CA2099879A1 - Cosmetic or pharmaceutical preparation - Google Patents
Cosmetic or pharmaceutical preparationInfo
- Publication number
- CA2099879A1 CA2099879A1 CA002099879A CA2099879A CA2099879A1 CA 2099879 A1 CA2099879 A1 CA 2099879A1 CA 002099879 A CA002099879 A CA 002099879A CA 2099879 A CA2099879 A CA 2099879A CA 2099879 A1 CA2099879 A1 CA 2099879A1
- Authority
- CA
- Canada
- Prior art keywords
- preparation
- tocopherol
- stated
- silymarin
- flavolignan
- Prior art date
- Legal status (The legal status 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 status listed.)
- Abandoned
Links
Classifications
-
- 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
-
- 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
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
- A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
-
- 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
- A61K8/678—Tocopherol, i.e. vitamin E
-
- 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
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
- A61K8/9783—Angiosperms [Magnoliophyta]
- A61K8/9789—Magnoliopsida [dicotyledons]
-
- 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
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
- A61K8/9783—Angiosperms [Magnoliophyta]
- A61K8/9794—Liliopsida [monocotyledons]
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
Abstract
ABSTRACT OF THE DISCLOSURE
The invention concerns a cosmetic or pharmaceutical preparation containing at least one flavolignan and tocopherol and/or an ester thereof. The preparation disclosed has a cell-protective action and is suitable for use in slowing the skin-aging process.
The invention concerns a cosmetic or pharmaceutical preparation containing at least one flavolignan and tocopherol and/or an ester thereof. The preparation disclosed has a cell-protective action and is suitable for use in slowing the skin-aging process.
Description
%Q~ 3~3 Cbsmetic or Pharmaoeutical Preparation The invention rela~es to a cosmetic or pbarmaoeutical preparation aompriging a flaNolignan and a tcccpherol or an ester thereof.
~ xidative and reductive proceEses in the cellular domain play a central r~le in metabolism. Iherein highly reactive short-livt~d intermediary metabollc produc~s are formed, namely fre~ radicals. oxygt~n radicals, sut~h as the peroxide radical anion, the hydkoQeroxlde radical and the hydroxyl radical, are of special significanc2 the~in.
m e c~ ulerce of free radicals can cause cytotoxicity, enzyme changes, attacks on nucleic acids, lipid peroxidation and 1055 of the integrity of cellular membranes. Connecte1 therewith are for example partic~lar diseases and rapid aging.
In general free radicals can be generated in the cell by a number of reactions or rubs*arces in the e~vironment. One p~ssibility for this is photolysis by W radiation. It is aocepted as certain that W rays which can penetrate thr~ the upper cell layers, co~tribute to the develcpnerlt of mali3nant skin carcin~ and aqing of the skin.
In ordex to suppre~s the formation of free radicals, n3~ucing radical irhibitors (antio~idants) are used, amor~ which are for e~nple vitamin C and E and silymarin. EP-A-180 505 describes for exzlmple a co~netic preparation c~prising two components for delaying the aging of skin. One of the two can~ponents, the hy~ilic one, ccn~rises an active ir~3redient which inter alia can be silymarin. m e ather oa~onent, the hy ~ ihcbic one, camprises for example unsaponiiab1e ~oy constituents, unsaponifiable avocado constitu~nts, nut oil etc.
FR-A-2 597 337 also describes a co~metic preparation for delaying aging of the skin. This preparation is also present in tWD ccmponents, wherein the one ~omponent ca~prises numerous constituents, amnng the~ silymarin. m e oil-soluble oomponent comprises also numercus constituents wherein, naturally, tocopherols are also listed. Due to the preparation being formulated in tw~ cc~pcrents, more of the active ingredient is said to be soluble in the oil phase and in the aqueous phase.
It has surprlsingly been found that a combinati~n of a flavolignan compound and tocopherol or an ester thereof acts synergistically as radical :.i~ . . . -.::. - , . . ..................... . . . .
, ., .. ,,, .. ,, . .. ., .. ; . .. - . . , . ,.. . ., , . - - . .: .:
% ~3 ~ t~
&2inhibit~r and therefore ean be us~d Ln a cosmetie or ph2rmaoeutir~1 preparation whieh is m particular useful for delaying aging of the skin.
Subject matter of the in~ention is therefore a eosmetie or pharmaeeutieal preparation which oomprises at least cn~ flavolignan and tocopherol an~/or an ester thereof.
m e flavolignans ussd in the prepar~tion aceording to the in~ention are in particular silymarin or derivativEs thereof. Silymarin is extractQd from the St. Mary thistle, Sllibum marianum. It is a mixture of several flavolignans, namely sily~in, silybinin, silydianin and silychristin.
Production and extLaction of the silymarin extract and individual cr~pcunns are described for example in DE-A-l9 23 082, DE-A-29 14 330, DE-A-35 37 656 and Arzneim.-Forsch. 24, No. 4, 466-471 (1974).
Usable silymarin derivatives are in particular salts and addition ccmF=unds (complex cccpcundn) o~ silymar m, such as the salts of silymarin wi~h mo=oam1no polyhydroxyl alcchols, for example l-met'hyl amino gluccse, described in DE-A-23 02 593: silybin1n hemisuccinate and silymarin c~clodextr m complexes, as describad in EP-A-90 118 964. Reference is made to the content of the stated applications in its full extent.
In tlhe preparation according to the invention tlhe silymarin mixture as well a also one or several of the indi~idual ccrpcurdn can ba used~ The flavolignans, and in particular silymarin, can also be used m ~he form of addition salts.
The tooopherols used aocording to the inventicn are cosroondn ]having vitamin E character. m ese a~e o~ , and ~- toccpherols, wherein o~toco~herol i8 preferred. Especially preferred is the application of the esters of tocopherol with an aliphatic carboxylic acid having 1 to 4 carbon ~ ~
atons, in particular acetic acid. :.
