rmax after 12 consecutive weeks of application of the test and control products (mean ± SD, *p < 0.05 after application compared to baseline, †p < 0.05 for the test group compared to the control group). [Figure 5] Shows the comparative sensory profiles (percentage, %) of the test and control groups for effectiveness. [Figure 6] Shows the comparative sensory profile (positive responses, %) of the test product for usability. [Figure 7] Shows the changes in visual evaluation after 12 consecutive weeks of application of the test and control products (mean ± SD, *p < 0.05 after application compared to baseline, †p < 0.05 for the test group compared to the control group). [Figure 8] Shows the changes in the average roughness Ra after 12 consecutive weeks of application of the test and control products (mean ± SD, *p < 0.05 after application compared to baseline, †p < 0.05 for the test group compared to the control group). [Figure 9]The changes in mean squared roughness Rq after 12 consecutive weeks of application of the test and control products are shown (mean ± SD, post-application *p<0.05 relative to baseline, test group †p<0.05 relative to control group). [Figure 10] The graph shows the change in maximum roughness (depth) Rmax after 12 consecutive weeks of application of the test and control products (mean ± SD, post-application *p<0.05 relative to baseline, test group †p<0.05 relative to control group). [Figure 11] The comparative sensory profiles (percentages, %) for the test group and the control group regarding efficacy are shown. [Figure 12] This shows a comparative sensory profile (positive responses, %) of the test products regarding their user experience. [Figure 13] The PCA plots for different treatment samples are shown. [Figure 14] The graph shows the top 10 pathways from the PAGE analysis. [Figure 15] A heatmap of all differentially expressed genes (DEGs) is shown. [Figure 16] This shows heatmaps for all DEGs with batch effects removed. [Figure 17] This shows a heatmap of DEGs located near DR2 or DR5. [Figure 18] A heatmap showing the effect of medication dosage is displayed. [Figure 19] The graph of the adapted dose-response model is shown. [Figure 20] The graph of the adapted dose-response model is shown. [Figure 21] This shows a heatmap of the Z-score from the PAGE analysis. [Figure 22] This study demonstrates the effect of peony extract on amphiregulin activation in human keratinocytes. [Modes for carrying out the invention]

[0021] definition As used herein, the term "in vitro" refers to an artificial environment and the processes or reactions occurring within it. Examples of in vitro environments include, but are not limited to, test tubes and cell cultures. The term "in vivo" refers to a natural environment (e.g., animals or cells) and the processes or reactions occurring within it.

[0022] As used herein, the term “effective dose” means an amount of a composition (e.g., a composition described herein) sufficient to produce a beneficial or desired result. An effective dose may be administered in one or more doses, applications, or dosages and is not intended to be limited to a particular formulation or route of administration.

[0023] As used herein, the term “administration” means the action of delivering a drug, prodrug or other agent or therapeutic treatment (e.g., a composition described herein) to a physiological system (e.g., a subject or in vivo, in vitro or ex vivo cells, tissues and organs). Exemplary routes of administration to the human body include the eye (ophthalmological), mouth (oral), skin (transdermal), nose (transnasal), lung (inhalation), oral mucosa (buccal), ear, injection (e.g., intravenous, subcutaneous, intratumoral, intraperitoneal, etc.), and topical administration.

[0024] As used herein, the term “concurrent administration” refers to the administration of at least two drugs (e.g., a combination of the compositions described herein and drugs known to treat or prevent a skin condition) or therapies to a target. In some embodiments, the concurrent administration of two or more drugs or therapies is simultaneous. In other embodiments, the first drug / therapy is administered before the second drug / therapy. Those skilled in the art will understand that the formulations and / or routes of administration of the various drugs or therapies used may vary. Appropriate dosages for concurrent administration can be readily determined by those skilled in the art. In some embodiments, when drugs or therapies are concurrently administered, each drug or therapy is administered at a lower dosage than the appropriate dosage for administration alone. Concurrent administration is therefore particularly desirable in embodiments where concurrent administration of drugs or therapies reduces the required dosage of potentially harmful (e.g., toxic) drugs.

[0025] As used herein, the term “toxicity” refers to any adverse or harmful effect on a subject, cell, or tissue compared to the same cell or tissue before administration of the toxic substance.

[0026] As used herein, the term “pharmaceutical composition” refers to a combination of an activator (e.g., one described herein) and a carrier, inert substance, or active substance that makes the composition particularly suitable for use in vitro, in vivo, or ex vivo for diagnostic or therapeutic purposes.

[0027] As used herein, the terms "pharmaceutically acceptable" or "pharmacologically acceptable" refer to a composition that, when administered to a subject, substantially does not produce any adverse reaction, such as toxicity, allergy, or immunological reaction.

[0028] As used herein, the term “topical” refers to the application of a composition (e.g., a composition described herein) to the surface of the skin and to mucosal cells and tissues (e.g., alveoli, buccal, tongue, masticatory organs or nasal mucosa and other tissues and cells in hollow organs or body cavities).

[0029] As used herein, the term “pharmaceutically acceptable carrier” refers to, but is not limited to, any standard pharmaceutical carrier, including, phosphate-buffered saline, water, emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents, all kinds of solvents, dispersions, coatings, sodium lauryl sulfate, isotonic and absorption retardants, disintegrants (e.g., potato starch or sodium starch glycolate), etc. The composition may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th edition, Mack Publ. Co., Easton, Pa. (1975), incorporated herein by reference.

