CA2114225A1 - Use of a tocopherol phosphate or one of its derivatives, for the preparation of cosmetic or pharmaceutical compositions and compositions so obtained - Google Patents
Use of a tocopherol phosphate or one of its derivatives, for the preparation of cosmetic or pharmaceutical compositions and compositions so obtainedInfo
- Publication number
- CA2114225A1 CA2114225A1 CA002114225A CA2114225A CA2114225A1 CA 2114225 A1 CA2114225 A1 CA 2114225A1 CA 002114225 A CA002114225 A CA 002114225A CA 2114225 A CA2114225 A CA 2114225A CA 2114225 A1 CA2114225 A1 CA 2114225A1
- Authority
- CA
- Canada
- Prior art keywords
- tocopherol
- radical
- salt
- formula
- methyl
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
- C07F9/65522—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring condensed with carbocyclic rings or carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
-
- 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
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q1/00—Make-up preparations; Body powders; Preparations for removing make-up
- A61Q1/02—Preparations containing skin colorants, e.g. pigments
-
- 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
-
- 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
- A61Q19/002—Aftershave preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/74—Biological properties of particular ingredients
- A61K2800/75—Anti-irritant
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/74—Biological properties of particular ingredients
- A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
- A61K2800/782—Enzyme inhibitors; Enzyme antagonists
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
- Y10T428/2984—Microcapsule with fluid core [includes liposome]
Abstract
ABSTRACT OF THE DISCLOSURE
The present invention relates to the use of a tocopherol phosphate, other than alpha-tocopherol phosphate, especially in its dl or d form, or one of its esters having general formula (I):
(I) in which:
R' is hydrogen atom, an alkyl radical having from 1 to 4 carbon atoms, such as the methyl or ethyl radical in particular, R'O is a tocopheryl radical; R" is a hydrogen atom, an alkyl radical having from 1 to 4 carbon atoms, such as the methyl or ethyl radical in particular, or R"O is an oxyethylene chain, of formula in which R4 and R5 are independently a hydrogen atom or a methyl radical, and n is an integer of 1 or over;
R1, R2 and R3 are independently a hydrogen atom or a methyl radical, it being understood that R1, R2 and R3 cannot simultaneously be a methyl radical.
A represents the groups: or
The present invention relates to the use of a tocopherol phosphate, other than alpha-tocopherol phosphate, especially in its dl or d form, or one of its esters having general formula (I):
(I) in which:
R' is hydrogen atom, an alkyl radical having from 1 to 4 carbon atoms, such as the methyl or ethyl radical in particular, R'O is a tocopheryl radical; R" is a hydrogen atom, an alkyl radical having from 1 to 4 carbon atoms, such as the methyl or ethyl radical in particular, or R"O is an oxyethylene chain, of formula in which R4 and R5 are independently a hydrogen atom or a methyl radical, and n is an integer of 1 or over;
R1, R2 and R3 are independently a hydrogen atom or a methyl radical, it being understood that R1, R2 and R3 cannot simultaneously be a methyl radical.
A represents the groups: or
Description
. :
Use of a tocopherol phosphate or one of its deriva-tives, for the preparation of cosmetic or pharmaceuti-cal compositions and compositions so obtained The present invention relates in general terms os to the use of a tocopherol phosphate or an ester or salt thereof for the preparation of cosmetic or pharma-ceutical compositions, especially dermatological compo-sitions, having an anti-allergic or anti-inflammatory activity or intend~d for the prevention or treatment of the harmful effects of free radicals, and to the cosmetic or pharmaceutical compositions, especially dermatological compositions, having an anti-allergic or anti-inflammatory activity or intended for the preven-tion or treatment of the harmful effects of free radicals, in which said compound is incorporated.
-- Vitamin E is known especially by the common name alpha-tocopherol (see Merck Index, 11th edition, reference 9832, page ~1437). `
alpha-Tocopherol is found in the natural state in a large number of plants, usually together with other compounds such as beta-tocopherolj gamma-toco~
phero} or delta-tocopherol. `.
It is also known that tocopherols occur in both the dl and d forms.
alpha-Tocopherol is essentially used for com~
bating vitamin E deficiencies or as a nutritional factor, especially for combating muscular degensration.
It is also used as an antioxidant, but at very ~ --specific doses.
