CA1137873A - Composition of treatment of hyperpigmentary dermatoses and the like - Google Patents
Composition of treatment of hyperpigmentary dermatoses and the likeInfo
- Publication number
- CA1137873A CA1137873A CA000301093A CA301093A CA1137873A CA 1137873 A CA1137873 A CA 1137873A CA 000301093 A CA000301093 A CA 000301093A CA 301093 A CA301093 A CA 301093A CA 1137873 A CA1137873 A CA 1137873A
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- Prior art keywords
- acid
- composition
- composition according
- dicarboxylic acid
- azelaic
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
-
- 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
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/36—Carboxylic acids; Salts or anhydrides thereof
- A61K8/362—Polycarboxylic acids
-
- 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
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/36—Carboxylic acids; Salts or anhydrides thereof
- A61K8/368—Carboxylic acids; Salts or anhydrides thereof with carboxyl groups directly bound to carbon atoms of aromatic rings
-
- 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
- A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
-
- 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
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
-
- 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
- A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
Abstract
ABSTRACT/ABRIDGEMENT OF THE DISCLOSURE
This invention relates to compositions for the treatment of hyperpigmentary dermatoses or skin hyperpigmentation which contain dicarboxylic acids having 7 to 13 carbon atoms, contain deriva-tives thereof having a reducing functional group or pharmaceutically acceptable salts thereof. Also provided by the present invention are methods for preparing the mercapto derivatives of the dicarboxy-lic acids.
This invention relates to compositions for the treatment of hyperpigmentary dermatoses or skin hyperpigmentation which contain dicarboxylic acids having 7 to 13 carbon atoms, contain deriva-tives thereof having a reducing functional group or pharmaceutically acceptable salts thereof. Also provided by the present invention are methods for preparing the mercapto derivatives of the dicarboxy-lic acids.
Description
~3~373 This invention relates to compositions for the treatment and cure of hyperpigmentary dermatoses and the like.
Dermatoses, such as skin hyperpigmentations (which frequently produce a disfiguring effect, such as in the case or chloasma of the face), constitute a problem not only of an esthetic but also of a therapeutic nature, for which as yet no basic solution has been found. Only hydroquinone and its derivatives have up to now shown some effectiveness, in vivo, for the treatment of skin hyperpigmentations. However, they cause as a side effect, the development of long-lasting hypopigmented zones, which are at times irreducible.
The class of hyperpigmentary dermatoses includes, but with far more serious aspects and consequences, certain patho-logical conditions which fall under the generic name of precancerous dermatoses, namely, lentigo maligna which is other-wise known as precancerous melanosis of Dubreuilh, and cancerous dermatoses, namely, lentigo maligna melanoma, superficial spread-ing melanoma, and nodular melanoma (such as premalanomic conditions and melanomas). No effective remedies have been as yet found for these dermatoses either.
An object of the present invention is to provide com-positions which are useful for the above indicated purposes;
namely, capable of normalizing the color of skin affected by hyperpigmentation, as well as to arrest, and cause the regression of certain forms of precancerous and cancerous dermatoses.
Accordingly, one embodiment of this invention provides composition for the treatment of hyperpigmentary dermatoses or skin hyperpigmentations comprising as active ingredient a therapeutically effective amount of as least one dicarboxylic acid containing from 7 to 13 carbon atoms or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
~ - 3 -1~378~3 The invention, in another embodiment, resides in a mercapto derivative of a dicarboxylic acid selected from the group consisting of suberic, azelaic, sebacic; 1,9-nonanedicarboxylic; 1,10-decanedicarboxylic and l,ll-undecanedicar~oxylic acids.
~ 3a -11378~3 Another embodiment of this invention provides a method of treating hyperpigmentary dermatoses comprising the administration of a therapeutically effeetive amount of a composition comprsing a dicarboxylic acid having from 7 to 13 carbon atoms, a derivative thereof containing at least one redueing functional group in the molecule or a phar~aceutically acceptably salt thereof.
Specifically, the dicarboxylic acids employed in the eompositions of this invention are selected from the group eonsisting of pimelic, suberic, azelaic, sebacic, l,9-non-anedicarboxylic, l,10-decanedicarboxylic, and l,ll-undecane-dicarboxylic acids. The derivatives may be mono- or di-substituted with a reducing functional group. Pharmaceutically aeceptable salts include the sodium salts.
In a preferred embodiment of the invention, the composition eomprises a mercapto derivative of the dicarboxylic acid.
In a still further preferred embodiment, the dicarboxylic acid is azelaic acid.
The eompositions of this invention may be administered orally, by subeutaneous injeetion or topieal applieation as in the form of creams, ointments, unguents or lotions.
The eompositions of the present i~vention have been found in partieular capable of inhibiting the forma-tion of the skin pigment (melanin) by blocking the dopa-tyrosinase reaetion by a eompetitive type mechanism. The exaet mechanism of this action has not been definitely established. The applicant has, however, encountered a meehanism which may represent or be related to that exhibited by the active component of the composition.
~3~7;3 While these observations are presented to further the understanding of the invention, they are not to be considered a definitive explanation of the mechanism involved, nor are they to be considered in any way a limitation on the scope of the disclosed invention.
In studies on the behavior of a fungus, Pityrosporum orbiculare, which is the cause of a der-matosis which manifests itself by the appearance of achromic or whitish flecks or spots (Pitiriasi versi-colore) observations carried out in vitro and in vivo reasonably indicate that the fungus metabolizes the fatty acids normally present on the skin and necessary for sur-vival and diffusion and causes the formation of dicarboxy-lic acids which thereafter have an inhibiting effect on melano-genesis.