According to a preferred e~bod1mcnt, the preparations accordlng to the invention also contain a prote~n hy*rolysate. The molecular weiyht of the pro~ein hy~rolysate is in general in the range of 300 to 50 000, in particular 500 to 25 000 daltons. The protein hydrolysates can be of plant or animal origin, for example they can be from wheat or soy prcteLn, collagen etc. Suitable protein hydrolysates are commercially available, for example Gluadin AGP (Henkel), oktained by enzymatic hydrolysis of wheat proteins, pH
value 4.5 to 5.0 tlO% solution), mDlecular weight 2000 to 25 000, or Nutrilan molecular weight 500 to 2000.
Asoording to a furth@r preferred emb~diment, the preparations aocording to the invention co~prise at least ~n~ amino acid, ln particular methionine or cysteine. Advisably an amino acid mixture is l~cP~t for exa~ple the ocmmercially available pro~uct A5M-Cl (Degussa) with the following amino acid oomposition:
Ala 6.17 % Lys 2.50 %
Arg 0.98 % Orn 7.94 %
Asp 4.02 % Phe 1.04 %
Glu 1.97 % Pro 1.02 %
Gly 12.18 % Ser 19.48 %
His 5.00 % Thr 5.16 %
Ile 1.02 ~ Irp 1.01 %
Leu 2.04 % Tyr 1.43 %
Clt 5.70 % Val 3.62 %.
or an amino acid mixture having the following composition:
Threonine 1.9 %
Serine 1.4 %
GlycLne 9.2 ~
Alanine 10.4 %
Valine 7.0 %
Methionine 2.4 %
Isoleucine 5.4 %
Leucine 8.5 %
Tyrosina 4.4 %
Ph~nylalanine 2.6 ~
~~-amlno butyric acid 0.5 %
Lysine 1.5 %
Proline 39.4 ~
Arginine 5.5 %
The quantitative ratio of flavolignan to toccFh~rol or an es~r thereof can vary within a wide range. In general the quantity by weight of tocopherol or an ester thereof to flavolignan iB in the range of 5:1 to 20:1, in particular 10:1 to 20:1. If a prckein hydrolysate or an amuno acid (mixtNre) is present in the p ~ ation, the prqportions of toccpherol or an ester thereof to the prokein hydr~lysate or amino acid (mixture) is in general 2:1 to 15:1, in particular 3:1 to 10:1.
m e preparation aocording to the invention can cc~pri~e conventional ~ ~ 9 ~ C~
additives. Sub6kances to be listed hexe are in parti~lar eubst~nces for the care of the skin, such as katicnic ~aternary polymrs; moisturizers, such as glyCermQ, 80rbit41, pentaerythrite, inc~itol, pyrrolidone carboxylic acid and ~heir salts: artificial tannlng agents, such as dihydroxy acetone, erythrulcse, glyoerin aldehyde, o~-dialdehydes, such as 2,3-dihydroxy succinaldelhyde, potentially ~cgether wit~ fur~her oolori~g subst~nces for the skin; agents for the prokection of ~kin against the sun; antiperspirants;
deodorants; adstringents; fresheners and fortifyers; extracts of animal and plant tissues; fragrances in water; coloring agents; unsaturated higher fatty acid~, vitamins, hormones, antibiotics, etc.
m e preparaticns aocording to tlhe ~ ~ention can be available in a form suitable for topi~al use. For this purpcse it is generally available in the form of a creme, ~olution, gel or emulsian. Apart from the previously stated constituents, the pr~paration can also comprise ad~uvants conventionally used Eor thls purF~se, for example prxservative 6u`u6tYnCe6, sequestering agents, ~hickeners, emulsifiers etc.
If the prYparation i8 present in the form of a creme, the carrier can be formulated on the basis of soap~ or fatty alcohols in the presence of emulsifiers. qhe soaps can be formed s~arting fram natural or synthetic C12-C18 ~atty acids (for example lauric acid, myristic acid, palmitic acid, steaxic acid) in a quantity of 10 to 30 percent by weight as wEll as alkalizing agents (~uch as sodium hydroxide, pokassium hydro~ide, ammonia, monomethanolamins, diethsnolanine, triathanolamine).
The ¢remes can camprise additlon21ly ad~uvants such as fatty amides and fatty alcaihol~. Usable fatty amides ara in parti~llar mono- or diethanolamides o~ thQ oooonNt fatty a¢id~, lauric acid or oleic acid in a quantity of up to 10 percent by waight relative to the to~al weight of the preparation. Usable fatty alcchol~ are in p~rticular oleyl aloahol, myristyl alcoihol, cetyl alochol, stearyl alco~ol or isostearyl alcoihol in a q~antity of up to 10 percent by wei~ht relative to the total wei~ht of the preparation.
~he cremes can also be formulated on the basis of natural or synthetic C12-C18 alcchols together wi~h emLlsifiers. Usable fatty alcahols are in particular o xonut fatty aloohol, m~ristyl alodhol, oe tyl aloQhol, stearyl alcchol, hydr~xystearyl aloahol in a guantity of 5 to 25 percent by weight, 2 ~ 3 ~
.
alt~bhol, hydroxystearyl al~ohol in a quantity of 5 t~ 25 percent ky weight, relative to the tc~L weit~ht of the preparation.
Useful emulsifiers are:
Oxethylated or polyglyoerinatt~d fatty aloohols, for example polyetht~Kylatt~d oleyl alcohol, oxethylt~matel t~etyl ~lt~dhol, t~xethylt~matt~d oetyl stt~aryl alcohol, oKe~hylenated oleoo~tyl alodhol, oKethylt~mated stearyl aladhol, polyglycerated oleyl ~Loohol, polyt~Kethy]Lenated Cg- C15 fatty aLt~ihols etc.