[0030] As used herein, the term “cell culture” refers to any in vitro culture of cells, including, for example, prokaryotic and eukaryotic cells. This term includes serial cell lines (e.g., immortal phenotypes), primary cell cultures, transformed cell lines, finite cell lines (e.g., untransformed cells), bacterial cultures in solid or liquid media, and any other cell populations maintained in vitro.

[0031] As used herein, the term “sample” is used in its broadest sense. In one sense, it means specimens or cultures obtained from any source, as well as biological and environmental samples. Biological samples may be obtained from animals (including humans) and may include fluids, solids, tissues, and gases. Examples of biological samples include blood products, such as plasma and serum. Such examples are not to be construed as limiting the types of samples applicable to this disclosure.

[0032] Detailed explanation of this disclosure This specification provides compositions and methods for treating skin disorders. In particular, this specification provides compositions that enhance retinoid-based skin treatment while preventing side effects.

[0033] Topical application of retinol to human skin induces growth factors that activate epidermal growth factor receptors (EGFRs). This activation contributes to the undesirable side effects of topical retinol, characterized by disruption of epithelial homeostasis, which are perceived by consumers as "irritation." This irritation limits the concentration of retinol that can be included in topical formulations.

[0034] To address these limitations of existing treatments, during the development of embodiments of this disclosure, experiments identified Peonia safruticosa root extract as a potent inhibitor of the amphiregulin pathway and Centipeda cucumeris extract as an effective anti-inflammatory agent. Combinations of Centipeda and Peonia extracts were tested in skin creams containing 0.20% or 0.40% retinol. Clinical trials showed that skin creams containing the Centipeda and Peonia combination allowed for the use of higher levels of retinol with less irritation. In addition, transcriptome analysis of skin biopsies derived from study subjects revealed that the Peonia and Centipeda combination enhanced the activity of retinol. Thus, the combination of plant-derived substances increased the potency of retinol. Modeling showed that the biological response of the skin to a preferred final concentration of 0.15% retinol combined with Peonia and Centipeda was equivalent to that of 0.25% retinol alone.

[0035] Accordingly, this specification provides skincare compositions comprising retinol in combination with peony and centipede, which reduce the potential for irritation caused by retinol use and simultaneously increase the potency of retinol. This enables more potent skincare products that are better tolerated than could otherwise be achieved.

[0036] For example, in some embodiments herein, a composition is provided which comprises a) 0.05-0.25% (e.g., 0.05-0.1%, 0.05-0.15%, 0.15-0.2%, 0.05-0.25%, 0.1-0.15%, 0.1-0.2%, 0.1-0.25%, 0.15-0.2%, 0.1-0.25%, 0.1-0.2%, or 0.15%) (w / w) of a retinoid compound; b) an extract of the root of Peonia safruticosa; and c) an extract of Centipeda kunningami, which is formulated for topical administration. In some embodiments, the extract comprises 2 parts Centipeda kunningami to 1 part Peonia safruticosa. In some embodiments, the extract or composition contains 0.01-3.0% (e.g., 0.1-3%, 1.0-3%, 1.5-3%, 0.5-3%, 0.5-2%, 0.5-2.5%, 0.5-1.5%, 1.0-3.0%, or 1.0-2.0%) (w / w) of Peonia safruticosa and 0.5-4% (e.g., 0.5-1%, 0.5-1.5%, 0.5-2%, 0.5-2.5%, 0.5-3%, 0.5-3.5%, 1-3%, 1-4%, 1.5-4%, 1.5-3%, 2.0-3.0%) (w / w) of Centipeda kunningami. In some embodiments, the extract comprises 1.33% Peonia safruticosa and 2.67% Centipeda kunningami. In some embodiments, the composition comprises 1.33% Peonia safruticosa and 2.67% Centipeda kunningami. In some embodiments, the extract comprises an organic solvent.

[0037] This disclosure is not limited to specific sources of Peonia safruticosa and Centipeda kunningami extracts. In some embodiments, the extracts are commercially available or prepared via known extraction processes.

[0038] In some embodiments, Centipeda kunningami is extracted in water or an organic solvent (e.g., alcohol (e.g., ethanol) or diol (e.g., butylene glycol)).

[0039] Commercial sources of Centipeda kunningami extract include, but are not limited to, Native Extracts (NSW Australia) and Plantolin BG manufactured by Bio Actives Export (Melbourne, Australia). Exemplary extraction methods are described, for example, in U.S. Patent Application Publication No. 20020044977, Australian Patent No. 577058, and International Patent No. 2006023710; each of these patents is incorporated herein by reference in whole.

[0040] In some embodiments, Peonia safruticosa is extracted in water or an organic solvent (e.g., alcohol (e.g., ethanol) or diol (e.g., butylene glycol)). In some embodiments, after extraction, the extract is resuspended in a second solvent that is the same as or different from the initial extraction solvent. In some embodiments, the final extract contains one or more preservatives.

[0041] Commercial sources of Peonia safruticosa extract include, but are not limited to, Ichimaru Pharcos (Japan), Botanicals Plus (Fairfield, New Jersey), Shanghai JAKA Biotech (China), Dermalab (Korea), Innovacos (Mt Arlington, NJ), Koei Kogyo (Tokyo, Japan), and the Garden of Natural Solution (Osan, South Korea). An exemplary extraction method is described, for example, in U.S. Patent Application Publication No. 20160367616, which is incorporated herein by reference in its entirety.