In this respect, it should be noted that from an examination of cultures of Pityrosporum orbiculare, to which technical oleic acid was added as lipid supplement after saponification there was also found the presence of pimelic, azelaic, and l,9-nonandicarboxylic (Cll) acids, identified by gas chromatography and mass spectrometry.
The C9 and Cll members of the series of dicarboxylic acids have shown, in vitro, a substantial anti-tyrosinase activity, which has also been encountered in dicarboxylic acids having 8, 10 and 12 carbon atoms.
This invention further relates to novel derivatives of dicarboxylic acids having from 7 to 13 carbon atoms and characterized by the fact that they contain at least one reducing group and their pharmaceutically acceptable salts.
1~1 3~7~73 These derivatives exhibit superior action in inhibiting the dopa-tyrosinase reaction over the 7 to 13 carbon atom dicarboxylic acids from which they are derived.
In a preferred embodiment of the dicarboxylic acid derivative, the reducing group is a mercapto group.
In a further preferred embodiment, the dicarboxy-lic acid derivatives contain two reducing groups, preferably both mercapto.
The invention, in another aspect, provides a process for producing mercapto substituted derivatives of dicarboxylic acids.
The process comprises brominating the dicarboxylic acid to introduce as many bromine atoms into the acid as are to be replaced by mercapto groups, reacting said bromo derivative with thiourea in a solvent to form the corres-ponding thiouronium salt and then saponifying the salt so formed to obtain the corresponding mercapto derivatives.
The bromination of the dicarboxylic acid may be accomplished by first reacting the dicarboxvlic acid with phosphorus pentachloride until the mixture is entirely melted then adding anhydrous bromine to the melt with agita-tion at a temperature maintained at 60-70C. The bromine derivative thus formed may then be isolated by conventional means.
In a preferred embodiment to produce the monomercapto derivatives of the dicarboxylic acids one mole of dicarboxylic acid is reacted with 50 grams o phosphorus pentachloride;
the reaction product is then reacted with 60 ml of anhydrous bromine, added in small portions over a period of about six hours to produce the monobromo derivative of the dicarboxylic acid. One mole of the monobromo derivative is then reacted with 50 ml of ethyl alcohol and 1.1 moles of thiourea to form the corresponding alkyl thiouronium salt which is then saponified to obtain the corresponding monomercapto derivative.
~137~373 In a preferred embodiment to produce the dimercapto substituted dicarboxylic acid derivatives one mole of acid is reacted with 50 grams of phosphorus pentachloride and 120 ml of anhydrous bromine is added to the resulting melt in small portions over a period of 18 hours while the temperature is maintai~ed at 90 to 100C. One mole of the resulting dibro-mide is then reacted with 2.2 moles of thiourea in 100 ml of ethyl alcohol to produce the corresponding alkyl thiouronium salt is then saponified to obtain the corresponding dimercapto derivatives.
The dicarboxylic acids, or their derivatives or pharmaceutically acceptable salts, thereof described above may be applied in a variety of pharmaceutically acceptable vehicles which would depend on the mode of treatment. Thus, for example, they may be used in the form of an injectable suspen-sion of the active material in saline solution. On the other han~, if they are intended for topical application, they may be applied in creams. Moreover, they may be given in orally administerable form. The quantity of active ingredient that ~0 will be contained in these compositions may vary somewhat. All that is required is that the dicarboxylic acids or their deriva-tives be present in therapeutically effective amounts.
The quantity of dicarboxylic acid or its derivatives or pharmaceutically acceptable salts thereof that will be con-tained in the compositions of this invention will vary depend-ing upon the dosage form and/or the condition treated. Thus, for example, when given orally they may comprise all or sub-stantially all of the dosage forms. On the other hand, when contained in a dosage form suitable for subcutaneous injection they may comprise between about 20~ to 30% by weight, and preferably about 25% by weight based on the total weight of the composition. In the _ase the composition takes the form of a cream or lotion suitable for topical application the dicarbox~lic acid or its derivative may consitute between about 10% to 20% by weight and preferably about 15% by weight based on the total weight of the composition.
It has also been found to be advantageous to in-clude a keratolytic agent in the compositions of this inven-tion. This is pa~ticularly the case when the compositions are intended to be applied to the skin. By way of example of the keratolytic agents that may be employed herein, mention may be made of salicylic acid, vitamin A acid, resorcinol, phenol, cresol, etc. The quantity of keratolytic agent that can advantageously be employed herein also varies.
Ordinarily, this will constitute from about 2~ to about 4%
by weight based on the total weight of the composition.
Considering the preparation of these derivatives more specifically, the examples which follow are intended to illustrate it, without consituting any undue limitation.
(a) Preparation of the Alpha-Monobromo Derivative:
1 mol of dicarboxylic acid (for instance, azelaic acid) is introduced into a 3 liter flask placed on a magnetic agitator provided with a heating plate, and 500 g of phosphorus pentachloride are added. After the reaction has taken place (complete melting), 60 ml of anhydrous bromine are added in small portions in the course of about 6 hours, with continuous agitation. The reaction temperature is maintained at 60 to 70C.
'73 A^~er ~he reacti~n is co.~plete~ it is cooled and thereupon about 500 ~1 of distilled water are cautiously added; it is then warmed on the magnetic agitator for about 30 minutes and cooled.
The low organic phase, for.~.ed of an oily liquid of dark yellow color, constitutes the crude monobromo derivative, which is distilled under vacu~.