Ihese non-ionic t~N~Lsifiers are in t3~r~L present in a t~lantity of S to 25 percen~ by wei~ht r~Lative to the t~*~L weight of the ~ tion.
Further usable emulsifiers are esters of higher fatty acids, such as ~kearic acid with polyalcohol~, 6uch as glyoerin, sorbitol, propyl~ne glycol, polyethylene glyools, etc. as well as potentially oxethylated aIkyl sulfate~, such as triethanolaminQ, lauryl sulfate, ~Kethyla~ed sodium lauryl ether sulfate and oKethyla~Qd ma.noethanolamine lauryle~her sulfate.
If the preparations according to the invention are present in the foxm of emulsions, these can be formulated on the basis of non-ionic or anionic surface-active agents. Non-ionic emLlsions comprise in general oils andVor waxes, fatty alcohols, polyethoxylat~d fatty alcchols, such as for example stearyl alcohol or polyethoxylated oetyl stearyl alcchol. Anionic emLlsions are in general formulated on the basis o~ soaps.
Suitable ~olvents or solutions and gels are water or mix*ures of water and alcohol, ~or e~ample water/ethanol or water/iscprcpanol. Suitable ~el formers are in parti~llar cellulose derivatives, such as cartcxymothyl cellulose, hydroxyethyl cellulo~e, and polyacrylic acids (for example Carbopole).
Ihe preparation~ aocord~ng to tha in~ention have a protective efect on the oe lls and are therefore cap~ble of delaying effectively the ag mg prccess of the skin. Thi8 could be ceDor~trated in in vitro studies as well as also in in vivo studies.
m e in vitro investigations were carried out on human keratinocytes which were irradiated with UV A radiation in order to induoe cell damage through free radicals. Fbr ~his purpcse isolated keratinocytes frcm the fore~kin of a tw~ months old child were used. ISe keratinocytes were ~i, . . . . . .
~:?~. : : . -.,, . ~ , .
'','- ''- . , ' ~ : ' .,, .. ~ . . . .
:,. . . .
., . . - - . .
,.,; . .. . .
,'. i:: , . . . .
.: . . , 3 I~
cortis~ne, ins~lin, calci~n (0.1 nM). The ~tr~tion of ~e pituita~y extract was 0. 5 % (70 ~/ml) .
The cells were maintained irl Cornir~ culture o~ntainers with a diaoeter of 100 nun in a m~ist ab~ with 5% C~2 at 37 C. q~e keratino~tes were inoculated every 8 days at constant oell d~nsity: 1 x 105 oells/10 ml culhlre ~dium.
Determination of the rate of gr ~ was carried aIt colorimetrically based on the metabolic activity of the cYlls with ~he aid of a tetrazolium salt tMIT test, Mk~mann 1983). A blue cclor develcped whose int~nsity was proportional to the call density. The ab60rptian at 570 nm was de ~ d The follcwing test subs~ances and solutions were ~-CP~
Stock solutions o~ ~I3coph2rol 150 mg/ml in ethanol 96 % (A) Cetiol B 0.1 ~ /ml in HanXs solution withcut phenol red (B) Silybinin h~misuocinate 2 mg~ml in Hanks solution without phenol red (C) Gluadin 0.5 m~ml in HanXs solution without phen~l red (D) Frcm these stock solutions the following test solutions were prepared:
Tokal mixture !alLactiv~ lP~n~dients) A 20 ~
B 100 pl C 100 pl D 1 ml Culture solution ~KDB 153 or Hank~ electrolyte ~olution without phenol red to 10 ml.
Tocopherol aoeta~e solution A 20 ml B 100 ~1 :
j.":~`., ~ '.'' '. ' ' ' ' . ` ' " . ''" "' '. . ' ' ' ' " '` ' ! :~ s -` .
2~9~s~71~
to 10 ml.
Sily~inin hemisuocinate solutior C 100 ~11 Cultl~re solutic~ YCDB 153 or H~1)CB e~ te SolUtiQn Withalt F~le~?l red to 10 ml.
Control 20 pl ethanol 98 %
B 100 )11 D 1 ml Cult~e solutian MfDB 153 or ~cs electrolyte solutian witha~t ~enol red to 10 n~.
m e ~ test so1ution~ are u6ed undiluted or dillxted to 1/2, 1/10, arKl 1~20.
100 ~ of these sDlutions ar~ added to 100 ~ of cell culture ~edium. m e following test ccnoentrations are dbtain2d from them:
~1 1) locopherol acetate 150 Silybin hemisuocinatQ 10 Gluadin 25 2) ~occpher~l acetate 75 Silybin hemisuccinats 5 Gluadin 12.5 3) TocopherDl aoetate 15 Silybin hemi6uocina~
Gluadin 2.5 4) locopherol aoetate 7.5 Silybin hemisuoc~nate 0.5 Gluadin 1.25 ~ . . . . . . .
'.,;'.,'' ' - '," '' ~ . ~
2 ~
Each of the ooncentrations was tested on five cell cultuxes.
Irradiation m e generation of free radical. took place with W -A radiation with a mrcury vapor lamp Vilber Lourma~ (T 40 M). The maximum of the emlssion spectrum oocurred at 365 nm.
An intensity of 6 jcules/cm2 led to a toxicity of aFpraximately 50 % on the kerati ~ 24 hours after the irradiation. The irradiation of thQ
keratinocytes took pla oe in Hanks solution withcut phenol red. After the irradiation the electrolyte sDlution was removed and the cells w~re allowed to stand for 24 hnurs in their ccmplete culture medium. The viability of he cells was subsequently de~ermlned colorimetri~lly with MIT.
