WO2015179570A1 - Compositions topiques aqueuses pour l'administration d'acide azélaïque pour le traitement d'affections cutanées telles que l'acné vulgaire, l'acné rosacée, et la parakératose séborrhéique - Google Patents

Compositions topiques aqueuses pour l'administration d'acide azélaïque pour le traitement d'affections cutanées telles que l'acné vulgaire, l'acné rosacée, et la parakératose séborrhéique Download PDF

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Publication number
WO2015179570A1
WO2015179570A1 PCT/US2015/031846 US2015031846W WO2015179570A1 WO 2015179570 A1 WO2015179570 A1 WO 2015179570A1 US 2015031846 W US2015031846 W US 2015031846W WO 2015179570 A1 WO2015179570 A1 WO 2015179570A1
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Prior art keywords
waterborne
azelaic acid
composition
percent
topical composition
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English (en)
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Christopher J. DANNAKER
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Epikinetics Pharma LLC
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Epikinetics Pharma LLC
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Priority claimed from US14/283,073 external-priority patent/US20150119427A1/en
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Publication of WO2015179570A1 publication Critical patent/WO2015179570A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents

Definitions

  • the present invention relates to waterborne topical compositions for humans, and more particularly to waterborne topical compositions delivering azelaic acid to the human skin.
  • These formulations are suited for treatment of acne vulgaris, rosacea, seborrheic dermatitis, or other skin conditions.
  • the formulations of the present invention result in enhanced and rapid penetration of azelaic acid into human skin and substantiated reduced potential for irritant dermatitis. The reduction in irritant dermatitis potential also promotes patient compliance
  • acne comes from a corruption of the Greek ⁇ (acme in the sense of a skin eruption).
  • the most common form of acne is known as "acne vulgaris", meaning “common acne”.
  • Acne vulgaris is a skin disease; caused by changes in the pilosebaceous units, namely skin structures consisting of a hair follicle and its associated sebaceous gland.
  • Severe acne is inflammatory, but acne can also manifest in non-inflammatory forms. Acne lesions are commonly referred to as pimples, spots, or zits.
  • Acne is most common during adolescence, affecting more than 85% of teenagers, and frequently continues into adulthood. For most people, acne diminishes over time and tends to disappear, or at least decrease, after one reaches their early twenties. There is, however, no way to predict how long it will take for it to disappear entirely, and some individuals will continue to suffer from acne decades later, into their thirties and forties and even beyond.
  • Acne develops as a result of blockages in follicles. Formation of a plug of keratin and sebum, a microcomedo, is the earliest change.
  • the microcomedo may enlarge to form an open comedo, also commonly called a blackhead, or closed comedo, also commonly called a whitehead.
  • open comedo also commonly called a blackhead
  • closed comedo also commonly called a whitehead.
  • Propionibacterium acnes can cause inflammation, leading to inflammatory lesions, such as papules, infected pustules, or nodules, in the dermis around the microcomedo or comedo, which results in redness and may result in scarring and/or hyper-pigmentation.
  • Rosacea is a common, but often misunderstood, condition that is estimated to affect over 45 million people worldwide. It typically affects white-skinned people of mostly north-western European descent, and has been nicknamed the "curse of the Celts" by some in the British Isles. It begins as erythema, flushing and redness, on the central face and across the cheeks, nose, or forehead but can also less commonly affect the neck and chest.
  • telangiectasia which is a dilation of superficial blood vessels on the face
  • red domed papules (small bumps) and pustules red gritty eyes
  • burning and stinging sensations and in some advanced cases, a red lobulated nose, known as rhinophyma.
  • the disorder can be confused with and can co-exist with acne vulgaris.
  • compositions available for treating inflammatory acne vulgaris and rosacea including topical and systemic antibiotics and retinoids.
  • Metronidazole l-(2-hydroxyethyl)-2-methyl-5-nitroimidazole
  • metronidazole has also been shown to be useful in treating various skin disorders, including acne rosacea, bacterial ulcers, and perioral dermatitis. See, U.S. Pat. No. 4,837,378 which is incorporated herein by reference.