(b) Preparation of the ~ercapto Derivative:
1 mol of alpha-~onobromo derivative is intro-duced, under a hood, into a 2 liter flask provided with condenser thereupon 50 ml of ethyl alcohol are added at 95C and 1.1 mol of thiourea. The mixture is brought to a boil for 6 hours, whereupon the alkyl thiouronium salt is separated out by cooling.
For the saponification of this salt, 500 ml of 5N NaOH are added to the mixture and it is boiled under reflux for an additional two hours. The reaction mixture, after being cooled, is acidified with 5N HCl andS after agitation for about 10 minutes, an oil~ la~er form3, which is removed, The aqueous layer is extracted 3 times with ethyl ether, and this ether extract is added to the oily layer whic~l was previously removed, w~ich was then dried over anhydrous Na2S04. After removal of the ether by distillation, the crude mercapto derivative is purified in a colu.~n containing silica gel.
For the preparation of dimercaQto derivatives, the procedure of the preced~ng Example is repeated with the following differences:
1. The cibromo derivative of the dicarbox~lic acid is prepared in the same manner as the monobro.~o deriv~-tive, but doubling the amount of bromine added and tripling the reaction times; the reaction temperature is maintained at 90 io 100C.
~L~.3~73 ~ ri~lg the plase of preparation of tre mer-capto derivati~e, twice the quantities of alcohol, thiourea, and soda respectively are used for each mol of dibromide.
In order to evaluate the activity of the compo-sitions in accordance with the present invention, and there-t~ore of the respective active ingredients, pharmacol3gical studies were carried out as well as tests in vivo.
From the co.~bined lipid extracts (cellular and from the filtrate) o cultures of Pit~rosporum orbiculare (strain 4709) grown f2r 20-30 days on a conventional syn-t~.etic ~edium to which oleic acid was added, there was o~tained a saponifiable portion having substantial activity in inhibiting tyrosinase. Sub~ecting this portion to tnin layer chrornatography (TLC), a fraction was isolated, of Rf = 1.3, capable of inhibiting the dopa-tyrosinase reac~ion.
Analysis by gas chromatography and subsequent analysis by mass spectrometry have shown the presence in this fraction of a series of C5-Cg dicarboxylic acids with a quantitative predominance of pim.elic and azelaic acids.
From a comparative test using samples of pure acidsJ it has been possible to exclude any tyrosinase in~ib-iting activity on the part of glutaric acid (C5) while such activity becomes evident starting with the C7 member, and is a maximum for the Cg and Cll mem~ers.
In particular, enzymatic kinetics tests have shown that azelaic acid is a competitive inhibitor o~ tyrosinase with a Ki - 4.10-4~.
~XA~PIE 2 The in vivo applications of the compositions of the present invention are illustrated by the following experiments:
A crea~ having a base of azelaic acid (see Exa.mpl2s 3-5 below) was applied for 30 days to the dark spots on the following patients:
~ a) 20 patients suffering from chloasma (b) 3 patients suffering from poikiloderma of Civatte (c) 1 patient suffering from circumscribed precancer-ous melanosis of Dubreuilh (malignant freckle).
1~37~3 All the patients, at the end of the treatment, showed a clear lightening of the hyperpigmented zones, and in most cases, there was obtained an apparently complete cure without collateral effects. After five months of observation, none of the patients treated showed any traces of leukoderma.
It will not escape attention that precancerous circumscribed melanosis falls within the category of pre-cancerous dermatoses. It is of fundamental importance that in this patient there was obtained not only a clinical cure but also a histological cure.
Examples 3 through 5 below are exemplary of cream compositions that are used in the procedure described in Example 2 above.
% by Wt.
Azelaic acid 15.0 Chlorocresol 0.1 Titanium dioxide 1.0 SaLicy:Lic acid 2.0 Glycerol monostearate 2.0 Cetyl alcohol 3.0 "Tween 80"* 5.0 Sodium laurylether-sulfate 10.0 Ethanolamine lauryl-ether sulfate 1.0 Olive oil 2.0 Vitamin C 1.0 Distilled water to 100%
EXA~PLE 4 Same as Example 3, except salicylic acid is used at a 3% level.
*Trademark for polyoxyethylene ~20) sorbitan monooleate; it iS a nonionic surfactant.
1~3~
.
Same as Example 3, except that salicylic acid is used at a 4% level.
EXAMPLE_6 With regard to the treatment of melanoma, experi-ments have been carried out on laboratory animals in the following manner.
Samples of Harding-Passey melanoma were taken from infected rats and grafted in small pieces in the subcutaneous tissue of the left side of Balb's C. rats. The animals had been divided into two groups of 30 rats each, one of which was treated daily introperitoneally by injecting a saline suspension containing 2 mg of alpha-mercapto azelaic acid.
The control animals were treated by injecting 0.1 ml of 0.9% saline solution. The treatment was continued until the death of the controls, histological studies then being carried out both of the melanoma of the animals treated and that of the control animals.
The preliminary conclusions which can be drawn from these experimentS are as follows:
(a) the means survival of the animals treated with the suspension containing said azelaic acid is lengthened;
(b) a substantial initial delay is noted in the development of the melanoma in the treated animals;
(c) in some of the treated animals, the melanoma is considerably reduced in size and extent;
(d) in other treated animals, instead of the tumor, ~he~e is noted the formation of a black crust or else the lack of appearance of the melanoma; and (e) finally, the presence of extensive necrotic zones are ~ound, by histological examination, in the animals treated.
11.~7B~3 Human volunteers affected with Malignant Melanoma were treated orally with pure azelaic acid.
The azelaic acid was given by mouth at a daily dose level of 10 grains for a period of one month with very good tolerability.