[0042] This disclosure is not limited to specific retinoid compounds. Examples include, but are not limited to, retinol, retinal, tretinoin (retinoic acid), isotretinoin, tretinoin, adapalene, tazarotene, alitretinoin, etretinate, acitretinor, adapalene, bexarotene, tazarotene, and triphalotene. In some embodiments, the extracts increase the efficacy of the retinoids and reduce side effects (e.g., skin irritation). In some embodiments, the extracts inhibit the activity of one or more amphireglins.

[0043] In some embodiments, the retinoid, the root extract of Peonia safruticosa, and the extract of Centipeda cucumeris are supplied in the same composition. Instead of or in addition to the combination of the root extract of Peonia safruticosa and the extract of Centipeda cucumeris with the retinoid, one or more separate compositions containing the root extract of Peonia safruticosa and the extract of Centipeda cucumeris and a dermatologically suitable carrier may be applied to the patient as needed and / or in combination with the application of the retinoid. It is preferable to start using the composition containing the extracts some time before the patient starts retinoid therapy, preferably 1 to 48 hours before. Preferably, the use of the extracts should be continued for some time after the completion of retinoid therapy, preferably at least 1 day, more preferably about 1 week. Because different patients may respond differently, and the extract in the primary composition may not yield the optimal effect, the separate composition is also useful, even when combined with the primary composition, which is a combination of retinoids and extracts of Peonia safruticosa root and Centipeda kunningamia. For the separate extract composition, there may be further beneficial components or extracts that do not interfere with retinoid therapy, in particular those that may help alleviate the side effects of retinoid therapy. Such components may include humectants, moisturizers, emollients, and even mild antimicrobial agents (e.g., benzalkonium chloride) and mild anesthetics (e.g., benzocaine), as well as compatible mixtures thereof. Further conventionally used components, including fragrances, colorants, etc., may be present if desired. The primary retinoid / extract composition, the separate extract composition, or both, may be provided as creams, gels, lotions, sprays, and other forms as typically formulated in the dermatology and cosmetic industries.

[0044] In some embodiments, the composition (e.g., those described herein) is formulated into a composition (e.g., a pharmaceutical composition, a nutritional supplement composition, or a cosmetic) for administration to the skin.

[0045] Examples of pharmaceutical compositions and formulations for topical administration include transdermal patches, ointments, lotions, creams, gels, eye drops, suppositories, sprays, liquids, mouthwashes, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oil-based bases, thickeners, etc., may be necessary or desirable.

[0046] The pharmaceutical compositions of this disclosure include, but are not limited to, liquid formulations, emulsions, and liposome-containing formulations. These compositions can be produced from a variety of components, but are not limited to, pre-formed liquids, self-emulsifying solids, and self-emulsifying semi-solids.

[0047] The composition may further contain other additive components conventionally found in pharmaceutical compositions. For example, the composition may contain further compatible pharmaceutically active materials, such as antipruritics, astringents, topical anesthetics, or anti-inflammatory agents, or further materials useful for physically formulating compositions in various dosage forms, such as dyes, preservatives, antioxidants, opacifiers, thickeners, and stabilizers. However, if such materials are added, they should not excessively interfere with the biological activity of the components of the composition. The formulation may be sterilized and, if desired, may be mixed with adjuvants that do not adversely interact with the active ingredients of the formulation, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts affecting osmotic pressure, buffers, colorants, fragrances, and / or aromatic substances.

[0048] The compositions of this disclosure may be formulated as liquids, gels, lotions, creams, ointments, oil-in-water emulsions, water-in-oil emulsions, or other pharmaceutically acceptable forms. The compositions of this disclosure may also contain various known and conventional cosmetic ingredients, provided that they do not adversely affect the desired outcome.

[0049] Vehicles permitted in cosmetics act as diluents, dispersants, or carriers for other materials present in the composition, thereby facilitating their distribution when the composition is applied to the skin.

[0050] Other vehicles include liquid or solid softeners, solvents, humectants, thickeners, and powders. For example, the following vehicles can be used individually or in combination of one or more vehicles.

[0051] While not limited to these, other softening agents include stearyl alcohol, glyceryl ricinoleate, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecane-2-ol, isocetyl alcohol, eicosanyl alcohol, behenyl alcohol, cetyl palmitate, silicone oils such as dimethylpolysiloxane, di-n-butyl sebacate, isopropyl myristate, and isopropyl palmitate. Examples include ointment, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, cocoa butter, corn oil, cottonseed oil, olive oil, palm kernel oil, rapeseed oil, safflower seed oil, evening primrose oil, soybean oil, sunflower seed oil, avocado oil, sesame seed oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohol, petrolatum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate and / or myristyl myristate.