~-Tocopherol esters, in particular the succi-nate, nicotinate or acetate, have also been described (Merck Index, lOth~edition, references 9832l 9833, page 1437). The~synthesis of alpha-tocopherol acetate is also described in~the document US-A-2 723 278 and the s synthesis of other esters is described in the document .
,~
. Amer. Chem. Soc. (1943) 65, 918-924.
dl-alpha-Tocopherol phosphate is also known (see P. KARRER et al., Helv. Chim. Acta (1940) 23, 1137-8), as is its action on muscle metabolism (see J.
05 Biol. Chem. 1942, 146, pages 309-321). Another docu-ment describes its biological role as an antioxidant on brain tissue (Biol. Antioxidants Trans., 1st Conf., 1946, pages 61-62). Its anticoagulant effect by acting on the polymerization of fibrin has al50 been described (Can. J. Biochem. and Physiol. 1959, 37, pages 501-505). Its in vitro antimicrobial action on B. subtilis and S. aureus has also been described (Naturwissen-schaften 1960, 47, page 17).
It has now been discovered, totally surpri-singly and unexpectedly, that tocopherol phosphates -~ other than alpha-tocopherol phosphate, especially in their dl or d form, or of an ester or salt thereof possess an anti-ailergic, anti-inflammatoxy and anti-free-radical activity, enabling them ~ to be used advantageously for the preparation of cosmetic ;or pharmaceutical compositions, especially dexmatological compositions, having a reduced allergizing or irrita~
ting potential or intended~ for the prevention or treatment of~ allergic or anti-inflammatorv~mànifesta~
tions, or else for the prevention or treatmènt of the ; harmful effeats of ~ree radicals.
The object~o~ the present invention is thus~to solve the new technical problem which consi~ts in the ~ provision of an~active substance having~ a~good~ant ; 30 allergic activity, especially for the prevention~or~
treatment of skin~allergy or bronchial asthma,~or~ a good anti-inflammatory activityl or else a preventive or curative activity towards the harmful effects~o~
free radicals, in particular by topical or general 3s administration, there~y constituting a valuable active . ' ~' ingredient for the preparation of cosmetic or pharma-ceutical compositions, especially dermatological com-positions.
The present invention solves this new technical 05 problem in a satisfactory manner by means of a particu-larly simple solution which can be used on the indus-trial scale.
Thus, according to a first feature, the present invention covers the use of a tocopherol phosphate other than alpha-tocopherol phosphate, especially in its dl or:d form, or of an ester thereof, of general formula (I) below~
R2 ~ 8 R 0 ~ ~0 ~ P~ R
R"0 o in which~
R' is a hydrogen atom or an alkyl radical:;having from 1 to 4 carbon~atoms, suah as the`methyl or ethyl radical~
25 in particular,;or R~lo~ ~is a tocopheryl radic~al;~
R" is a hydrogen atom or an alkyl radical having from~
to 4 carbon:atoms~ such as the::methyl~:~or:ethyl~radical~
in particular, or R"O is an oxyethylenated chain of:the -(O-CH2-CH3~-oR5 in which R4 and R, independently are a hydrogen atom or :
a methyl radical and n is an integer greater than or equal to 1;
R1, R2 and R3 independently are a hydrogen atom or a methyl radical, it being understood that R~, R2 and R3 os cannot simultaneously be a methyl radical; and A is the group : ~::
: CH3 CIH3 . '':~
-CH2-CH- or -CH=C-, ~
: ~ 10 ", :~ :
or of a~cosmetically or pharmaceutically acceptable ~: .
salt thereof, for the preparation of a cosmetic or pharmaceutical composition, especially dermatological '~
15 composition, having a reduced allergizing or irritating .' __ potential or intended for the prevention or treatment of allergic manifestations such as skin allergy or bronchial asthma, or inflammatory manifestations, or .
for:the prevention~or treatment of the harmful e~fects . .
of free radicals.
In~the above~ formula, the pre~erred ;.compounds~
: ~ are tocol, be~a-tocopherol or 5,8-dimethyltocol, gamma- ': "~'~'' `'.-'' tocopherol or 7,~8-dimethyltocol, ~zeta-2-tocopherol ~or~
5,7-dimethyltocol,.~delta~tocophero'l or~ 8-methyltocol',~
eta-tocopherol~or ~7-methyltocol~,~tocotrlenol~l~ zeka-1-~
tocopherol: or'' 5,7,8-trimethyltocotrien-3',7',~ ol, : ::.~:':':::~':~.:
: epsilon-tocopherol :or~ 5,8-dimèthyltocotrien-3',~7',~
ol, yamma-tocotrienol and delta-~ocotrienol. .