The following composition is suitable for use for subcutaneous injection of alphamercapto azelaic acid:
Alpha-monomercapto-azelaic acid 2 mg "Tween 80"* 5 mg Vitamin C 1 mg To further test the inhibitory effect of azelaic or dodecandioic acid or their corresponding sodium salts our Harding-Passey melanoma when administered intraperiton-eally, subcutaneously or orally, the following experiments were carried out:
Balb's C albino rats transplanted with Harding-Passey melanoma were treated by intraperitoneal, subcutaneous, or oral routes with compositions containing azelaic acid (C-9) or dodecandioic acid (C-12) or their corresponding sodium salts. Treatment was started 24 hours after the animals were inoculated with the melanoma. The control animals were given daily intraperitoneal or subcutaneous injection of 120 ml of a saline solution containing 1 mg Vitamin C
and 2.5 mg of "Tween 80".
Each test animal was treated in one of the following fashions indicated below:
(a) Cgintraperitoneal (1): Daily intraperit-oneal injection of 120 ml of saline containing 1 mg of azelaic acid dissolved in 5 mg of its dimethylesters, *Trademark ~3~
1 mg Vitamin C and 2.5 mg. "Tween 80".
(b) Cgsubcutaneous (1): Daily subcutaneous injection of the composition given in (a) above.
(c) C12subcutaneous (1): Daily subcutaneous injection of 120 ul of saline containing 1 mg dodecandioic acid dissolved in 5 mg. of its dimethylesters, 1 mg.
Vitamin C and 2.5 mg "Tween 80".
Cg per os:
Oral administration, ad libitum, of an aqueous solution containing 20 mg. of the sodium salt of azelaic acid and 1 mg. of Vitamin C per cc of water.
C10per os:
Oral administration, ad libitum, of an aqueous solution containing 20 mg. of the sodium salt of dodecan-dioic acid and 1 mg. of Vitamin C per cc of water.
The results of this study are summarized in Table I below. This indicates that intraperitoneal, subcutaneous or oral administration of azelaic acid, dodecandioic acid or their sodium salts to albino mice with transplanted Harding Passey mealanomas resulted in significant retardation of the tumor growth.
1~l37~3 ~ ~ ~ ~ a e E E e E
o ~ ~ I E E E E E
roQ~ . O ~ OO O O
E E
C 3 ~
C ~;~ L~ N_~ NN C~l N
O ~
'O O
ac~ Qc~~ C~ ~ O _i , a~ 0 o o ~ o ~ ;~ k ~ N ~ ~ ~ _~_ Q~ ~15 , ~E m C E E
o ,1 a) u~ _, C _, ~o Q ~ N O ~
_I m o _ ; ~
~; Z o ~ C~
V C
m ~ O ~ ~ Ç~ EG-- ~E ~ ~
~:1 C ~ O Q~ ~ Lf~ ~ C
O bD E E ,1 ~,1 ~ ) ~ ~ ~D Id ~1 c ~ .~ l l l 'l l ' ~ c~
m' ~} ~ ~ N O NN C~J N
C O
~0 0 5~ ~ t~ ~ _~ O
c c ~ a~ In ~N ~ ~ ~ O
E ~ 0 Q O O ~ ~ N
o c 0 s.~ :~a~ ~ ~ 3 C ~ ~ ~ ~ N _I ,1 8~
E 0 ~ * * 3, G ~o x O
0 _I 0 * * ~ ,1 0 ~: N
m 5 ~ * *
Q ~ ~ C~ N ~ Q
H q I 0 o H 3~ 3 1::; Z
OD m o ~
E~ ~ ~m ~ bGD ;~
0c ~ s s ~ s ,~ .Ei ~ , o :~ 0 t~
~ 0 ,1 ,1,i ,1_I C~ N~ C
0 ~ o a, rlC ~ 0 ~ 4~
a~ ~ --~I E O E~ ~~
_I _ _ _~ c r~ O
o ~ og ~ ,~
t- u ~ ~ _I
C
O ~ O ^ _I: G ~ a~
0 ~ O ^ 0 ~ ~
~ ~ ~ 0 N C-- ,C ~1 0 0 --I ~D h --c 0 0 ~~n oq o 0 oo ~ ~ ~o ~ O
~: O ,1 0 --I :5 0 c~
O ~ ~ O c~,0 h ~ 1 0 o~
E t~ C) OID ' 5~ 0 E --I
C C) O --I O Q G;U ~y ~ O 1~ 3 ~ a~
C~ ! ~; _l ~ ~ O
4 a~ , C O -~
o ~ a~
~ _~ ~&00 0 0 ~5 ;~
E o O ~ u~L'~~\ ~ ~ C S.l Q
4 E O ~ ~ r~ ~~ ~1 E ~ cs _!--I H
0 :s r ~ R~ ~
:' 0 X G ~ O
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C C~ ~i ~ C ~ 0 & . ¢ci~c; ~ O ,. ..
r a * ~ _ C ~ H ~ *S~ O H C~.
1--; ~3 Z H H * * * _ ~
/
_ ,,5-_
Dermatoses, such as skin hyperpigmentations (which frequently produce a disfiguring effect, such as in the case or chloasma of the face), constitute a problem not only of an esthetic but also of a therapeutic nature, for which as yet no basic solution has been found. Only hydroquinone and its derivatives have up to now shown some effectiveness, in vivo, for the treatment of skin hyperpigmentations. However, they cause as a side effect, the development of long-lasting hypopigmented zones, which are at times irreducible.