  • Metronidazole has been found to have an anti- inflammatory activity when used topically to treat dermatologic disorders. See U.S. Pat. No. 5,849,776 which is incorporated herein by reference.
  • compositions containing metronidazole for treatment of dermatologic disorders are available in cream, lotion and gel forms.
  • One commercially available metronidazole cream product, sold under the NORITATETM brand from Dermik Laboratories, Inc., Collegeville, Pa. 19426 USA contains 1 % metronidazole in which the insoluble drug is suspended in the opaque cream.
  • Patents 7,348,3217 and 6,881,726 which patents are incorporated herein by reference, disclose a method for making an aqueous composition containing a dissolved concentration of metronidazole greater than 0.75% w/w comprising combining metronidazole, beta- cyclodextrin (BCD), and niacin or niacinamide in an aqueous fluid, wherein the BCD and the niacin or niacinamide are combined in the aqueous fluid in amounts that provide a synergistic effect on the solubility of metronidazole.
  • BCD beta- cyclodextrin
  • Patent 7,981,916 which patent is incorporated herein by reference, discloses a method in which metronidazole is solubilized in an aqueous phase, by mixing same with niacinamide and at least two glycolic cosolvents; the resulting solutions and pharmaceutical compositions comprised thereof are described as useful for the treatment of dermatological conditions/afflictions, notably rosacea.
  • Azelaic acid or nonanedioic acid
  • azelaic acid has been found to be irritating to skin.
  • Carriers such as alcohols, added to enhance absorption of the azelaic acid at lower concentrations, have been found to cause drying of the skin and hence additional irritation. It would be desirable to provide an effective treatment composition for acne vulgaris and rosacea that is non- irritating and non-drying yet allow for effective release of azelaic acid from the vehicle and subsequent rapid penetration into the skin.
  • Ideal topical drugs for rosacea should not damage the skin barrier function and enhance hydration while allowing such difficult-tO-dlSSOlve drugs as azelaic acid to be solubilized and bioavailable.
  • formulations containing hydrogels consisting of triglyceride, propylene glycol, at least one polysorbate, polyacrylic acid and soy lecithin have been devised. These vehicles deliver more azelaic acid into the skin than the earlier formulation.
  • formulations with 15% azelaic acid, such as sold under the brand name FINACEA® utilizing this delivery vehicle have been found to be significantly more irritating when compared to other rosacea topical treatments, such as metronidazole 0.75%.
  • U.S. Patent 6,534,070 is representative of the prior art and is incorporated herein by reference.
  • U.S. Patent 6,534,070 teaches a pharmaceutical composition having the following constituents: azelaic acid, polyacrylic acid, triacylglyceride, propylene glycol, polysorbate, soya lecithin, water and salts.
  • the composition is a hydrogel which is suited for the treatment of rosacea, presbyderma, melasma or skin irritations.
  • This composition is essentially a description of the commercially available FINACEA® product. The composition appears to suggest the polyacrylic base enhances the relevant acid penetration.
  • U.S. Published Patent Application 2009-0182054 which is incorporated herein by reference teaches a topical composition containing solubilized azelaic acid formulated in an aqueous carrier.
  • the publication asserts that in-vitro skin penetration and bioavailability study demonstrates higher bioavailability of the solubilized azelaic acid in the cutaneous organs.
  • the topical composition is designated for the treatment of skin disorders associated with skin inflammation such as rosacea, seborrheic dermatitis, perioral dermatitis, and facial dermatitis.
  • U.S. Published Patent Application 2005-0169948, which is incorporated herein by reference, discloses topical composition for the treatment of acne vulgaris or acne rosacea comprises 1-12% nicotinamide by weight and less than 1% by weight of nicotinic acid.
  • the composition was described to be more effective in the treatment of acne than the same composition would be without the nicotinic acid.
  • U.S. 6,734,210 which is incorporated herein by reference discloses a composition useful for the treatment of acne and rosacea comprising an effective amount of a mixture of azelaic acid and chitosan whereby the mixture is prepared by mixing azelaic acid and chitosan in water to form a solution and drying the solution.