Addition of the test solutions 1. ~efore the irradiation ~he test solutions diluted wit,h Hanks solution without phenol red are added immediately before the irradiation and remain in oontac~ with the keratinocytes for approximately 45 minutes.
2. After the irradiation The test solutions diluted with complete culture medium (MCDB 153) are added immediately befor~ the irradiation and remain m contact with the keratinocytes for 24 ho~rs. ~ i Contr~ls Ihe cultures withaut the solutio~ containir~ the act;ve ir~dient are ooveresl with al~ni~ foil durir~g the irradiation.
~ " ' ' .
me irr~diation led to a decrease ~y appr~nately 50 % of the oell activity of the keratinocyt~ = toocicity. A~3 a measure of the pr~tective effect against free radicals, canseguerltly, can be rated an ~sed oell yleld of the treated cultures c~pared to untr~ated controls. ~ -~: ~,, , .. , . . , - . : . . , - .. ,., ;, ... .... .. .. . . .
2~n~ 7~3 .. ..
Example:
Toxicity trea~ed = 50 %
Tbxicity untreat~d = 80 %
Ihcrease of cell yield ~ 30 The resNlts are shown in figure 1.
The solvents (oontrol) + Gluadin as well as also tooopherol acetate showed no incre~sed cell yield and therewith no prokective effect. Only silybin hemisuccinate effects a slight mcrease of the cell yield. This preparatlon aoc~rding to the invention (total nixture), in contrast, increased the cell yield markedly as a function of the quantity added. This prokective effect is statistically significan~ (p < 0.05) ~cmpared to the individual d n~rkedly superadlltive. The effect of this preparation can therefore be oonsidered to be synergistic.
Ihe follcwing examples explain the invention without limiting it.
Example 1: Creme %
PEG-40 Stearate 1.80 Sorbitan stearate 3.60 stearic acid 0.40 Cetearyl alcdhol 2.00 Lanoline oil 2.00 Capry~ic/oapric/0tearic/triglyceride 4.00 Cetearyl isoncr~nc~te 4.00 Dimethioone 1.00 Demineralized water tD 100.00 Meth~lparaben 0.15 Phenoxyethsnol 0.45 Propylene glyool 0.90 PEG-40~ 4.00 Hy~rolized wheat protein 0.50 Tocopherol aoatate 3.00 Chlorohexidlne diglucona~e 0.04 Silymarin 0.20 9 ,"j r~
Example 2. Creme Glycer m monostearate 3.60 Na-Cet ~ 1 sulfate 0~80 C2tearyl alcchGl 3.60 ~ pylene glycol ~tearate 1.00 Octyl dodecyl lanDlate 4.00 Cet~ryl iso~orcncate 6.00 Octyl dodecanol 6.00 Mineral oil 2.00 Dimethicone 1.00 Phenoxy ethanol and methyl paraben 1.00 and et~yl paraben ~ bu~l par~
Demineralized water to100.00 Silymarin 0.20 PEG-400 4.00 Tbccpher~l aoetate 3.00 Wheat protein hydr~lysate ~Gluadin AGP) 0.50 ExEmple 3: Twv-phase product Joioka oil 4.00 Toocpher~l aoetate 2.00 Octyl methoxycinnamate 3.00 l~cc~erDl O . 01 Mineral oil 16.00 Demineralized water to100.00 Hyaluronic acid 0.08 Fyrrolidone carboxylate Na 0.25 Sodium ao~tate 0.25 Methyl paraben 0.18 Phenoxyethanol 0.54 Propylene glycol 1.08 Magnesium sulfate 1.00 Silymarin 0.20
~ xidative and reductive proceEses in the cellular domain play a central r~le in metabolism. Iherein highly reactive short-livt~d intermediary metabollc produc~s are formed, namely fre~ radicals. oxygt~n radicals, sut~h as the peroxide radical anion, the hydkoQeroxlde radical and the hydroxyl radical, are of special significanc2 the~in.
m e c~ ulerce of free radicals can cause cytotoxicity, enzyme changes, attacks on nucleic acids, lipid peroxidation and 1055 of the integrity of cellular membranes. Connecte1 therewith are for example partic~lar diseases and rapid aging.
In general free radicals can be generated in the cell by a number of reactions or rubs*arces in the e~vironment. One p~ssibility for this is photolysis by W radiation. It is aocepted as certain that W rays which can penetrate thr~ the upper cell layers, co~tribute to the develcpnerlt of mali3nant skin carcin~ and aqing of the skin.
In ordex to suppre~s the formation of free radicals, n3~ucing radical irhibitors (antio~idants) are used, amor~ which are for e~nple vitamin C and E and silymarin. EP-A-180 505 describes for exzlmple a co~netic preparation c~prising two components for delaying the aging of skin. One of the two can~ponents, the hy~ilic one, ccn~rises an active ir~3redient which inter alia can be silymarin. m e ather oa~onent, the hy ~ ihcbic one, camprises for example unsaponiiab1e ~oy constituents, unsaponifiable avocado constitu~nts, nut oil etc.
FR-A-2 597 337 also describes a co~metic preparation for delaying aging of the skin. This preparation is also present in tWD ccmponents, wherein the one ~omponent ca~prises numerous constituents, amnng the~ silymarin. m e oil-soluble oomponent comprises also numercus constituents wherein, naturally, tocopherols are also listed. Due to the preparation being formulated in tw~ cc~pcrents, more of the active ingredient is said to be soluble in the oil phase and in the aqueous phase.
It has surprlsingly been found that a combinati~n of a flavolignan compound and tocopherol or an ester thereof acts synergistically as radical :.i~ . . . -.::. - , . . ..................... . . . .
, ., .. ,,, .. ,, . .. ., .. ; . .. - . . , . ,.. . ., , . - - . .: .:
% ~3 ~ t~
&2inhibit~r and therefore ean be us~d Ln a cosmetie or ph2rmaoeutir~1 preparation whieh is m particular useful for delaying aging of the skin.