The class of hyperpigmentary dermatoses includes, but with far more serious aspects and consequences, certain patho-logical conditions which fall under the generic name of precancerous dermatoses, namely, lentigo maligna which is other-wise known as precancerous melanosis of Dubreuilh, and cancerous dermatoses, namely, lentigo maligna melanoma, superficial spread-ing melanoma, and nodular melanoma (such as premalanomic conditions and melanomas). No effective remedies have been as yet found for these dermatoses either.
An object of the present invention is to provide com-positions which are useful for the above indicated purposes;
namely, capable of normalizing the color of skin affected by hyperpigmentation, as well as to arrest, and cause the regression of certain forms of precancerous and cancerous dermatoses.
Accordingly, one embodiment of this invention provides composition for the treatment of hyperpigmentary dermatoses or skin hyperpigmentations comprising as active ingredient a therapeutically effective amount of as least one dicarboxylic acid containing from 7 to 13 carbon atoms or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
~ - 3 -1~378~3 The invention, in another embodiment, resides in a mercapto derivative of a dicarboxylic acid selected from the group consisting of suberic, azelaic, sebacic; 1,9-nonanedicarboxylic; 1,10-decanedicarboxylic and l,ll-undecanedicar~oxylic acids.
~ 3a -11378~3 Another embodiment of this invention provides a method of treating hyperpigmentary dermatoses comprising the administration of a therapeutically effeetive amount of a composition comprsing a dicarboxylic acid having from 7 to 13 carbon atoms, a derivative thereof containing at least one redueing functional group in the molecule or a phar~aceutically acceptably salt thereof.
Specifically, the dicarboxylic acids employed in the eompositions of this invention are selected from the group eonsisting of pimelic, suberic, azelaic, sebacic, l,9-non-anedicarboxylic, l,10-decanedicarboxylic, and l,ll-undecane-dicarboxylic acids. The derivatives may be mono- or di-substituted with a reducing functional group. Pharmaceutically aeceptable salts include the sodium salts.
In a preferred embodiment of the invention, the composition eomprises a mercapto derivative of the dicarboxylic acid.
In a still further preferred embodiment, the dicarboxylic acid is azelaic acid.
The eompositions of this invention may be administered orally, by subeutaneous injeetion or topieal applieation as in the form of creams, ointments, unguents or lotions.
The eompositions of the present i~vention have been found in partieular capable of inhibiting the forma-tion of the skin pigment (melanin) by blocking the dopa-tyrosinase reaetion by a eompetitive type mechanism. The exaet mechanism of this action has not been definitely established. The applicant has, however, encountered a meehanism which may represent or be related to that exhibited by the active component of the composition.
~3~7;3 While these observations are presented to further the understanding of the invention, they are not to be considered a definitive explanation of the mechanism involved, nor are they to be considered in any way a limitation on the scope of the disclosed invention.
In studies on the behavior of a fungus, Pityrosporum orbiculare, which is the cause of a der-matosis which manifests itself by the appearance of achromic or whitish flecks or spots (Pitiriasi versi-colore) observations carried out in vitro and in vivo reasonably indicate that the fungus metabolizes the fatty acids normally present on the skin and necessary for sur-vival and diffusion and causes the formation of dicarboxy-lic acids which thereafter have an inhibiting effect on melano-genesis.
In this respect, it should be noted that from an examination of cultures of Pityrosporum orbiculare, to which technical oleic acid was added as lipid supplement after saponification there was also found the presence of pimelic, azelaic, and l,9-nonandicarboxylic (Cll) acids, identified by gas chromatography and mass spectrometry.
The C9 and Cll members of the series of dicarboxylic acids have shown, in vitro, a substantial anti-tyrosinase activity, which has also been encountered in dicarboxylic acids having 8, 10 and 12 carbon atoms.
This invention further relates to novel derivatives of dicarboxylic acids having from 7 to 13 carbon atoms and characterized by the fact that they contain at least one reducing group and their pharmaceutically acceptable salts.
1~1 3~7~73 These derivatives exhibit superior action in inhibiting the dopa-tyrosinase reaction over the 7 to 13 carbon atom dicarboxylic acids from which they are derived.
In a preferred embodiment of the dicarboxylic acid derivative, the reducing group is a mercapto group.
In a further preferred embodiment, the dicarboxy-lic acid derivatives contain two reducing groups, preferably both mercapto.
The invention, in another aspect, provides a process for producing mercapto substituted derivatives of dicarboxylic acids.
The process comprises brominating the dicarboxylic acid to introduce as many bromine atoms into the acid as are to be replaced by mercapto groups, reacting said bromo derivative with thiourea in a solvent to form the corres-ponding thiouronium salt and then saponifying the salt so formed to obtain the corresponding mercapto derivatives.
The bromination of the dicarboxylic acid may be accomplished by first reacting the dicarboxvlic acid with phosphorus pentachloride until the mixture is entirely melted then adding anhydrous bromine to the melt with agita-tion at a temperature maintained at 60-70C. The bromine derivative thus formed may then be isolated by conventional means.
In a preferred embodiment to produce the monomercapto derivatives of the dicarboxylic acids one mole of dicarboxylic acid is reacted with 50 grams o phosphorus pentachloride;
the reaction product is then reacted with 60 ml of anhydrous bromine, added in small portions over a period of about six hours to produce the monobromo derivative of the dicarboxylic acid. One mole of the monobromo derivative is then reacted with 50 ml of ethyl alcohol and 1.1 moles of thiourea to form the corresponding alkyl thiouronium salt which is then saponified to obtain the corresponding monomercapto derivative.