  • U.S. Patent Publication 2010-0004338 which is incorporated herein by reference discloses a gel composition comprising of about 15 wt % azelaic acid; about 0.1 wt % benzoic acid; about 0.1 wt % disodium ethylenediaminetetraacetic acid; about 0.85 wt % CARBOMER® 940 (or CARBOPOL® 980); about 1.5 wt % POLYSORBATE®. 80; about 12 wt % propylene glycol; about 2.0 wt % isopropyl myristate; about 0.2 wt % sodium hydroxide and purified water.
  • the composition is taught to be administered for the treatment of rosacea, presbyderma, melasma, acne and/or skin irritations.
  • U.S. Patent 8,729,108 which is incorporated herein by reference addresses many of the deficiencies of the prior art and is directed to waterborne topical compositions for humans, and more particularly to waterborne topical compositions delivering azelaic acid to the human skin.
  • the formulations of the '108 patent are suited for treatment of acne vulgaris, rosacea, seborrheic dermatitis, or other skin conditions.
  • the formulations of the '108 patent application result in enhanced and rapid penetration of azelaic acid into human skin and substantiated reduced potential for irritant dermatitis relative to prior formulations.
  • the reduction in irritant dermatitis in the formulations of the '108 patent also promotes patient compliance.
  • One embodiment of the present invention provides a waterborne topical composition for the enhanced penetration of azelaic acid into human skin in the treatment of acne vulgaris, rosacea and other skin conditions.
  • the composition according to one embodiment comprises effective amounts of azelaic acid, niacinamide, and hydroxypropyl beta and wherein the composition demonstrates a penetration rate of at least 5% active ingredient/hr, within 2.5 hours of application to human skin.
  • One embodiment of the invention provides a waterborne topical composition comprising: effective amounts of azelaic acid, wherein the azelaic acid is present in an amount of 4 percent to 20 percent by weight; effective amounts of niacinamide, wherein the niacinamide is present in an amount of 4 to 10 percent by weight; and effective amounts of cyclodextran, wherein the cyclodextran is present in an amount of 0.1 to 6 percent by weight.
  • One embodiment of the invention provides a waterborne topical composition for topical application of at least one active ingredient comprising effective amounts of azelaic acid, niacinamide, and hydroxypropyl beta.
  • any numerical range recited herein is intended to include all sub-ranges subsumed therein.
  • a range of "1 to 10" is intended to include all sub-ranges between (and including) the recited minimum value of 1 and the recited maximum value of 10, that is, having a minimum value equal to or greater than 1 and a maximum value of equal to or less than 10.
  • compositions of the present invention are waterborne. They may be prepared in the form of a liquid, cream, gel, fluid, lotion, emulsion or microemulsion as desired. Viscosity of the composition may be altered using any of various formulating methods, such as by changing the amount of carrier medium.
  • U.S. Patent 8,729,108 which is incorporated herein by reference addresses many of the deficiencies of the prior art and is directed to waterborne topical compositions for humans, and more particularly to waterborne topical compositions delivering azelaic acid to the human skin.
  • the formulations of the '108 patent are suited for treatment of acne vulgaris, rosacea, seborrheic dermatitis, or other skin conditions.
  • the formulations of the '108 patent application result in enhanced and rapid penetration of azelaic acid into human skin and substantiated reduced potential for irritant dermatitis relative to prior formulations.
  • the reduction in irritant dermatitis in the formulations of the '108 patent also promotes patient compliance.
  • the present invention builds upon the teachings of the '108 patent and improves the effective amounts, the stability of the composition and the irritation caused by the compositions.
  • composition of one embodiment of the present invention contains effective amounts of components azelaic acid, niacinamide, and cyclodextran.
  • Azelaic acid is a saturated dicarboxylic acid found naturally in wheat, rye, and barley. It is a natural substance that is produced by Malassezia furfur (also known as Pityrosporum ovale), a yeast that lives on healthy skin.
  • Azelaic acid is typically present in the composition of the present invention in amounts of about 3 to 30 percent by weight, preferably 4 to 20 percent by weight, with 5 to 20 percent by weight being most common, although 10 to 20 percent by weight and 15 to 20 percent by weight have proven to yield effective formulations.