Subject matter of the in~ention is therefore a eosmetie or pharmaeeutieal preparation which oomprises at least cn~ flavolignan and tocopherol an~/or an ester thereof.
m e flavolignans ussd in the prepar~tion aceording to the in~ention are in particular silymarin or derivativEs thereof. Silymarin is extractQd from the St. Mary thistle, Sllibum marianum. It is a mixture of several flavolignans, namely sily~in, silybinin, silydianin and silychristin.
Production and extLaction of the silymarin extract and individual cr~pcunns are described for example in DE-A-l9 23 082, DE-A-29 14 330, DE-A-35 37 656 and Arzneim.-Forsch. 24, No. 4, 466-471 (1974).
Usable silymarin derivatives are in particular salts and addition ccmF=unds (complex cccpcundn) o~ silymar m, such as the salts of silymarin wi~h mo=oam1no polyhydroxyl alcchols, for example l-met'hyl amino gluccse, described in DE-A-23 02 593: silybin1n hemisuccinate and silymarin c~clodextr m complexes, as describad in EP-A-90 118 964. Reference is made to the content of the stated applications in its full extent.
In tlhe preparation according to the invention tlhe silymarin mixture as well a also one or several of the indi~idual ccrpcurdn can ba used~ The flavolignans, and in particular silymarin, can also be used m ~he form of addition salts.
The tooopherols used aocording to the inventicn are cosroondn ]having vitamin E character. m ese a~e o~ , and ~- toccpherols, wherein o~toco~herol i8 preferred. Especially preferred is the application of the esters of tocopherol with an aliphatic carboxylic acid having 1 to 4 carbon ~ ~
atons, in particular acetic acid. :.
According to a preferred e~bod1mcnt, the preparations accordlng to the invention also contain a prote~n hy*rolysate. The molecular weiyht of the pro~ein hy~rolysate is in general in the range of 300 to 50 000, in particular 500 to 25 000 daltons. The protein hydrolysates can be of plant or animal origin, for example they can be from wheat or soy prcteLn, collagen etc. Suitable protein hydrolysates are commercially available, for example Gluadin AGP (Henkel), oktained by enzymatic hydrolysis of wheat proteins, pH
value 4.5 to 5.0 tlO% solution), mDlecular weight 2000 to 25 000, or Nutrilan molecular weight 500 to 2000.
Asoording to a furth@r preferred emb~diment, the preparations aocording to the invention co~prise at least ~n~ amino acid, ln particular methionine or cysteine. Advisably an amino acid mixture is l~cP~t for exa~ple the ocmmercially available pro~uct A5M-Cl (Degussa) with the following amino acid oomposition:
Ala 6.17 % Lys 2.50 %
Arg 0.98 % Orn 7.94 %
Asp 4.02 % Phe 1.04 %
Glu 1.97 % Pro 1.02 %
Gly 12.18 % Ser 19.48 %
His 5.00 % Thr 5.16 %
Ile 1.02 ~ Irp 1.01 %
Leu 2.04 % Tyr 1.43 %
Clt 5.70 % Val 3.62 %.
or an amino acid mixture having the following composition:
Threonine 1.9 %
Serine 1.4 %
GlycLne 9.2 ~
Alanine 10.4 %
Valine 7.0 %
Methionine 2.4 %
Isoleucine 5.4 %
Leucine 8.5 %
Tyrosina 4.4 %
Ph~nylalanine 2.6 ~
~~-amlno butyric acid 0.5 %
Lysine 1.5 %
Proline 39.4 ~
Arginine 5.5 %
The quantitative ratio of flavolignan to toccFh~rol or an es~r thereof can vary within a wide range. In general the quantity by weight of tocopherol or an ester thereof to flavolignan iB in the range of 5:1 to 20:1, in particular 10:1 to 20:1. If a prckein hydrolysate or an amuno acid (mixtNre) is present in the p ~ ation, the prqportions of toccpherol or an ester thereof to the prokein hydr~lysate or amino acid (mixture) is in general 2:1 to 15:1, in particular 3:1 to 10:1.
m e preparation aocording to the invention can cc~pri~e conventional ~ ~ 9 ~ C~
additives. Sub6kances to be listed hexe are in parti~lar eubst~nces for the care of the skin, such as katicnic ~aternary polymrs; moisturizers, such as glyCermQ, 80rbit41, pentaerythrite, inc~itol, pyrrolidone carboxylic acid and ~heir salts: artificial tannlng agents, such as dihydroxy acetone, erythrulcse, glyoerin aldehyde, o~-dialdehydes, such as 2,3-dihydroxy succinaldelhyde, potentially ~cgether wit~ fur~her oolori~g subst~nces for the skin; agents for the prokection of ~kin against the sun; antiperspirants;
deodorants; adstringents; fresheners and fortifyers; extracts of animal and plant tissues; fragrances in water; coloring agents; unsaturated higher fatty acid~, vitamins, hormones, antibiotics, etc.
m e preparaticns aocording to tlhe ~ ~ention can be available in a form suitable for topi~al use. For this purpcse it is generally available in the form of a creme, ~olution, gel or emulsian. Apart from the previously stated constituents, the pr~paration can also comprise ad~uvants conventionally used Eor thls purF~se, for example prxservative 6u`u6tYnCe6, sequestering agents, ~hickeners, emulsifiers etc.
If the prYparation i8 present in the form of a creme, the carrier can be formulated on the basis of soap~ or fatty alcohols in the presence of emulsifiers. qhe soaps can be formed s~arting fram natural or synthetic C12-C18 ~atty acids (for example lauric acid, myristic acid, palmitic acid, steaxic acid) in a quantity of 10 to 30 percent by weight as wEll as alkalizing agents (~uch as sodium hydroxide, pokassium hydro~ide, ammonia, monomethanolamins, diethsnolanine, triathanolamine).