~137~373 In a preferred embodiment to produce the dimercapto substituted dicarboxylic acid derivatives one mole of acid is reacted with 50 grams of phosphorus pentachloride and 120 ml of anhydrous bromine is added to the resulting melt in small portions over a period of 18 hours while the temperature is maintai~ed at 90 to 100C. One mole of the resulting dibro-mide is then reacted with 2.2 moles of thiourea in 100 ml of ethyl alcohol to produce the corresponding alkyl thiouronium salt is then saponified to obtain the corresponding dimercapto derivatives.
The dicarboxylic acids, or their derivatives or pharmaceutically acceptable salts, thereof described above may be applied in a variety of pharmaceutically acceptable vehicles which would depend on the mode of treatment. Thus, for example, they may be used in the form of an injectable suspen-sion of the active material in saline solution. On the other han~, if they are intended for topical application, they may be applied in creams. Moreover, they may be given in orally administerable form. The quantity of active ingredient that ~0 will be contained in these compositions may vary somewhat. All that is required is that the dicarboxylic acids or their deriva-tives be present in therapeutically effective amounts.
The quantity of dicarboxylic acid or its derivatives or pharmaceutically acceptable salts thereof that will be con-tained in the compositions of this invention will vary depend-ing upon the dosage form and/or the condition treated. Thus, for example, when given orally they may comprise all or sub-stantially all of the dosage forms. On the other hand, when contained in a dosage form suitable for subcutaneous injection they may comprise between about 20~ to 30% by weight, and preferably about 25% by weight based on the total weight of the composition. In the _ase the composition takes the form of a cream or lotion suitable for topical application the dicarbox~lic acid or its derivative may consitute between about 10% to 20% by weight and preferably about 15% by weight based on the total weight of the composition.
It has also been found to be advantageous to in-clude a keratolytic agent in the compositions of this inven-tion. This is pa~ticularly the case when the compositions are intended to be applied to the skin. By way of example of the keratolytic agents that may be employed herein, mention may be made of salicylic acid, vitamin A acid, resorcinol, phenol, cresol, etc. The quantity of keratolytic agent that can advantageously be employed herein also varies.
Ordinarily, this will constitute from about 2~ to about 4%
by weight based on the total weight of the composition.
Considering the preparation of these derivatives more specifically, the examples which follow are intended to illustrate it, without consituting any undue limitation.
(a) Preparation of the Alpha-Monobromo Derivative:
1 mol of dicarboxylic acid (for instance, azelaic acid) is introduced into a 3 liter flask placed on a magnetic agitator provided with a heating plate, and 500 g of phosphorus pentachloride are added. After the reaction has taken place (complete melting), 60 ml of anhydrous bromine are added in small portions in the course of about 6 hours, with continuous agitation. The reaction temperature is maintained at 60 to 70C.
'73 A^~er ~he reacti~n is co.~plete~ it is cooled and thereupon about 500 ~1 of distilled water are cautiously added; it is then warmed on the magnetic agitator for about 30 minutes and cooled.
The low organic phase, for.~.ed of an oily liquid of dark yellow color, constitutes the crude monobromo derivative, which is distilled under vacu~.
(b) Preparation of the ~ercapto Derivative:
1 mol of alpha-~onobromo derivative is intro-duced, under a hood, into a 2 liter flask provided with condenser thereupon 50 ml of ethyl alcohol are added at 95C and 1.1 mol of thiourea. The mixture is brought to a boil for 6 hours, whereupon the alkyl thiouronium salt is separated out by cooling.
For the saponification of this salt, 500 ml of 5N NaOH are added to the mixture and it is boiled under reflux for an additional two hours. The reaction mixture, after being cooled, is acidified with 5N HCl andS after agitation for about 10 minutes, an oil~ la~er form3, which is removed, The aqueous layer is extracted 3 times with ethyl ether, and this ether extract is added to the oily layer whic~l was previously removed, w~ich was then dried over anhydrous Na2S04. After removal of the ether by distillation, the crude mercapto derivative is purified in a colu.~n containing silica gel.
For the preparation of dimercaQto derivatives, the procedure of the preced~ng Example is repeated with the following differences:
1. The cibromo derivative of the dicarbox~lic acid is prepared in the same manner as the monobro.~o deriv~-tive, but doubling the amount of bromine added and tripling the reaction times; the reaction temperature is maintained at 90 io 100C.
~L~.3~73 ~ ri~lg the plase of preparation of tre mer-capto derivati~e, twice the quantities of alcohol, thiourea, and soda respectively are used for each mol of dibromide.
In order to evaluate the activity of the compo-sitions in accordance with the present invention, and there-t~ore of the respective active ingredients, pharmacol3gical studies were carried out as well as tests in vivo.
From the co.~bined lipid extracts (cellular and from the filtrate) o cultures of Pit~rosporum orbiculare (strain 4709) grown f2r 20-30 days on a conventional syn-t~.etic ~edium to which oleic acid was added, there was o~tained a saponifiable portion having substantial activity in inhibiting tyrosinase. Sub~ecting this portion to tnin layer chrornatography (TLC), a fraction was isolated, of Rf = 1.3, capable of inhibiting the dopa-tyrosinase reac~ion.
Analysis by gas chromatography and subsequent analysis by mass spectrometry have shown the presence in this fraction of a series of C5-Cg dicarboxylic acids with a quantitative predominance of pim.elic and azelaic acids.
From a comparative test using samples of pure acidsJ it has been possible to exclude any tyrosinase in~ib-iting activity on the part of glutaric acid (C5) while such activity becomes evident starting with the C7 member, and is a maximum for the Cg and Cll mem~ers.
In particular, enzymatic kinetics tests have shown that azelaic acid is a competitive inhibitor o~ tyrosinase with a Ki - 4.10-4~.