[0052] As used herein, “softener” refers to a material used for the prevention or reduction of dryness and for the protection of the skin. A wide variety of suitable softeners are known and may be used herein. Sagarin, Cosmetics, Science and Technology, 2nd edition, Vol. 1, pp. 32-43 (1972), incorporated herein by reference, contains numerous examples of suitable materials. Examples of useful classes of softeners include: 1. Hydrocarbon oils and waxes. Examples include mineral oil, petrolatum, paraffin, ceresin, ozokerite, microcrystalline wax, polyethylene, and perhydrosqualene. 2. Silicone oils, such as dimethylpolysiloxane, methylphenylpolysiloxane, water-soluble and alcohol-soluble silicone glycol copolymers. 3. Triglyceride esters, for example, vegetable and animal fats. Examples include castor oil, safflower oil, cottonseed oil, corn oil, olive oil, cod liver oil, almond oil, avocado oil, palm oil, sesame oil, and soybean oil. 4. Acetoglyceride esters, for example, acetylated monoglycerides. 5. Ethoxylated glycerides, for example, ethoxylated glyceryl monostearate. 6. Alkyl esters of fatty acids having 10 to 20 carbon atoms. Methyl, isopropyl, and butyl esters of fatty acids are particularly useful herein. Examples of other useful alkyl esters include hexyl laurate, isohexyl laurate, isohexyl palmitate, isopropyl palmitate, decyl oleate, isodecyl oleate, hexadecyl stearate, decyl oleate, isodecyl oleate, hexadecyl stearate, decyl stearate, isopropyl isostearate, diisopropyl adipate, diisohexyl adipate, dihexyldecyl adipate, diisopropyl sebacate, lauryl lactate, myristyl lactate, and cetyl lactate. 7. Alkenyl esters of fatty acids having 10 to 20 carbon atoms. Examples include oleyl myristate, oleyl stearate, and oleyl oleate. 8. Fatty acids having 10 to 20 carbon atoms. Suitable examples include pelargonic acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, hydroxystearic acid, oleic acid, linoleic acid, ricinoleic acid, arachidonic acid, behenic acid, and erucic acid. 9. Fatty alcohols having 10 to 20 carbon atoms. Lauryl alcohol, myristyl alcohol, cetyl alcohol, hexadecyl alcohol, stearyl alcohol, isostearyl alcohol, hydroxystearyl alcohol, oleyl alcohol, ricinoleyl alcohol, behenyl alcohol, and erucyl alcohol, as well as 2-octyldodecanol, are satisfactory examples of fatty alcohols. 10. Fatty alcohol ethers. Examples of ethoxylated fatty alcohols with 10 to 20 carbon atoms include lauryl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, octyl alcohol, and cholesterol alcohol, which are bonded with 1 to 50 ethylene oxide groups or 1 to 50 propylene oxide groups. 11. Ether esters, e.g., fatty acid esters of ethoxylated fatty alcohols. 12. Lanolin and its derivatives. Lanolin, lanolin oil, lanolin wax, lanolin alcohol, lanolin fatty acids, isopropyl lanolin fatty acids, ethoxylated lanolin, ethoxylated lanolin alcohol, ethoxylated cholesterol, propoxylated lanolin alcohol, acetylated lanolin, acetylated lanolin alcohol, linoleic acid lanolin alcohol, ricinoleic acid lanolin alcohol, acetate esters of ricinoleic acid lanolin alcohol, acetate esters of ethoxylated alcohol esters, hydrolysis of lanolin, ethoxylated hydrolysis lanolin, ethoxylated sorbitol lanolin, and liquid and semi-solid lanolin absorption bases are examples of lanolin-derived emollients. 13. Polyhydric alcohols and polyether derivatives. Propylene glycol, dipropylene glycol, polypropylene glycol 2000 and 4000, polyoxyethylene polyoxyethylene glycol, polyoxypropylene polyoxyethylene glycol, glycerol, sorbitol, ethoxylated sorbitol, hydroxypropyl sorbitol, polyethylene glycol 200-6000, methoxypolyethylene glycol 350, 550, 750, 2000 and 5000, poly[ethylene oxide]-homopolymer (100,000-5,000,000), polyalkylene glycols and derivatives, hexylene glycol (2-methyl-2,4-pentanediol), 1,3-butylene glycol, 1,2,6-hexanetriol, ethohexadiol USP (2-ethyl-1,3-hexanediol), C 15 ~C 18 Examples of materials in this class include polyoxypropylene derivatives of vicinal glycol and trimethylopropane. 14. Polyhydric alcohol esters. Ethylene glycol mono and di fatty acid esters, diethylene glycol mono and di fatty acid esters, diethylene glycol mono and di fatty acid esters, polyethylene glycol (200-6000) mono and di fatty acid esters, propylene glycol mono and di fatty acid esters, polypropylene glycol 2000 monooleate, polypropylene glycol 2000 monostearate, ethoxylated propylene glycol monostearate, glyceryl mono and di fatty acid esters, polyglycerol poly fatty acid esters, ethoxylated glyceryl monostearate, 1,3-butylene glycol monostearate, 1,3-butylene glycol distearate, polyoxyethylene polyol fatty acid esters, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters are polyhydric alcohols satisfactory for use herein. 15. Wax esters, such as beeswax, whale wax, myristyl, myristate, and stearyl stearate. 16. Beeswax derivatives, e.g., polyoxyethylene sorbitol beeswax. These are reaction products of beeswax with ethoxylated sorbitol of various ethylene oxide content, forming ether-ester mixtures. 17. Vegetable waxes, including carnauba and candelilla waxes. 18. Phospholipids, such as lecithin and its derivatives. 19. Sterols. Cholesterol and cholesterol fatty acid esters are examples. 20. Amides, for example, fatty acid amides, ethoxylated fatty acid amides, solid fatty acid alkanolamides.

[0053] Vehicles may also include propellants such as propane, isobutane, dimethyl ether, carbon dioxide, and nitrous oxide; and solvents such as ethyl alcohol, isopropanol, acetone, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, or powders such as chalk, talc, fuller's earth, kaolin, starch, gum, colloidal silica, sodium polyacrylate, tetraalkyl and / or trialkylarylammonium smectite, chemically modified aluminum magnesium silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose and / or ethylene glycol monostearate.

[0054] The composition may optionally include sunscreens, such as inorganic and organic sunscreens, that provide protection from the harmful effects of excessive sun exposure during use of the composition of this disclosure.