The ¢remes can camprise additlon21ly ad~uvants such as fatty amides and fatty alcaihol~. Usable fatty amides ara in parti~llar mono- or diethanolamides o~ thQ oooonNt fatty a¢id~, lauric acid or oleic acid in a quantity of up to 10 percent by waight relative to the to~al weight of the preparation. Usable fatty alcchol~ are in p~rticular oleyl aloahol, myristyl alcoihol, cetyl alochol, stearyl alco~ol or isostearyl alcoihol in a q~antity of up to 10 percent by wei~ht relative to the total wei~ht of the preparation.
~he cremes can also be formulated on the basis of natural or synthetic C12-C18 alcchols together wi~h emLlsifiers. Usable fatty alcahols are in particular o xonut fatty aloohol, m~ristyl alodhol, oe tyl aloQhol, stearyl alcchol, hydr~xystearyl aloahol in a guantity of 5 to 25 percent by weight, 2 ~ 3 ~
.
alt~bhol, hydroxystearyl al~ohol in a quantity of 5 t~ 25 percent ky weight, relative to the tc~L weit~ht of the preparation.
Useful emulsifiers are:
Oxethylated or polyglyoerinatt~d fatty aloohols, for example polyetht~Kylatt~d oleyl alcohol, oxethylt~matel t~etyl ~lt~dhol, t~xethylt~matt~d oetyl stt~aryl alcohol, oKe~hylenated oleoo~tyl alodhol, oKethylt~mated stearyl aladhol, polyglycerated oleyl ~Loohol, polyt~Kethy]Lenated Cg- C15 fatty aLt~ihols etc.
Ihese non-ionic t~N~Lsifiers are in t3~r~L present in a t~lantity of S to 25 percen~ by wei~ht r~Lative to the t~*~L weight of the ~ tion.
Further usable emulsifiers are esters of higher fatty acids, such as ~kearic acid with polyalcohol~, 6uch as glyoerin, sorbitol, propyl~ne glycol, polyethylene glyools, etc. as well as potentially oxethylated aIkyl sulfate~, such as triethanolaminQ, lauryl sulfate, ~Kethyla~ed sodium lauryl ether sulfate and oKethyla~Qd ma.noethanolamine lauryle~her sulfate.
If the preparations according to the invention are present in the foxm of emulsions, these can be formulated on the basis of non-ionic or anionic surface-active agents. Non-ionic emLlsions comprise in general oils andVor waxes, fatty alcohols, polyethoxylat~d fatty alcchols, such as for example stearyl alcohol or polyethoxylated oetyl stearyl alcchol. Anionic emLlsions are in general formulated on the basis o~ soaps.
Suitable ~olvents or solutions and gels are water or mix*ures of water and alcohol, ~or e~ample water/ethanol or water/iscprcpanol. Suitable ~el formers are in parti~llar cellulose derivatives, such as cartcxymothyl cellulose, hydroxyethyl cellulo~e, and polyacrylic acids (for example Carbopole).
Ihe preparation~ aocord~ng to tha in~ention have a protective efect on the oe lls and are therefore cap~ble of delaying effectively the ag mg prccess of the skin. Thi8 could be ceDor~trated in in vitro studies as well as also in in vivo studies.
m e in vitro investigations were carried out on human keratinocytes which were irradiated with UV A radiation in order to induoe cell damage through free radicals. Fbr ~his purpcse isolated keratinocytes frcm the fore~kin of a tw~ months old child were used. ISe keratinocytes were ~i, . . . . . .
~:?~. : : . -.,, . ~ , .
'','- ''- . , ' ~ : ' .,, .. ~ . . . .
:,. . . .
., . . - - . .
,.,; . .. . .
,'. i:: , . . . .
.: . . , 3 I~
cortis~ne, ins~lin, calci~n (0.1 nM). The ~tr~tion of ~e pituita~y extract was 0. 5 % (70 ~/ml) .
The cells were maintained irl Cornir~ culture o~ntainers with a diaoeter of 100 nun in a m~ist ab~ with 5% C~2 at 37 C. q~e keratino~tes were inoculated every 8 days at constant oell d~nsity: 1 x 105 oells/10 ml culhlre ~dium.
Determination of the rate of gr ~ was carried aIt colorimetrically based on the metabolic activity of the cYlls with ~he aid of a tetrazolium salt tMIT test, Mk~mann 1983). A blue cclor develcped whose int~nsity was proportional to the call density. The ab60rptian at 570 nm was de ~ d The follcwing test subs~ances and solutions were ~-CP~
Stock solutions o~ ~I3coph2rol 150 mg/ml in ethanol 96 % (A) Cetiol B 0.1 ~ /ml in HanXs solution withcut phenol red (B) Silybinin h~misuocinate 2 mg~ml in Hanks solution without phenol red (C) Gluadin 0.5 m~ml in HanXs solution without phen~l red (D) Frcm these stock solutions the following test solutions were prepared:
Tokal mixture !alLactiv~ lP~n~dients) A 20 ~
B 100 pl C 100 pl D 1 ml Culture solution ~KDB 153 or Hank~ electrolyte ~olution without phenol red to 10 ml.
Tocopherol aoeta~e solution A 20 ml B 100 ~1 :
j.":~`., ~ '.'' '. ' ' ' ' . ` ' " . ''" "' '. . ' ' ' ' " '` ' ! :~ s -` .
2~9~s~71~
to 10 ml.
Sily~inin hemisuocinate solutior C 100 ~11 Cultl~re solutic~ YCDB 153 or H~1)CB e~ te SolUtiQn Withalt F~le~?l red to 10 ml.