~XA~PIE 2 The in vivo applications of the compositions of the present invention are illustrated by the following experiments:
A crea~ having a base of azelaic acid (see Exa.mpl2s 3-5 below) was applied for 30 days to the dark spots on the following patients:
~ a) 20 patients suffering from chloasma (b) 3 patients suffering from poikiloderma of Civatte (c) 1 patient suffering from circumscribed precancer-ous melanosis of Dubreuilh (malignant freckle).
1~37~3 All the patients, at the end of the treatment, showed a clear lightening of the hyperpigmented zones, and in most cases, there was obtained an apparently complete cure without collateral effects. After five months of observation, none of the patients treated showed any traces of leukoderma.
It will not escape attention that precancerous circumscribed melanosis falls within the category of pre-cancerous dermatoses. It is of fundamental importance that in this patient there was obtained not only a clinical cure but also a histological cure.
Examples 3 through 5 below are exemplary of cream compositions that are used in the procedure described in Example 2 above.
% by Wt.
Azelaic acid 15.0 Chlorocresol 0.1 Titanium dioxide 1.0 SaLicy:Lic acid 2.0 Glycerol monostearate 2.0 Cetyl alcohol 3.0 "Tween 80"* 5.0 Sodium laurylether-sulfate 10.0 Ethanolamine lauryl-ether sulfate 1.0 Olive oil 2.0 Vitamin C 1.0 Distilled water to 100%
EXA~PLE 4 Same as Example 3, except salicylic acid is used at a 3% level.
*Trademark for polyoxyethylene ~20) sorbitan monooleate; it iS a nonionic surfactant.
1~3~
.
Same as Example 3, except that salicylic acid is used at a 4% level.
EXAMPLE_6 With regard to the treatment of melanoma, experi-ments have been carried out on laboratory animals in the following manner.
Samples of Harding-Passey melanoma were taken from infected rats and grafted in small pieces in the subcutaneous tissue of the left side of Balb's C. rats. The animals had been divided into two groups of 30 rats each, one of which was treated daily introperitoneally by injecting a saline suspension containing 2 mg of alpha-mercapto azelaic acid.
The control animals were treated by injecting 0.1 ml of 0.9% saline solution. The treatment was continued until the death of the controls, histological studies then being carried out both of the melanoma of the animals treated and that of the control animals.
The preliminary conclusions which can be drawn from these experimentS are as follows:
(a) the means survival of the animals treated with the suspension containing said azelaic acid is lengthened;
(b) a substantial initial delay is noted in the development of the melanoma in the treated animals;
(c) in some of the treated animals, the melanoma is considerably reduced in size and extent;
(d) in other treated animals, instead of the tumor, ~he~e is noted the formation of a black crust or else the lack of appearance of the melanoma; and (e) finally, the presence of extensive necrotic zones are ~ound, by histological examination, in the animals treated.
11.~7B~3 Human volunteers affected with Malignant Melanoma were treated orally with pure azelaic acid.
The azelaic acid was given by mouth at a daily dose level of 10 grains for a period of one month with very good tolerability.
The following composition is suitable for use for subcutaneous injection of alphamercapto azelaic acid:
Alpha-monomercapto-azelaic acid 2 mg "Tween 80"* 5 mg Vitamin C 1 mg To further test the inhibitory effect of azelaic or dodecandioic acid or their corresponding sodium salts our Harding-Passey melanoma when administered intraperiton-eally, subcutaneously or orally, the following experiments were carried out:
Balb's C albino rats transplanted with Harding-Passey melanoma were treated by intraperitoneal, subcutaneous, or oral routes with compositions containing azelaic acid (C-9) or dodecandioic acid (C-12) or their corresponding sodium salts. Treatment was started 24 hours after the animals were inoculated with the melanoma. The control animals were given daily intraperitoneal or subcutaneous injection of 120 ml of a saline solution containing 1 mg Vitamin C
and 2.5 mg of "Tween 80".
Each test animal was treated in one of the following fashions indicated below:
(a) Cgintraperitoneal (1): Daily intraperit-oneal injection of 120 ml of saline containing 1 mg of azelaic acid dissolved in 5 mg of its dimethylesters, *Trademark ~3~
1 mg Vitamin C and 2.5 mg. "Tween 80".
(b) Cgsubcutaneous (1): Daily subcutaneous injection of the composition given in (a) above.
(c) C12subcutaneous (1): Daily subcutaneous injection of 120 ul of saline containing 1 mg dodecandioic acid dissolved in 5 mg. of its dimethylesters, 1 mg.
Vitamin C and 2.5 mg "Tween 80".
Cg per os:
Oral administration, ad libitum, of an aqueous solution containing 20 mg. of the sodium salt of azelaic acid and 1 mg. of Vitamin C per cc of water.
C10per os:
Oral administration, ad libitum, of an aqueous solution containing 20 mg. of the sodium salt of dodecan-dioic acid and 1 mg. of Vitamin C per cc of water.
The results of this study are summarized in Table I below. This indicates that intraperitoneal, subcutaneous or oral administration of azelaic acid, dodecandioic acid or their sodium salts to albino mice with transplanted Harding Passey mealanomas resulted in significant retardation of the tumor growth.
1~l37~3 ~ ~ ~ ~ a e E E e E
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r a * ~ _ C ~ H ~ *S~ O H C~.
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/
_ ,,5-_
Claims (10)
1. A composition for the treatment of hyperpigmentary dermatoses or skin hyperpigmentations comprising as the active ingredient a therapeutically effective amount of at least one dicarboxylic acid selected from the group consisting of pimelic, suberic, azelaic, sebacic, 1,9-nonanedicarboxylic, 1,10-decanedicarboxylic, and 1,11-undecanedicarboxylic acids, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; said composition being either in a form suitable for oral administration or in the form of a cream, ointment, unguent or lotion suitable for topical application.