[0055] The composition may also optionally include, as a sunscreen, titanium dioxide, zinc oxide having an average particle size of 1 to 300 nm, iron oxide having an average particle size of 1 to 300 nm, and silica having an average particle size of 1 to 100 nm, such as fumed silica. When used as a component in the emulsion according to this disclosure, it should be noted that silica may provide protection from infrared radiation.

[0056] In some embodiments, the composition is an emulsion, in which case an oil or oily material (softener) is typically present together with an emulsifier that yields either a water-in-oil emulsion or an oil-in-water emulsion, depending largely on the mean hydrophilic-lipophilic balance (HLB) of the emulsifier used. If a water-in-oil emulsion is required, one or more selected emulsifiers should typically have an mean HLB value of 1 to 6. If an oil-in-water emulsion is required, one or more selected emulsifiers should have an mean HLB value greater than 6.

[0057] Examples of suitable emulsifiers, though not limited to these, include sorbitan trioleate, glycerol monooleate, glycerol monostearate, glycerol monolaurate, sorbitan sesquioleate, sorbitan monooleate, sorbitan monostearate, polyoxyethylene (poloxyethylene) stearyl ether, polyoxyethylene (poloxyethylene) sorbitol, beeswax derivatives, PEG 200 dilaurate, sorbitan monopalmitate, polyoxyethylene (3.5) nonylphenol, PEG 200 monostearate, sorbitan monolaurate, PEG 400 dioleate, polyoxyethylene (5) monostearate, polyoxyethylene (4) sorbitan monostearate, polyoxyethylene (4) lauryl ether, polyoxyethylene (5) sorbitan monooleate, and PEG 300 Monooleate, Polyoxyethylene (20), Sorbitan Tristearate, Polyoxyethylene (20), Sorbitan Trioleate, Polyoxyethylene (8) Monostearate, PEG 400 Monooleate, PEG 400 Monostearate, Polyoxyethylene 10 Monooleate, Polyoxyethylene (10) Stearyl Ether, Polyoxyethylene (10) Cetyl Ether, Polyoxyethylene (9.3) Octylphenol, Polyoxyethylene (4), Sorbitan Monolaurate, PEG 600 Monooleate, PEG 1000 Dilaurate, Polyoxyethylene Sorbitol, Lanolin Derivative, Polyoxyethylene (12) Lauryl Ether, PEG Examples include 1500 dioleate, polyoxyethylene (14) laurate, polyoxyethylene (20) Tween, sorbitan monostearate, polyoxyethylene 20 sorbitan, monooleate, polyoxyethylene (20) stearyl ether, polyoxyethylene (20), sorbitan monopalmitate, polyoxyethylene (20) cetyl ether, polyoxyethylene (25), oxypropylene monostearate, polyoxyethylene (20), sorbitol monolaurate, polyoxyethylene (23) lauryl ether, polyoxyethylene (50), monostearate and / or PEG 4000 monostearate.

[0058] It should be understood that two or more emulsifiers may be used if desired. The amount of emulsifier or mixture thereof that may be optionally incorporated into the composition is 1-50% by weight, 2-20% by weight, or 2-10% by weight of the composition.

[0059] The composition may also typically contain up to 95% by weight, for example, 5-95% by weight of water.

[0060] The composition may also optionally contain, in place of or in addition to, the optional emulsifiers already mentioned, a high molecular weight silicone surfactant that can act as an emulsifier.

[0061] When present in the composition, the amount of silicone surfactant is typically up to 25% by weight of the emulsion, preferably 0.5 to 15% by weight.

[0062] Examples of conventional additives that may be used optionally include preservatives, e.g., para-hydroxybenzoates; antioxidants, e.g., butylhydroxytoluene; humectants, e.g., glycerol, ethoxylated glycerin, e.g., glycereth-26, sorbitol, 2-pyrrolidone-5-carboxylate, dibutylphthalate, gelatin, polyethylene glycol, e.g., PEG 200-600; buffering agents containing bases, e.g., triethanolamine or sodium hydroxide; waxes, e.g., beeswax, ozokerite wax, paraffin wax; plant extracts, e.g., aloe vera, cornflower, witch hazel, elderflower, cucumber; and acerola cherry ferment filtrate; thickeners; activity enhancers; colorants; and fragrances. Cosmetic additives may form the remainder of the composition.

[0063] It may also be desirable to incorporate anti-inflammatory and / or anti-irritant agents. Natural anti-inflammatory and / or anti-irritant agents are preferred. For example, licorice and its extracts, dipotassium glycyrrhizinate, oats and oat extracts, candelilla wax, alfabisabolol, aloe vera, manjista (extracted from plants of the genus Rubia, especially Rubia cordifolial) and guggal (extracted from plants of the genus Commiphora, especially Commiphora mukul).

[0064] Further skin-beneficial agents, such as ceramides, glycoceramides, pseudoceramides, sphingolipids, such as sphingomyelin, cerebrosides, sulfatides and gangliosides, sphingosine, dihydrosphingosine, phytosphingosine, and phospholipids, may also be incorporated separately or in mixtures. Fatty acids may also be combined with these skin-beneficial agents. For example, ceramides and glycoceramides are those described in U.S. Patents No. 5,589,178, No. 5,661,118, and No. 5,688,752, whose relevant parts are incorporated herein by reference. For example, pseudoceramides are those described in U.S. Patents No. 5,198,210, No. 5,206,020, and No. 5,415,855, whose relevant parts are incorporated herein by reference.