In :one variant o~ the use according~to :~:the~
present ~invention~ e`'~x~ure~of:tocopherol(s)~ ~ sph~t~s,~
~ at least one~of'whi~ch; is ~other than ~alpha-toco~bro1 : phosphate,~or~of;~esters~or salts thereof~is::'us~d,~sald~
~- mixture being::obtained espec1ally~by:the~.phosphatiza-~
: tion of a:~mixture of tocopherols extracted~from a~plant~
such as soya.
~: :..
: ~:
~\ ~
The tocopherol phosphates can be manufactured by the well-known process for the manufacture of alpha-tocopherol phosphate. A process for the preparation of alpha-tocopherol phosphate and salts thereof is des-05 cribed in the document JP-A-37-1737 in the name of Tomoda Pharm. Manuf. Co. Limited, to which those skilled in the art may refer. ;
The products used according to the present invention will thus be tocopherol phosphates other than alpha-tocopherol phosphate, or esters thereof, it being possible for these products to take the ~orm of cos- :
metically or pharmaceutically acceptable salts, espe- ;~
cially dermatological acceptable salts, such as, for example, alkali metal salts, especially sodium salts 15 (monosodium or disodium salt), or alkaline earth metal ~2 -salts, especially magnesium salts, or else ammonium salts or salts of primary, secondary or tertiary amines such as diethylamine, diethanolamine, triethylamine or triethanolamine in pa~ticular.
In formula (I), the alkyl radicals can have a linear or branched chain. - -~
` An alkyl rad~cal having from 1 to 4 carbon atoms is for example methyl, ethyl, propyl, isopropyl or butyl, preferably methyl or ethyl.
Tocopheryl radical is understood as meaning~the radical of formula (II) below:
R2 ~ / ~ 3 ~ 1 J CH2-(CH2-A-CH2)3 H (II) -O \~ ~/
in which R1, R2 and R3 independently are a hydrogen atom or a methyl radical and A is the group ., -CH2-CH- or -CH=C-;
~ ~ ' when R"O is an oxyethylenated chain, n will generally be greater~than or equal to 1, for example between 2 and 50, preferably between 2 and 25 and in particular equal to 2 or 5.
In another advantageous embodiment according to the invention, a compound of formula I as defined above, preferably as a salt, is used in the form of small liposome-type vesicles obtained by the dispersion -- of said compound or said salt in water or an aqueous medium such as a buffer solution, especially by means of mechanical agitàtion followed by homogeni ation, for example by means of ultrasound or a homogenizer under ~ pressure.~
Preferably, the size of these vesicles ~is ad~usted to a value oP between about 6~10-2 ~m~and 2 ~m by modification of the homogenization parameters such ~:~
as the energy and duration.
~ ~ 25 In one advantageous variant~ oP the~previous~ --;~ embodiment,~the above-mentioned~aqu~eous~me~ium~contains~
a biologically active agent, sàid~agent~being at~least~
partially~encapsulated, after dispersion, in the above-mentioned vesicles~
~ The~above-mentioned active agent~ lS preferably~
; an anti-allergic ~substance such~ as an~ extract ~of ; ~Scutellaria, for example~a root extract of Scutellaria baicalensis Georgi described in the document F~-A-2 628 317, or an anti-inflammatory substance.
In one advantageous emhodiment of the use :.
J
`:
according to the invention, the concentration by weight of the above-mentioned compound of formula (I), of a salt thereof or of mixtures thereof is between 0.001 and 10%, preferably between 0.01% and 1% and particu-05 larly preferably between 0.05 and 0.5%, based on the total weight of the composition.
In a currently preferred embodiment, the above-mentioned compound of formula (I) is delta-tocopherol phosphate. The preferred salts are the monosodium salts and the disodium salt.
The compounds used according to the invention are generally available commercially and can be pre-pared especially by following procedures described in ~ ~-the literature, for example in Chem. Pharm. Bull.
(1971), 19, t4), pages 687 to 695; Khim.-Pharm. Zh.