  • azelaic acid is present in an amount typically of at least 4 percent by weight. In countries other than the United States, azelaic acid may be allowed in over the counter (OTC) formulations and typically contain azelaic acid at less than 4 percent by weight.
  • Azelaic acid is only slightly soluble in water, cosmetic oils and alcohols; thus each of these solvents has conventionally had limitations as a carrier for topical formulations containing azelaic acid.
  • an aqueous solution of azelaic acid would contain a maximum of about 0.24% by weight (w/w) azelaic acid, which is not enough to be effective.
  • Azelaic acid has little or no solubility in cosmetic oils. Alcohols are unsatisfactory in high concentrations as they have the undesirable side effect of drying and irritating the skin.
  • Niacinamide also known as nicotinamide and nicotinic acid amide, is the amide of nicotinic acid (vitamin B3). Nicotinamide is a water-soluble vitamin and is part of the vitamin B group. Typically the niacinamide is present in an amount of up to 10 percent by weight in the composition, typically 1 to 10 percent by weight in the composite on, and commonly 4 to 10 percent by weight in the composition of the present invention. Though not intending to be bound by theory, it is believed that the combination of azelaic acid and niacinamide in the composition of the present invention surprisingly offers greater therapeutic benefits than either component used alone. Azelaic acid is believed to enhance the penetration and effect of niacinamide.
  • azelaic acid on follicular inflammatory conditions such as acne rosacea is enhanced by the niacinamide. It is believed that this effect is due in part to increased aqueous solubility of dicarboxylic acids such as azelaic acid in the presence of niacinamide.
  • One embodiment of the present invention uses discussed further below effective amounts of a cyclodextran, niacinamide and azelaic acid.
  • the Niacinamide in combination with cyclodextrin is believed to act as a solubility enhancer of azelaic acid.
  • the niacinamide is present in an amount at least sufficient to enhance penetration of the azelaic acid into skin.
  • Niacinamide may be used in combination with nicotinic acid in the composition of the present invention; usually, however, the composition is essentially free of nicotinic acid.
  • essentially free is meant that if the material is present in the composition, it is present incidentally in an amount less than 0.1 percent by weight, preferably less than trace amounts.
  • Glycerin is a chemical compound also commonly called glycerol or glycerine. It is a colorless, odorless, viscous liquid.
  • Glycerin is a sugar alcohol, and has three hydrophilic alcoholic hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature.
  • the glycerin is present in the composition of the present invention in an amount of up to 10 percent by weight, generally 1 to 10 percent by weight, typically 5 to 10 percent by weight.
  • Glycerol has been found to enhance penetration of monoazelate esters into the skin. It is proposed in U.S. Pat. No. 7,300,957, incorporated herein by reference, that glycerin esterified with azelaic acid enhances the percutaneous penetration of azelaic acid into the skin, after which the glycerin disassociates. Unexpectedly, it has been found that this process does not necessarily require the prior esterification of azelaic acid with glycerol to form glycerol monoazelate. Compositions of the present invention are essentially free of azelaic acid esters, including reaction products of azelaic acid and glycerin.
  • Aquaporins are fairly newly-discovered "channels" in biological tissues such as skin that allow for the passage of certain molecules into cells to enhance cellular hydration.
  • Aquaporins are integral membrane proteins from a larger family of major intrinsic proteins (MIP) that form pores in the membranes of biological cells. They compose six trans-membrane alpha helical structures arranged in a right-handed bundle and form tetramers in the cell membrane.
  • MIP major intrinsic proteins
  • the main aquaporin in the epidermis is-known as aquaporin-3 also known as aquaglyceroporin. Aquaporin-3 controls water transport in addition to movement of glycerol, C0 2 , ammonia and urea.
  • Aquaporin-3 expression is increased in human skin diseases with elevated transepidermal water loss such as rosacea. Not intending to be bound by theory, it is believed that glycerin in the composition of the present invention allows for enhanced absorption of the active ingredients into the skin through aquaporins as well as function as hydrators of the skin to minimize the potential for skin irritation from azelaic acid.
  • the topical composition of the present invention may optionally contain additional components as active ingredients or as inert additives.
  • the composition of the present invention may further comprise hyaluronic acid and/or a derivative thereof.