2. A composition according to claim 1 including a keratolytic agent.
3. A composition according to claim 2 in which said keratolytic agent is salicylic acid.
4. A composition according to claim 1 in orally administerable form.
5. A composition according to claim 1 or claim 2 wherein the dicarboxylic acid is azelaic acid.
6. A composition according to claim 1 or claim 2 wherein the dicarboxylic acid is 1,10-decanedicarboxylic acid.
7. A composition according to claim 1 which is in the form of a cream or lotion suitable for topical application, said dicarboxylic acid being present in an amount ranging from about 10% to about 20% by weight of the composition.
8. A composition according to claim 7 wherein the dicarboxylic acid is present in an amount of about 15% by weight of the composition.
9. A composition according to claim 7 or claim 8 wherein the dicarboxylic acid is azelaic acid.
10. A composition in accordance with claim 7 which has the following formulation:
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT22617/77A IT1075741B (en) | 1977-04-19 | 1977-04-19 | COMPOSITION FOR THE TREATMENT OF HYPERPIGMENTARY DERMATOSIS |
| IT22617-A/77 | 1977-04-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1137873A true CA1137873A (en) | 1982-12-21 |
Family
ID=11198481
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000301093A Expired CA1137873A (en) | 1977-04-19 | 1978-04-13 | Composition of treatment of hyperpigmentary dermatoses and the like |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPS53130433A (en) |
| AU (1) | AU524602B2 (en) |
| BE (1) | BE866151A (en) |
| CA (1) | CA1137873A (en) |
| CH (1) | CH638099A5 (en) |
| DE (1) | DE2817133A1 (en) |
| GB (1) | GB1603563A (en) |
| IT (1) | IT1075741B (en) |
| ZA (1) | ZA782125B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8302683D0 (en) * | 1983-02-01 | 1983-03-02 | Unilever Plc | Skin treatment composition |
| JPS61130205A (en) * | 1984-11-30 | 1986-06-18 | Sunstar Inc | Aqueous composition containing stabilized ascorbic acid |
| US4713394A (en) * | 1986-01-17 | 1987-12-15 | Thornfeldt Carl R | Treatment of nonacne inflammatory and infectious dermatoses and hair loss |
| JP2565513B2 (en) * | 1987-09-25 | 1996-12-18 | 三省製薬株式会社 | Topical drug for suppressing melanin production |
| EP0345081A3 (en) * | 1988-06-02 | 1990-03-28 | Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo | Enzyme formation suppressing agent |
| KR910000101A (en) * | 1988-06-02 | 1991-01-29 | 유다까 미시마 | Enzyme inhibitor |
| DE10039783A1 (en) * | 2000-08-16 | 2002-02-28 | Cognis Deutschland Gmbh | Cosmetic preparations |
| ITMI20041567A1 (en) * | 2004-07-30 | 2004-10-30 | Maycos Italiana Di Comini Miro | "N-ACYLATED DERIVATIVES OF BICARBOXYLIC ACIDS WITH AMINO ACIDS AND WITH HYDROLYZED VEGETABLE PROTEINS AND THEIR APPLICATION IN COSMETIC, DERMO-PHARMACEUTICAL AND PHARMACEUTICAL PRODUCTS" |
| DE102006004804A1 (en) | 2006-01-23 | 2007-07-26 | Intendis Gmbh | Use of alpha, omega-N-alkanedicarboxylic acid and retinoid for producing rosacea treatment preparation |
| IL181577A0 (en) * | 2007-02-26 | 2007-07-04 | Jacob Bar Tana | Combination therapy composition and methods for the treatment of cardiovascular disorders and immune-related disorders |
| DE102010021671A1 (en) | 2010-05-27 | 2011-12-01 | Intendis Gmbh | Azelaic acid-containing formulation with added pigment |
| JP2013170158A (en) * | 2012-02-22 | 2013-09-02 | Kao Corp | Oral ultraviolet light resistance improver |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2878237A (en) * | 1955-06-15 | 1959-03-17 | American Cyanamid Co | Mercapto dibasic acids as regulators for the polymerization of acrylic acids, amidesand salts |
-
1977
- 1977-04-19 IT IT22617/77A patent/IT1075741B/en active
-
1978
- 1978-01-01 CH CH690677A patent/CH638099A5/en not_active IP Right Cessation
- 1978-04-12 AU AU35027/78A patent/AU524602B2/en not_active Expired
- 1978-04-13 ZA ZA00782125A patent/ZA782125B/en unknown
- 1978-04-13 CA CA000301093A patent/CA1137873A/en not_active Expired
- 1978-04-14 JP JP4340978A patent/JPS53130433A/en active Granted
- 1978-04-18 GB GB15187/78A patent/GB1603563A/en not_active Expired
- 1978-04-19 BE BE186928A patent/BE866151A/en not_active IP Right Cessation
- 1978-04-19 DE DE19782817133 patent/DE2817133A1/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS53130433A (en) | 1978-11-14 |
| CH638099A5 (en) | 1983-09-15 |
| AU3502778A (en) | 1979-10-18 |
| GB1603563A (en) | 1981-11-25 |
| ZA782125B (en) | 1979-03-28 |
| JPS631287B2 (en) | 1988-01-12 |
| IT1075741B (en) | 1985-04-22 |
| DE2817133A1 (en) | 1978-11-02 |
| BE866151A (en) | 1978-10-19 |
| AU524602B2 (en) | 1982-09-23 |
| DE2817133C2 (en) | 1988-08-11 |
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