Control 20 pl ethanol 98 %
B 100 )11 D 1 ml Cult~e solutian MfDB 153 or ~cs electrolyte solutian witha~t ~enol red to 10 n~.
m e ~ test so1ution~ are u6ed undiluted or dillxted to 1/2, 1/10, arKl 1~20.
100 ~ of these sDlutions ar~ added to 100 ~ of cell culture ~edium. m e following test ccnoentrations are dbtain2d from them:
~1 1) locopherol acetate 150 Silybin hemisuocinatQ 10 Gluadin 25 2) ~occpher~l acetate 75 Silybin hemisuccinats 5 Gluadin 12.5 3) TocopherDl aoetate 15 Silybin hemi6uocina~
Gluadin 2.5 4) locopherol aoetate 7.5 Silybin hemisuoc~nate 0.5 Gluadin 1.25 ~ . . . . . . .
'.,;'.,'' ' - '," '' ~ . ~
2 ~
Each of the ooncentrations was tested on five cell cultuxes.
Irradiation m e generation of free radical. took place with W -A radiation with a mrcury vapor lamp Vilber Lourma~ (T 40 M). The maximum of the emlssion spectrum oocurred at 365 nm.
An intensity of 6 jcules/cm2 led to a toxicity of aFpraximately 50 % on the kerati ~ 24 hours after the irradiation. The irradiation of thQ
keratinocytes took pla oe in Hanks solution withcut phenol red. After the irradiation the electrolyte sDlution was removed and the cells w~re allowed to stand for 24 hnurs in their ccmplete culture medium. The viability of he cells was subsequently de~ermlned colorimetri~lly with MIT.
Addition of the test solutions 1. ~efore the irradiation ~he test solutions diluted wit,h Hanks solution without phenol red are added immediately before the irradiation and remain in oontac~ with the keratinocytes for approximately 45 minutes.
2. After the irradiation The test solutions diluted with complete culture medium (MCDB 153) are added immediately befor~ the irradiation and remain m contact with the keratinocytes for 24 ho~rs. ~ i Contr~ls Ihe cultures withaut the solutio~ containir~ the act;ve ir~dient are ooveresl with al~ni~ foil durir~g the irradiation.
~ " ' ' .
me irr~diation led to a decrease ~y appr~nately 50 % of the oell activity of the keratinocyt~ = toocicity. A~3 a measure of the pr~tective effect against free radicals, canseguerltly, can be rated an ~sed oell yleld of the treated cultures c~pared to untr~ated controls. ~ -~: ~,, , .. , . . , - . : . . , - .. ,., ;, ... .... .. .. . . .
2~n~ 7~3 .. ..
Example:
Toxicity trea~ed = 50 %
Tbxicity untreat~d = 80 %
Ihcrease of cell yield ~ 30 The resNlts are shown in figure 1.
The solvents (oontrol) + Gluadin as well as also tooopherol acetate showed no incre~sed cell yield and therewith no prokective effect. Only silybin hemisuccinate effects a slight mcrease of the cell yield. This preparatlon aoc~rding to the invention (total nixture), in contrast, increased the cell yield markedly as a function of the quantity added. This prokective effect is statistically significan~ (p < 0.05) ~cmpared to the individual d n~rkedly superadlltive. The effect of this preparation can therefore be oonsidered to be synergistic.
Ihe follcwing examples explain the invention without limiting it.
Example 1: Creme %
PEG-40 Stearate 1.80 Sorbitan stearate 3.60 stearic acid 0.40 Cetearyl alcdhol 2.00 Lanoline oil 2.00 Capry~ic/oapric/0tearic/triglyceride 4.00 Cetearyl isoncr~nc~te 4.00 Dimethioone 1.00 Demineralized water tD 100.00 Meth~lparaben 0.15 Phenoxyethsnol 0.45 Propylene glyool 0.90 PEG-40~ 4.00 Hy~rolized wheat protein 0.50 Tocopherol aoatate 3.00 Chlorohexidlne diglucona~e 0.04 Silymarin 0.20 9 ,"j r~
Example 2. Creme Glycer m monostearate 3.60 Na-Cet ~ 1 sulfate 0~80 C2tearyl alcchGl 3.60 ~ pylene glycol ~tearate 1.00 Octyl dodecyl lanDlate 4.00 Cet~ryl iso~orcncate 6.00 Octyl dodecanol 6.00 Mineral oil 2.00 Dimethicone 1.00 Phenoxy ethanol and methyl paraben 1.00 and et~yl paraben ~ bu~l par~
Demineralized water to100.00 Silymarin 0.20 PEG-400 4.00 Tbccpher~l aoetate 3.00 Wheat protein hydr~lysate ~Gluadin AGP) 0.50 ExEmple 3: Twv-phase product Joioka oil 4.00 Toocpher~l aoetate 2.00 Octyl methoxycinnamate 3.00 l~cc~erDl O . 01 Mineral oil 16.00 Demineralized water to100.00 Hyaluronic acid 0.08 Fyrrolidone carboxylate Na 0.25 Sodium ao~tate 0.25 Methyl paraben 0.18 Phenoxyethanol 0.54 Propylene glycol 1.08 Magnesium sulfate 1.00 Silymarin 0.20
Claims (8)
1. Cosmetic or pharmaceutical preparation comprising at least one flavolignan and tocopherol and/or an ester thereof.
2. Preparation as stated in claim 1, characterized in that the flavolignan is silymarin or a derivative thereof, in particular silybinin, silybinin hemisuccinate, the salts of silymarin with monoamino polyhydroxy alcohols and silymarin cyclodextrin complexes.
3. Preparation as stated in claim 1 or 2, characterized in that the tocopherol is ?-tocopherol or ?-tocopherol acetate.
4. Preparation as stated in one of the preceding claims, characterized in that the ratio by weight of tocopherol or an ester thereof to flavolignan is in the range of 5:1 to 20:1, in particular 10:1 to 20:1.