  • suitable components include alcohols such as cetyl alcohol, stearyl alcohol, and benzyl alcohol, surfactants such as sodium lauryl sulfate, isopropyl palmitate, sorbitol, and lactic acid. Mixtures of these components are often used.
  • Sunscreens may be used in combination with other ingredients in the composition of the present invention; usually, however, the composition is essentially free of sunscreens.
  • compositions of the present invention are also non-irritating and as such promote patient compliance.
  • the present formulations are the continuation of result of years of dermatologic research spelled out in the '108 patent to improve the effects of both azelaic acid and niacinamide while creating a product that was hydrating.
  • the formulations of the present invention not only supports the skin's hydration and barrier function, it remains non- comedogenic.
  • Previous prior art formulations containing azelaic acid have typically used either sd alcohol or propylene glycol to solubilize and dissolve azelaic acid into a cream or gel base, thus increasing the potential for skin irritation.
  • the present formulations effectively shrink the size of azelaic acid and niacinamide particles into micron sized droplets and then envelop these micronized particles with the hydrating effects of non- animal derived glycerin which improves and creates synergy between the well documented and favorable skin effects of both azelaic acid and niacinamide while preserving the skin's epidermal barrier function.
  • a further embodiment of the present invention provides that by combining azelaic acid, niacinamide/niacin and a cyclodextrin, then greater than 10%, even 15%, azelaic acid can be easily stabilized without the use of previously necessary and irritating glycols such as propylene glycol.
  • azelaic acid can be easily stabilized without the use of previously necessary and irritating glycols such as propylene glycol.
  • cyclodextrins (sometimes called cycloamyloses) are a family of compounds made up of sugar molecules bound together in a ring (cyclic oligosaccharides). Cyclodextrins are produced from starch by means of enzymatic conversion.
  • Cyclodextrins are composed of 5 or more a-D-glucopyranoside units linked 1-4, as in amylase (a fragment of starch).
  • Typical cyclodextrins contain a number of glucose monomers ranging from six to eight units in a ring, creating a cone shape: a (alpha)-cyclodextrin: 6-membered sugar ring molecule; ⁇ (beta)-cyclodextrin: 7-membered sugar ring molecule; ⁇ (gamma)-cyclodextrin: 8- membered sugar ring molecule
  • the formulation uses the niacinamide as a penetration and solubilization enhancer thus the relative concentration of cyclodextrin may be low.
  • this embodiment of the present invention is increasing the solubility of azelaic acid in an aqueous vehicle by combination with a cyclodextrin, prefereably betacyclodextrin, and niacinamide.
  • This embodiment of the present invention may be a water based gel solubilizing azelaic acid with niacinamide and betacyclodextrin.
  • betacyclodextrin and niacinamide are both utilized in the solution, the two compounds act synergistically to increase the solubility of azelaic acid in an aqueous vehicle.
  • the betacyclodextrin may be added in amounts of 0.1 to 6 percent by weight, generally 1 to less than 5% by weight and 2-3% by weight cyclodextrin are contemplated.
  • Preliminary formulations suggest that maximum solubility of azelaic acid in a formulation can be increased with either niacinamide, or betacyclodextran but with both the results exhibit a synergistic effect with regard to the solubility of azelaic acid in an aqueous vehicle.
  • the presents invention use hydroypropyl beta cyclodextran as the preferred cyclodextran agent and the formulation preferably utilizes less than 5%, generally 2-3% by weight, of this relatively expensive agent.
  • the present invention provides effective formulations of azelaic acid and other agents that are water-based in order to minimize irritation and drying to the skin.
  • An advantage of the formulations is they avoid harsh surfactants and organic solvents and contains only incidental concentrations of non-polar alcohols. Further they provide a vehicle that contains humectants that allow for moisturization of the skin and avoid the side effects of irritating substances such as azelaic acid.
  • the formulations allow for rapid penetration to the applied skin.
  • the formulations avoid fat and oil content so as to minimize comedogenicity to the skin.
  • the formulation demonstrates good physical and chemical stability over time. Additionally the formulations disclosed are designed as a green cosmeceutical products, as azelaic acid is derived from whole grain, and niacinamide is a form of naturally occurring B vitamin.