[0065] In some embodiments, the pharmaceutical or cosmetic composition contains a) the composition described herein; and b) one or more further agents useful for treating, preventing or reversing skin aging.

[0066] In some embodiments, the composition is administered in a maintenance or ongoing form (e.g., once or more daily, twice or more daily, once or more weekly). In some embodiments, the composition is administered continuously (e.g., via skin patches, bandages, or sustained-release formulations). In some embodiments, the composition is administered once, twice, five times, ten times, or more times. In some embodiments, the composition is administered over a period of several weeks, months, years, or indefinitely.

[0067] The compositions described may be applied at regular or irregular intervals (for example, as needed to reduce or prevent symptoms of a skin condition). In some embodiments, the compositions may be applied at least daily (for example, once, twice, or more times per day). In some embodiments, the compositions may be applied every two days, every three days, weekly, monthly, or at other intervals.

[0068] In some embodiments, the composition is applied for a period of one day to one week or more, or for one year or more, or indefinitely.

[0069] As described herein, the compositions of this disclosure are used to treat, prevent, or delay one or more skin conditions (e.g., those related to aging). This disclosure is not limited to specific skin conditions. Examples include, but are not limited to, acne, AIDS-related Kaposi's sarcoma, eczema, psoriasis, keratinization disorders, skin cancer, warts, cutaneous sarcoidosis, wrinkles, or photoaging of the skin.

[0070] experiment The following embodiments are provided to demonstrate and further illustrate certain embodiments of the present disclosure and should not be construed as limiting the scope of the present disclosure.

[0071] [Example 1] Tolerability studies The tolerance of three doses of retinol was tested over a four-week period. Retinol products were tested in Korean women at concentrations of 0.10% (a currently marketed product with good tolerability and a history of adherence to use), 0.15%, and 0.20% over a four-week period. These Korean women were habitual users of anti-aging facial skincare products, and approximately half reported having sensitive skin. Based on the study results, 0.15% retinol was determined to be within the predicted tolerability range compared to 0.10% retinol and significantly better tolerated than 0.20% retinol. Because the 0.15% formulation demonstrated sufficient efficacy in tolerability studies, including those involving sensitive skin, it was selected as the dose for the purpose of improving efficacy. The results are shown in the table below.

[0072] Table 1 shows a comparison of results for each cell group. Changes from baseline at weeks 1, 2, and 4 were statistically compared for significance (P ≤ 0.05). The p-values ​​are also shown.

[0073] [Table 1]

[0074] Comparisons between treatments based on the mean change from baseline in objective tolerability parameters showed statistically significant differences in erythema for group 1 compared to group 3 at week 2 and for group 2 at week 4. In addition, the comparisons showed statistically significant differences in dryness / desquamation for groups 1 and 2 compared to group 3 at week 2.

[0075] Table 2 shows the results of the subjective stimulus questionnaire analysis for subjects in each group. The mean values ​​for each parameter are listed. The p-values ​​are also shown for weeks 1, 2, and 4.

[0076] [Table 2]

[0077] Table 3 shows the results for each group. Values ​​at week 1, week 2, and week 4 were statistically compared for significance (p ≤ 0.05).

[0078] [Table 3]

[0079] Table 4 shows the aggregated frequency results of the subjective stimulus questionnaire at week 4 for each group of subjects. The number of subjects who selected each response is shown, and the percentage in parentheses represents the corresponding percentage of the subject sample.

[0080] [Table 4] JPEG2026511034000006.jpg115167

[0081] Based on the study results, the subjective sensation response of heat / stinging in the 0.15% retinol group increased during the start of the study but stabilized by week 4 and was comparable to that of the 0.1% retinol group. This result indicates that skin tolerance develops as the product is used over a longer period. The severity of most subjective sensations, including heat, stinging, and itching, experienced by the 0.15% retinol group was mild based on questionnaire responses from the subjects.

[0082] [Example 2] Efficacy research Thirty-two women were treated with a 0.15% retinol preparation on one half of their face and a vehicle control on the other half. The treatment of one half was randomized. Skin wrinkles were assessed at baseline and at weeks 2, 4, 8, and 12 by visual evaluation of crow's feet and 3D image analysis. In addition, self-assessment questionnaires regarding efficacy were completed at weeks 2, 4, 8, and 12, depending on the participant. A self-assessment questionnaire regarding user experience was completed at 12 weeks after treatment.

[0083] The results are shown in Figures 1-6. Throughout the study, there was a significant reduction in wrinkles in the study group at weeks 2, 4, 8, and 12 (Figure 1). Compared to baseline, the Ra, Rq, and Rmax parameters in the study group were significantly reduced at weeks 2, 4, 8, and 12 (p<0.05). The reduction ranged from 7.93% to 15.19%. In the control group, the Ra, Rq, and Rmax parameters were significantly reduced at week 2 (p<0.05). The reduction ranged from 4.70% to 5.19% (Figures 2-4).

[0084] Approximately 50%–72% of subjects in the test group and approximately 53%–66% of subjects in the control group positively reported the presence of "improvement in crow's feet" at 8 and 12 weeks. There were no significant differences between the groups at any time point (Figure 5). Approximately 72%–88% of subjects in the test group and approximately 66%–84% of subjects in the control group reported the presence of "color," "viscosity," "absorption," and "satisfaction." There were no significant differences between the groups for any of these items (Figure 6).

