WO1997020812A1 - ESTERS DE RETINYLE D'α-HYDROXY ACIDES DESTINES A L'AMELIORATION TOPIQUE DES FONCTIONS ET DE L'ASPECT DE LA PEAU - Google Patents

ESTERS DE RETINYLE D'α-HYDROXY ACIDES DESTINES A L'AMELIORATION TOPIQUE DES FONCTIONS ET DE L'ASPECT DE LA PEAU Download PDF

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Publication number
WO1997020812A1
WO1997020812A1 PCT/US1996/019580 US9619580W WO9720812A1 WO 1997020812 A1 WO1997020812 A1 WO 1997020812A1 US 9619580 W US9619580 W US 9619580W WO 9720812 A1 WO9720812 A1 WO 9720812A1
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WO
WIPO (PCT)
Prior art keywords
group
hydroxy
member selected
alkanoyl
acid
Prior art date
Application number
PCT/US1996/019580
Other languages
English (en)
Inventor
Thomas J. Bigger
Sergio Nacht
Steve Ng
Original Assignee
Advanced Polymer Systems, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Advanced Polymer Systems, Inc. filed Critical Advanced Polymer Systems, Inc.
Priority to AU12848/97A priority Critical patent/AU1284897A/en
Publication of WO1997020812A1 publication Critical patent/WO1997020812A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
    • C07C403/12—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by esterified hydroxy groups
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins
    • A61K8/671—Vitamin A; Derivatives thereof, e.g. ester of vitamin A acid, ester of retinol, retinol, retinal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • Retinol or vitamin A alcohol
  • Retinol is known to have attributes that are useful in the treatment of the human epidermis, particularly in accelerating skin renewal and skin proliferation.
  • Retinol itself is irritating to the skin, however, and its conjugated double bonds are susceptible to oxidation, both of which detract considerably from its usefulness as a skin conditioner.
  • These problems have been reduced by esterification of the retinol to form retinyl palmitate and acetate, for example, but these esters have shown reduced biological activity relative to the nonesterified form.
  • ⁇ -hydroxy acids such as glycolic acid, lactic acid, ⁇ -butyric acid, and longer chain species. These acids are known to improve skin function and appearance by accelerating desquamation and promoting stratum corneum renewal. Unfortunately, these acids as well are irritating to the skin, particularly at concentrations of 5% or higher and for individuals with sensitive skin.
  • ⁇ -hydroxy acid esters of retinol offer both a stabilized and nonirritating treatment agent, providing therapeutic and beneficial effects exceeding those of either the retinol or the ⁇ -hydroxy acids alone.
  • these esters are useful in free form, without the need to be protected by encapsulation or by liposomes.
  • the compounds can be incorporated into the types of formulations commonly used for topical administration to the skin, or they can diffuse into such formulations from the open pores of microscopic porous particles suspended in the formulations.
  • ⁇ -hydroxy acids are naturally occurring and extractable from their sources.
  • ⁇ -hydroxy acids can be synthesized by the hydrolysis of an ⁇ -halo acid or by the acid hydrolysis of the cyanohydrins of an aldehyde or ketone.
  • Aliphatic ⁇ -hydroxy acids that do not have side chains can be prepared in good yield by the hydrolysis of ⁇ -nitrato acids with aqueous sulfite solutions, the ⁇ -nitrato acids themselves being obtainable by reacting olefins and N 2 O 4 in the presence of oxygen.
  • the esters of this invention are readily prepared under esterification conditions well known to those of skill in the art, using a form of the ⁇ -hydroxy acid in which the ⁇ -hydroxy group is protected. Protection can be achieved by use of a cyclized diester dimer of the ⁇ -hydroxy acid, such as lactide for lactic acid. Protection can also be achieved by the use of protecting groups known to those skilled in the art of esterification.
  • the protecting groups include those that convert the hydroxy to an ether, an ester, a carbonate, or other forms which are cleavable after the esterification reaction to return the hydroxy group to the ⁇ -position. Some of the most common examples of protecting groups are alkyl groups, benzyl groups, and silyl groups.
  • the esters of this invention include monoesters, but also diesters and other oligoesters. Monoesters are preferred.
  • esters can vary widely in structure and molecular size.
  • Preferred esters are those made from acids having the formula
  • R 1 is either H, C,-C 12 hydrocarbyl, or C,-C 12 hydrocarbyl substituted with one or more carboxy groups, one or more hydroxy groups, or a combination
  • R 2 is either H or carboxy
  • R 3 is either H, C 2 -C 12 alkanoyl, or alpha-hydroxy C 2 -C 12 alkanoyl.
  • hydrocarbyl is used herein to denote any monovalent radical consisting solely of carbon and hydrogen atoms, including saturated and unsaturated groups, straight-chain and branched-chain groups. Saturated groups are preferred, and straight- chain groups are preferred. Unsaturated groups include double bonds as well as triple bonds.
  • alkanoyl is used herein to denote the anion R — COO of an ionized carboxylic acid
  • R denotes a hydrocarbyl group, preferably an alkyl (saturated hydrocarbyl) group, and most preferably a straight-chain alkyl group.
  • carboxy denotes the monovalent radical — COOH.
  • R 1 a preferred subclass is the group H, C r C g alkyl, and C,-C 8 alkyl substituted with one or more carboxy groups.
  • R 3 a preferred subclass is the group H, C 2 -C 8 alkanoyl, and alpha-hydroxy C 2 -C 8 alkanoyl.
  • Specific examples of ⁇ -hydroxy acids are glycolic ⁇ i.e. , hydroxyacetic) acid, glyceric (i.e. , 2,3-dihydroxypropanoic) acid, lactic (i.e.