  • OLAY TOTAL EFFECTS® Daily Moisturizer ingredients are: water, glycerin, niacinamide, isohexadecane, dimethicone, isopropyl isostearate, polyacrylamide, sodium ascorbyl phosphate, panthenol, tocopherol acetate, camellia senensis leaf extract, zinc oxide, titanium dioxide, sucrose polycottonseedate, sorbitan stearate, cetyl alcohol, cl3-14 isoparraffin, stearyl alcohol, dimethiconol, laureth-7, peg- 100 stearate, stearic acid, citric acid, propylparaben, disodium edta, , methylparaben, bht, benzyl alcohol, ethyl paraben, ammonium polyacrylate, triethoxycaprylylsilane, fragrance, yellow 5, red 40, vitamin b3, vitamin C,
  • the dermal percentage of azelaic acid was 4.3%, compared to the Olay/Finacea combination of 2.8%, a 71% increase.
  • Flow through the skin into the receptor fluid was 3.9% for the proposed formulation vs 9.5% for the Finacea® Olay Total Effects® combination.
  • Epidermal percentages were 18% for the proposed formulation, vs 38% for the Finacea ® Olay Total Effects® combination.
  • the optimized formula gave the lowest penetration into receptor fluid (which is desirable because the site of action is the skin) and the highest penetration into the dermis (which is good because that is where the hair follicles and sebaceous glands are located - e.g. site of action).
  • the FINACEA® plus OLAY TOTAL EFFECTS® combination significantly increased the amount of azelaic acid left in the epidermis 38% vs 18% for the proposed formulation.
  • the past experience is that most of what is in the epidermis is in the upper layers of the stratum corneum, so this does not get to the desired, dermal site of action.
  • the optimized formulation with excellent dermal penetration and concentration cannot be reproduced by simply adding a niacinamide and glycerin containing product such as OLAY TOTAL EFFECTS® to an optimized aqueous azelaic acid formulation such as FINACEA®.

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Abstract

La présente invention concerne une composition topique aqueuse qui est conçue spécifiquement pour résoudre le traitement de l'acné vulgaire, de l'acné rosacée, de la parakératose séborrhéique et d'autres affections cutanées. Une composition contient des quantités efficaces de composants essentiels acide azélaïque, niacinamide et glycérine pour créer un composé non irritant à pénétration rapide. Une composition contient des quantités efficaces de composants essentiels acide azélaïque, niacinamide et cyclodextrane pour créer un composé non irritant à pénétration rapide.
PCT/US2015/031846 2014-05-20 2015-05-20 Compositions topiques aqueuses pour l'administration d'acide azélaïque pour le traitement d'affections cutanées telles que l'acné vulgaire, l'acné rosacée, et la parakératose séborrhéique Ceased WO2015179570A1 (fr)

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US14/283,073 2014-05-20
US14/283,073 US20150119427A1 (en) 2008-06-17 2014-05-20 Waterborne topical compositions for the delivery of azelaic acid for treatment of skin conditions such as acne vulgaris, rosacea, seborrheic dermatitis

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3758727A1 (fr) * 2018-02-28 2021-01-06 Symrise AG Produit dermatologique
CN116211724A (zh) * 2023-03-14 2023-06-06 山西振东制药股份有限公司 壬二酸微乳及其制备方法和应用
CN117530874A (zh) * 2023-11-15 2024-02-09 无锡知妍生物科技有限公司 一种水溶性壬二酸体系及其制备方法
CN117547472A (zh) * 2023-11-27 2024-02-13 无锡知妍生物科技有限公司 具有协同美白增效的壬二酸液态des体系及其制备方法

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US20100004296A1 (en) * 2008-06-17 2010-01-07 Dannaker Christopher J Waterborne topical compositions for the delivery of azelaic acid
WO2012171106A1 (fr) * 2011-06-13 2012-12-20 Levy Phillip Compositions cosmétiques pour la peau comprenant un extrait de malus domestica et un extrait de bourgeon d'argania spinosa pour améliorer l'apparence de la peau

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