[0085] Of the 32 participants, two experienced adverse skin reactions. One participant observed erythema, dryness, desquamation, and tightness in both the test and control areas at 4 weeks after using the test product. This participant discontinued use after 4 days and then reused the test product. After reuse, the skin reaction disappeared, and this participant continued to participate until the end of the study. The other participant observed erythema, desquamation, dryness, and a burning sensation in the test area at 4 days after using the test product. The skin reaction disappeared within one week after discontinuing the test product. This participant discontinued the study. No adverse skin reactions were observed in any other participants during the study.

[0086] [Example 3] comparative study For comparison, a sister study was conducted in parallel with 0.075% retinol, which is currently recognized as a functional cosmetic level in Korea. Thirty women aged 37-55 years (mean age: 51.53 ± 3.34 years) with mild to moderate wrinkle grades participated. Skin wrinkles were evaluated at baseline and at weeks 2, 4, 8, and 12 by visual assessment of crow's feet and 3D image analysis. In addition, self-assessment questionnaires regarding effectiveness were completed at weeks 2, 4, 8, and 12, depending on the participant. A self-assessment questionnaire regarding user experience was completed at 12 weeks after treatment. All data obtained were statistically analyzed using SPSS® software.

[0087] The results are shown in Figures 7-12. Compared to baseline, the Ra parameter in the test group was significantly reduced at weeks 2, 4, 8, and 12, the Rq parameter in the test group was significantly reduced at weeks 2, 4, 8, and 12, and the Rmax parameter in the test group was significantly reduced at weeks 8 and 12 (p<0.05), with reductions ranging from 5.08% to 7.93% (Figures 7-10).

[0088] Regarding the results of the self-assessment questionnaire on effectiveness, approximately 70% to 77% of participants in both groups responded positively to "improvement of crow's feet" at weeks 8 and 12. There were no significant differences between the groups (Figure 11). Regarding the results of the self-assessment questionnaire on user experience, approximately 50% to 93% of participants in both groups responded positively to all items. There were no significant differences between the groups for any of the items (Figure 12).

[0089] No adverse skin reactions were observed in any of the 30 participants during the study.

[0090] [Example 4] gene expression Sixty human skin samples from 10 subjects were tested with six treatments (A-F), each of which was tested. A was the vehicle control, B-D were 0.1%, 0.2%, and 0.4% retinol treatments, and E-F were inhibitor conjugates including 0.2% and 0.4% retinol plus centipeda versus buttonia in a 2:1 ratio.

[0091] The inhibitor complex was prepared by extracting the root bark of Paeonia suffruticosa Andrews (Paeonia moutan Sims) (Paeoniaceae) with an ethanol solution. The solvent was removed, and the residue was dissolved in 1,3-butylene glycol and water. The final extract contained paeonol in an amount between 0.01 w / w% and 0.14 w / w%.

[0092] PCA plots using all expressed genes and all samples yielded results containing a single outlier. Comparing the PCA plot results to the previous all-heatmap results, we confirmed that the PC_F_S10 sample was abnormal. This sample was excluded in further DEG and pathway analyses. After excluding the outlier, the PCA plots showed that all treatment samples differed from vehicle (A) (Figure 13). Some further differences existed between concentrations (e.g., B vs. C vs. D), but the pattern was not clear due to the relatively large differences among the 10 individuals.

[0093] In the analysis of differentially expressed genes (DEGs), two factors—individual and treatment—we modeled to obtain the most accurate results regarding treatment-induced genetic changes. For upwardly regulated genes, immune response and matrixosome genes were highly enriched. For downwardly regulated genes, skin development and keratinization were enriched.

[0094] Retinol therapy versus vehicle functional enhancement at different concentrations and with or without inhibitor complexes exhibits similar patterns in enrichment pathways. Figure 14 shows a graph illustrating the top 10 pathways from PAGE analysis.

[0095] We analyzed a list of human genes possessing DR2 or DR5 retinoic acid receptor response elements (RAREs). In total, there were 7656 DR2 genes from the DR2 gene list (BMC Genomics.2007;8:23 (ncbi.nlm.nih.gov / pmc / articles / PMC1785376 / ) and 2959 DR5 genes from the DR5 gene list (J Biol Chem, September 23, 2011;286(38) (jbc.org / content / 286 / 38 / 33322.full)). A total of 1291 DEGs exist across all five different treatment-versus-vehicle comparisons: 648 upregulated DEGs and 643 downregulated DEGs. We used hypergeometric distribution to calculate the statistical significance of examining DR5 or DR2 genes in DEGs. Overlap between DEGs and DR5 or DR2 was significant. When DEGs are divided into upregulatory and downregulatory genes, DR5 or DR2 enrichment is primarily driven by upregulatory genes. Therefore, it was concluded that upregulation is strongly driven by direct targeting of the retinoic acid receptor. DEGs lacking the DR5 or DR2 motif may contain other types of RAREs or be indirectly regulated by retinol.

[0096] Heatmaps of all DEGs from treatment vs. vehicle comparisons are shown in Figure 15. The upper panel shows all samples, and the lower panel shows the mean data for each treatment. From B to D, a clear increase in the degree of regulation can be observed in both the upward and downward regulated DEGs. Treatment E appears to be an intermediate stage between C and D, and treatment F showed stronger regulation than treatment D. Further heatmaps are shown in Figures 16 and 17.