  • esters of this invention can be applied to skin as part of a solution or an emulsion, or any other fluid form which facilitates spreading over the skin surface.
  • Creams and lotions with well-known formulations will be useful. These formulations typically include such ingredients as vehicles or vehicle combinations to achieve a desired viscosity or spreadability, penetration enhancers to increase absorption into the skin, emollients, antioxidants, and preservatives.
  • preferred concentrations of the esters of this invention are from about 0.3% to about 3.0% by weight of the emulsions.
  • the esters may be retained in the pores of biologically inert microscopic porous particles which can in turn be suspended in creams or lotions, or if desired, applied as a powder or incorporated into make-up and other useful products.
  • the particles may be rigid or resiliently compressible, but in either case contain a network of interconnected pores open to the particle surface, providing substantially full communication between the internal pore space and the particle exterior.
  • Particles of this type are disclosed by Won, in U.S. Patent No. 4,690,825; Won, U.S. Patent No. 5,145,675; Katz et al , U.S. Patent No. 5,073,365; Katz et ai , 5,135,740; and Jankower et al , U.S. Patent No. 4,873,091. The disclosures of these patents are incorporated herein by reference.
  • the particles are frequently spherical in shape, most often ranging from about one to about 100 microns in diameter, particularly from about 10 to about 40 microns.
  • the pore dimensions within the particles may also vary, with optimum dimensions depending on the chemical characteristics of the polymers used to form the particles as well as the diffusive characteristics of the retinol ester retained inside. In general, best results are obtained with total pore volumes ranging from about 0.01 to about 4.0 cc/g, preferably from about 0.1 to about 2.0; surface areas ranging from about 0.1 to about 500 m 2 /g, preferably from about 1 to about 400; and average pore diameters ranging from about 0.001 to about 1.0 micron, preferably from about 0.003 to about 0.3 micron.
  • the particles are generally organic polymers, formed by suspension polymerization, as described in the patents referenced above.
  • Monoethylenically unsaturated monomers suitable for preparing the particles include ethylene, propylene, isobutylene, diisobutylene, styrene, ethylvinylbenzene, vinyltoluene and dicyclopentadiene; esters of acrylic and methacrylic acid, including the methyl, ethyl, propyl, isopropyl, butyl, sec-bx ⁇ y ⁇ , tert-butyl, amyl, hexyl, octyl, ethylhexyl, decyl, dodecyl, cyclohexyl, isobornyl, phenyl, benzyl, methylphenyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl,
  • Polyethylenically unsaturated crosslinking monomers suitable for use in the particles include diallyl phthalate, ethylene glycol diacrylate, ethylene glycol dimethacrylate, trimethylolpropanetrimethacrylate and divinylsulfone; polyvinyl and poly allyl ethers of ethylene glycol, of pentaerythritol, of diethyleneglycol and of resorcinol, divinylketone, divinylsulfide, allyl acrylate, diallyl maleate, diallyl fumarate, diallyl succinate, diallyl adipate, diallyl sebacate, divinyl sebacate, diallyl tartrate, and diallyl silicate.
  • Particularly preferred particles for use in the present invention are those formed by the copolymerization of styrene and divinylbenzene, vinyl stearate and divinylbenzene, or methylmethacrylate and ethylene glycol dimethacrylate.
  • the monoethylenically unsaturated monomer will be present at from about 20% to about 80% of the monomer mixture, with the polyethylenically unsaturated monomer forming the remainder of the mixture.
  • Resilient and compressible, as opposed to rigid, particles can be made by the use of curable elastomers.
  • elastomers are isoprene rubbers, butadiene rubbers, chloroprene rubbers, isobutylene-isoprene rubbers, nitrile-butadiene rubbers, styrene-butadiene rubbers, and ethylene-propylene-diene terpolymers.
  • concentration of the esters of this invention relative to the entire formulation is preferably from about 0.3% to about 10.0% by weight, and most preferably from about 2% to about 5%.
  • Retinol (1.42 g, 5 mmol) and L-(-)-lactide (0.72 g, 5 mmol) were weighted into a screw cap tube. The tube was tightly capped, then heated in an oil bath at 120°C for one hour. Column chromatography of the crude product using silica gel and methylene chloride yielded a soft solid weighing 0.6 g. Analysis by nuclear magnetic resonance (NMR) gave a spectrum that was consistent with the retinyl ester of O-(2-hydroxy- propanoyl)lactic acid according to structure shown above.
  • Part I Cetyl alcohol 5.0% by weight
  • Part III is heated to about 60 °C and mixed until uniform. Part I is heated separately to the same temperamre, then mixed until uniform and held at that temperamre. Part III is allowed to cool to about 40°C, and Part II is added with gentle agitation. The resulting mixmre is mixed until thoroughly dispersed. Part I is then added with stirring to form the emulsion. The mixmre is allowed to cool to about 40°C. Fragrance and/or color are added as desired.
  • Part III is heated to about 60°C and mixed until uniform. Part I is heated separately to the same temperamre, then mixed until uniform and held at that temperamre. Part III is allowed to cool to about 40 °C, and Part II is added with gentle agitation. The resulting mixmre is mixed until thoroughly dispersed. Part I is then added with stirring. The mixmre is allowed to cool to about 40 °C. Fragrance and/or color are added as desired.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Birds (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Dermatology (AREA)
  • Emergency Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Cosmetics (AREA)