5. Preparation as stated in one of the preceding claims, characterized in that it comprises in addition a protein hydrolysate and/or at least one amino acid.
6. Preparation as stated in claim 5, characterized in that the ratio of weight of tocopherol to protein hydrolysate or amino acid(s) is in the range of 2:1 to 15:1, in particular 3:1 to 10:1.
7. Preparation as stated in one of the preceding claims, characterized in that it exists in the form of a creme, solution, gel or an emulsion.
8. Preparation as stated in one of the preceding claims, characterized in that it comprises conventional cosmetic or pharmaceutical carriers, auxiliary substances and/or adjuvants.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4101122A DE4101122A1 (en) | 1991-01-16 | 1991-01-16 | COSMETIC OR PHARMACEUTICAL AGENT |
| DEP4101122.8 | 1991-01-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2099879A1 true CA2099879A1 (en) | 1992-07-17 |
Family
ID=6423117
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002099879A Abandoned CA2099879A1 (en) | 1991-01-16 | 1992-01-15 | Cosmetic or pharmaceutical preparation |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0567481A1 (en) |
| JP (1) | JPH06504282A (en) |
| CA (1) | CA2099879A1 (en) |
| DE (1) | DE4101122A1 (en) |
| WO (1) | WO1992012702A1 (en) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4323614A1 (en) * | 1993-07-12 | 1995-01-19 | Edelgard Schreiner | Composition for stimulating the growth and regeneration of hair |
| IT1265312B1 (en) * | 1993-12-21 | 1996-10-31 | Indena Spa | FORMULATIONS CONTAINING CAROTENOIDS AND PRO-CAROTENOIDS ASSOCIATED WITH POLYPHENOLS IN THE PREVENTION OF DAMAGES FROM ABNORMAL PRODUCTION OF |
| DE4431251C2 (en) * | 1994-09-02 | 1997-12-11 | Audor Pharma Gmbh | Skin cream |
| US6524599B2 (en) * | 2001-02-21 | 2003-02-25 | Skinceuticals, Inc. | Use of milk thistle extract in skin care compositions |
| DE10225772A1 (en) * | 2002-06-10 | 2003-12-24 | Beiersdorf Ag | Cosmetic or dermatological formulations for skin care after sunbathing or shaving |
| JP3926711B2 (en) * | 2002-08-30 | 2007-06-06 | 株式会社ファンケル | Composition for preventing skin aging to prevent, prevent and improve flattening of the epidermis |
| JP4648669B2 (en) * | 2004-09-24 | 2011-03-09 | 株式会社ファンケル | Silymarin-containing cosmetics |
| MX2007007624A (en) * | 2004-12-22 | 2007-08-03 | Gillette Co | Reduction of hair growth with survivin inhibitors. |
| JP4033877B2 (en) | 2005-09-29 | 2008-01-16 | 株式会社ファンケル | Composition for promoting type I collagen production |
| JP3914244B2 (en) * | 2005-10-03 | 2007-05-16 | 株式会社ファンケル | Abnormal protein removal composition |
| DE102005048779A1 (en) * | 2005-10-10 | 2007-04-12 | Beiersdorf Ag | Cosmetic formulations for improving skin barrier function |
| DE102005048778A1 (en) * | 2005-10-10 | 2007-04-12 | Beiersdorf Ag | Cosmetic formulations to improve the appearance of the skin |
| DE102005048780A1 (en) * | 2005-10-10 | 2007-04-12 | Beiersdorf Ag | Hydrous cosmetic preparation with dissolved flavonolignans |
| DE102006013925A1 (en) * | 2006-03-21 | 2007-09-27 | Lancaster Group Gmbh | Cosmetic for the sustainable treatment of deeper skin folds |
| JP2007056035A (en) * | 2006-10-19 | 2007-03-08 | Fancl Corp | Differentiation inhibiting agent for normal keratinized human epithelium cell |
| JP5351414B2 (en) * | 2006-12-25 | 2013-11-27 | 株式会社ファンケル | Silybin-containing cosmetic composition |
| WO2016149685A1 (en) | 2015-03-19 | 2016-09-22 | Cydex Pharmaceuticals, Inc. | Compositions containing silymarin and sulfoalkyl ether cyclodextrin and methods of using the same |
| DE102021122753A1 (en) | 2021-09-02 | 2023-03-02 | DR. HERMANS UG (haftungsbeschränkt) | DERMATOLOGICAL AGENT |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2597337B2 (en) * | 1984-10-19 | 1992-07-03 | Courtin Olivier | COSMETIC FOR DELAYING THE AGING OF THE SKIN AND METHOD OF APPLICATION. |
| FR2594691B1 (en) * | 1986-02-24 | 1990-08-03 | Bonne Claude | NEW COSMETIC PREPARATIONS CONTAINING EXTRACT OF SILYBUM MARIANUM FRUITS |
| EP0278809B1 (en) * | 1987-01-19 | 1992-03-25 | Parfums Rochas | Cosmetic or dermatologic compositions containing a silybum marianum fruit extract rich in sylimarin together with essential fatty acids |
-
1991
- 1991-01-16 DE DE4101122A patent/DE4101122A1/en not_active Withdrawn
-
1992
- 1992-01-15 EP EP92902119A patent/EP0567481A1/en not_active Withdrawn
- 1992-01-15 CA CA002099879A patent/CA2099879A1/en not_active Abandoned
- 1992-01-15 WO PCT/EP1992/000076 patent/WO1992012702A1/en not_active Application Discontinuation
- 1992-01-15 JP JP4502483A patent/JPH06504282A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| WO1992012702A1 (en) | 1992-08-06 |
| DE4101122A1 (en) | 1992-07-23 |
| JPH06504282A (en) | 1994-05-19 |
| EP0567481A1 (en) | 1993-11-03 |
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