[0097] Because the dose effect was very clear, a dose-response model was constructed using treatment samples B, C, and D, and data from E and F were fitted to the model. DEG, which showed a greater than 1.5-fold regulation and had an FDR of less than 0.8, was used as a candidate seed gene from the B vs. A, C vs. A, and D vs. A comparisons. Genes shown in all three comparisons were selected as sheet genes. Figure 18 shows the heatmap generated by the seed gene list. DEG was fitted to the dose-response model using the drm function of the R drc package (Figure 19). When this model was fitted, corresponding retinol doses for treatments E and F were obtained. The predicted dose for treatment E was 0.34, which is between C and D, and closer to D. The predicted dose for treatment F was 0.566, which is higher than D. The results demonstrate the enhancing effect of adding the inhibitor conjugate.

[0098] Using the observational data from A to D and the predicted values ​​from E and F, a dose-response model curve for retinol monotherapy was constructed (Figure 20). Using the observational data from A, E, and F, a dose-response model curve for retinol with an inhibitor complex was constructed. From these two models, it was predicted that 0.15% retinol treatment with an inhibitor complex would be equivalent to 0.25% retinol monotherapy (treatment G).

[0099] Pathway analysis was performed across 41 pathways related to skin function. The heatmap in Figure 21 shows the Z-scores of the PAGE analysis. Positive Z-scores indicate upregulation of the pathway, while negative Z-scores indicate downregulation. The WIKI_KERATINIZATION pathway showed strong regulation and was clearly scaled down to reveal the regulation of other pathways. Several pathways, such as the cell cycle, NF_Kappa_B signaling pathway, and TNG signaling pathway, were increased by retinol treatment. Other pathways, such as collagen biosynthesis, showed decrease. For keratinization, the gene set showed strong downregulation overall with retinol alone, but the effect was lower than that with inhibitor complexes. In fact, E vs. C and F vs. D show strong upregulation of keratinization genes. This indicates that inhibitor complexes have their own effects on keratinization.

[0100] For other pathways, not all genes were regulated in the same direction by retinol treatment. For example, keratinization genes have different subsets that are regulated upward, downward, or unchanged by retinol, and some of these may show different patterns when inhibitors are added. In some pathways, such as keratinization, inhibitor complexes showed the opposite effect to retinol. Since consistent pathway changes were observed in E vs. C and F vs. D, inhibitor vs. retinol comparisons were performed using all samples from these four treatments. Here, keratinization and skin development are strongly upregulated. Some muscle-related functions (myogenesis, myosin filaments, etc.) show downregulation, but the p-values ​​are not significant. Many keratin or keratin-related proteins are upregulated. However, not all of these genes crossed the FDR cutoff. A heatmap using upregulated keratinization genes showed that only some individuals in treatments E or F (retinol with inhibitors) showed upregulation of keratinization genes. This indicates that the upregulation of keratinization observed by the inhibitor complex may occur only in certain individuals and can be highly variable.

[0101] All publications, patents, patent applications, and accession numbers mentioned in the above specification are incorporated herein by reference in their entirety. Although the present invention is described in relation to specific embodiments, it should be understood that the claimed invention should not be unduly limited to such specific embodiments. In fact, various modifications and changes to the compositions and methods described in the present invention will be apparent to those skilled in the art and are intended to fall within the scope of the following claims.

Claims

1. A composition comprising a) 0.1-0.2% (w / w) of a retinoid compound; b) an extract of the root of Paeonia suffructicosa; and c) an extract of Centipeda cunninghammii, which is formulated for topical administration.

2. The composition according to claim 1, comprising 0.15% (w / w) of the retinoid.

3. The composition according to claim 1 or 2, wherein the extract comprises 2 parts Centipeda kunningami to 1 part Peonia safruticosa.

4. The composition according to any one of claims 1 to 3, wherein the extract comprises 0.01 to 4.0% (w / w) of Peonia safruticosa and 0.5 to 4% (w / w) of Centipeda kunningami.

5. The composition according to claim 4, wherein the extract comprises 1.33% Peonia safruticosa and 2.67% Centipeda kunningami.

6. A composition according to any one of claims 1 to 5, comprising 0.01 to 4.0% (w / w) of Peonia safruticosa and 0.5 to 4% (w / w) of Centipeda kunningami.

7. The composition according to claim 6, wherein the extract comprises 1.33% Peonia safruticosa and 2.67% Centipeda kunningami.

8. The composition according to any one of claims 1 to 7, wherein the retinoid is retinol.

9. The composition according to any one of claims 1 to 8, wherein the extract increases the effectiveness of the retinoid and reduces side effects.

10. The composition according to claim 9, wherein the aforementioned side effect includes skin irritation.

11. The composition according to any one of claims 1 to 10, wherein the extract inhibits one or more activities of amphireglin.

12. A composition according to any one of claims 1 to 11, selected from the group consisting of liquids, creams, lotions, gels, ointments, salves, and sprays.

13. A method for treating or preventing a skin condition, A method comprising administering a composition according to any one of claims 1 to 12 to the skin of a subject in a condition, wherein the composition treats or prevents one or more signs or symptoms of the skin condition of the subject.

14. The method according to claim 13, wherein the skin condition is selected from the group consisting of acne, AIDS-associated Kaposi's sarcoma, eczema, psoriasis, keratinization disorder, skin cancer, warts, cutaneous sarcoidosis, and photoaged skin.

15. The method according to claim 14, wherein the photoaged skin includes wrinkles and / or sagging.

16. The method according to any one of claims 13 to 15, wherein the composition is applied at least daily.

17. Use of the composition according to any one of claims 1 to 12 for treating or preventing a skin condition in a subject.

18. A composition according to any one of claims 1 to 12 for use in the treatment or prevention of a skin condition in a subject.

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