Abstract

Cette invention concerne des esters de rétinol et d'α-hydroxy acides qui se révèlent, de façon inattendue, efficaces en tant qu'agents dermatologiques revitalisants et sont associés à une réduction significative des problèmes d'irritation caractéristiques du rétinol et des α-hydroxy acides sous forme non estérifiée.
PCT/US1996/019580 1995-12-04 1996-12-02 ESTERS DE RETINYLE D'α-HYDROXY ACIDES DESTINES A L'AMELIORATION TOPIQUE DES FONCTIONS ET DE L'ASPECT DE LA PEAU WO1997020812A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU12848/97A AU1284897A (en) 1995-12-04 1996-12-02 Retinyl esters of alpha-hydroxy acids for topical improvement of skin function and appearance

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US56687895A 1995-12-04 1995-12-04
US08/566,878 1995-12-04

Publications (1)

Publication Number Publication Date
WO1997020812A1 true WO1997020812A1 (fr) 1997-06-12

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Application Number Title Priority Date Filing Date
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Country Status (2)

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AU (1) AU1284897A (fr)
WO (1) WO1997020812A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6180670B1 (en) * 1995-07-20 2001-01-30 Avon Products, Inc. Retinoid conjugate compounds useful for the treatment of aging skin
WO2003016259A2 (fr) * 2001-08-16 2003-02-27 Pharmacon-Forschung Und Beratung Gmbh Composes contenant des elements d'acide lactique, leur procede de preparation et leur utilisation comme principes actifs pharmaceutiques
EP1369411A1 (fr) * 2002-06-07 2003-12-10 Cognis France S.A. Compositions cosmétiques et/ou pharmaceutiques contenant des esters de rétinol
WO2012015790A1 (fr) * 2010-07-29 2012-02-02 Eastman Chemical Company Esters d'acides hydroxycarboxyliques o-substitués et leur synthèse
WO2012154243A1 (fr) * 2011-02-21 2012-11-15 Eastman Chemical Company Esters d'oligomère d'acide hydroxyalcanoïque et d'acide hydroxyalcanoïque de rétinol
WO2013121284A1 (fr) 2012-02-14 2013-08-22 Universite De Strasbourg Produits iodés destinés à être utilisés pour l'imagerie médicale et leurs procédés de préparation
US8613940B2 (en) 2010-09-03 2013-12-24 Eastman Chemical Company Carbonate derivatives as skin care

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995016659A1 (fr) * 1993-12-15 1995-06-22 Avon Products, Inc. Nouveaux composes conjugues de retinoides et procedes de traitement du vieillissement de la peau
DE4415204A1 (de) * 1994-04-30 1995-11-02 Carl Heinrich Dr Weischer Neue Retinol (Vitamin A) -Derivate, deren Herstellung und Verwendung als Arzneimittel und Kosmetika

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995016659A1 (fr) * 1993-12-15 1995-06-22 Avon Products, Inc. Nouveaux composes conjugues de retinoides et procedes de traitement du vieillissement de la peau
DE4415204A1 (de) * 1994-04-30 1995-11-02 Carl Heinrich Dr Weischer Neue Retinol (Vitamin A) -Derivate, deren Herstellung und Verwendung als Arzneimittel und Kosmetika

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6180670B1 (en) * 1995-07-20 2001-01-30 Avon Products, Inc. Retinoid conjugate compounds useful for the treatment of aging skin
WO2003016259A2 (fr) * 2001-08-16 2003-02-27 Pharmacon-Forschung Und Beratung Gmbh Composes contenant des elements d'acide lactique, leur procede de preparation et leur utilisation comme principes actifs pharmaceutiques
WO2003016259A3 (fr) * 2001-08-16 2003-09-12 Pharmacon Forschung & Beratung Gmbh Composes contenant des elements d'acide lactique, leur procede de preparation et leur utilisation comme principes actifs pharmaceutiques
EP1369411A1 (fr) * 2002-06-07 2003-12-10 Cognis France S.A. Compositions cosmétiques et/ou pharmaceutiques contenant des esters de rétinol
WO2003104183A1 (fr) * 2002-06-07 2003-12-18 Cognis France S.A. Preparations cosmetiques et/ou pharmaceutiques a base d'esters de retinol
CN103249709A (zh) * 2010-07-29 2013-08-14 伊士曼化工公司 O-取代的羟基羧酸的酯及其制备
WO2012015790A1 (fr) * 2010-07-29 2012-02-02 Eastman Chemical Company Esters d'acides hydroxycarboxyliques o-substitués et leur synthèse
JP2013539457A (ja) * 2010-07-29 2013-10-24 イーストマン ケミカル カンパニー Ｏ−置換されたヒドロキシカルボン酸のエステルおよびその製造
US8846723B2 (en) 2010-07-29 2014-09-30 Eastman Chemical Company Esters of O-substituted hydroxy carboxylic acids and preparations thereof
CN103249709B (zh) * 2010-07-29 2016-01-06 伊士曼化工公司 O-取代的羟基羧酸的酯及其制备
US9532938B2 (en) 2010-07-29 2017-01-03 Eastman Chemical Company Esters of O-substituted hydroxy carboxylic acids and preparations thereof
US8613940B2 (en) 2010-09-03 2013-12-24 Eastman Chemical Company Carbonate derivatives as skin care
WO2012154243A1 (fr) * 2011-02-21 2012-11-15 Eastman Chemical Company Esters d'oligomère d'acide hydroxyalcanoïque et d'acide hydroxyalcanoïque de rétinol
US8329938B2 (en) 2011-02-21 2012-12-11 Eastman Chemical Company Hydroxyalkanoic acid and hydroxyalkanoice acid oligomer esters of retinol
CN103380111A (zh) * 2011-02-21 2013-10-30 伊士曼化工公司 羟基羧酸和羟基羧酸低聚物的视黄基酯
JP2014514249A (ja) * 2011-02-21 2014-06-19 イーストマン ケミカル カンパニー レチノールのヒドロキシアルカン酸及びヒドロキシアルカン酸オリゴマーエステル
WO2013121284A1 (fr) 2012-02-14 2013-08-22 Universite De Strasbourg Produits iodés destinés à être utilisés pour l'imagerie médicale et leurs procédés de préparation

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Publication number Publication date
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