-_ (1983), 17, (7), pages 840 to 844; Xhim.-Pharm. Zh.
(1985), 19, (1), pages 75 to 77; or else in the patents US-2 457 932 or JP`54-54 978.
The nomenalature of the tocopherols~ and~com~
pounds derived therefrom has been described in~Europ~-enne J. Biochem. (1982), 1~, 473-475. The preparation of delta-tocopherol has been described in J. ~m.~Chem.
Soc. (1947), 69, pages 869-874. Likewise, the prepaira-tion of natural alpha-, beta- and gamma-tocopherol and those esters which are of physiological value ha~s~been described in J. ~m. Chem. Soc. tl943), 65, pages 918-924. The document GB-A-900 085 desaribes~yet another process for the manufacture of delta-tocopherol. The synthesis of zeta-1-tocopherol, epsllon-tocopherol~ and the tocotrienols is described~in~the~document Hel~etica Chimica Acta (~1963)! 46,~pages~2517-2526.~ The~ synt~e-sis of eta-tocopherol or 7-methyltocol~is described~in the document Nature (1956), 177, pages 86-87.~ Other information on~the tocopherols can be ~ound in the Merck Index, which is well known to those skilled in , .
?
:
the art.
According to a second feature, the present invention covers a cosmetic or pharmaceutical compo~
sition, especially dermatological composition, having a 05 reduced allergizing or irritating potential or intended especially for the prevention or treatment of allergic `
manifestations such as skin allergy or bronchial ~`
asthma, or inflammatory manifestations, or for the prevention or treatment of the harmful effects of free ' '~
radicals,~ said composition comprising, as the active ingredient, at least one compound of formula (I) or a `
cosmetically or pharmaceutically acceptable salt there-of, as defined above. `'~ '-In one variant, the compositions of the inven- '' '~
tion comprise, as the active ingredient, a mixture of -- tocopherol phosphates, at least one of which is other than alpha tocopherol phosphate, or esters or salts thereof, obtained especially by the phosphatization of i~
a mixture o~ tocopherols extracted from~a;plant such~as soya.
In one advantàgeous embodiment, the~;cosmetic or dermatologiaaI'~composition comprises, as~thè ~active ingredient, at leaæt one compound of~formula~(I);~;as defined~above~ ~preferably; as~a salt,~in~the' f'orm of 25 small liposome-type~vesicles obtained by th~ dispersion ~' ' of~said compoùnd'or~said salt in watèr or~an~a~ùeous ;
medium such~as;'a~buffor~ solution, espec~laIly~byi~mëans~
~i of mechanical agi~atIon followed by homogeniza~ion,~for ~example by~ means ~of;;~ultrasound or~a homogen~izer~under~
~pr~essure.`~
; Preferably,~ the ~size of~ these ~vesicles is ~adjusted~to~a'~value'of'between about~6-~1O-2~ m~and 2~m~
by ~modification~of 'the~homogenization paraméters~such as the~energy~and duration.
~ In one advantageous variant of the previous :: :: . ::
~: ' `:
embodiment, the above-mentioned aqueous medium contains a biologically active agent, said agent being at least partially encapsulated, after dispersion, in the above-mentioned vesicles.
05 The above-mentioned active agent is preEerably an anti-allergic substance such as an extract of Scutellaria, Eor example a root extract of Scutellaria baicalensis Georgi described in the document FR-A-2 628 317, or an anti-inflammatory substance.
In another advantageous embodiment, said cos~
metic or dermatological compositions are prepared so as to have a reduced allergizing or irrita~ing potential or so as to be intended for the prevention and treat-ment of allergic manifestations such as skin allergy or bronchial asthma, or inflammatory manifestations, or -- for the prevention or treatment of the harmful effects of free radicals.
The aoncentration of active ingredients in these cosmetic or dermatological compositions is as described above for the use~ ~
The compositions acaording to the invention can be formulated in any form acceptable for their use in cosmetology, dermatology or pharmacy. In particular, they can be in the form of a cream for the prevention ~5 and cure of skin allergies, a soo~hing anti-allergic cream, a soothing anti-allergic oil, a preventive or curative anti-allergic lotionl an alcoholic after-shave lotion for soothing skin irritation, a hypoallergenic cream, a colloidal anti-asthmatic solution or else a solution intended for combating the toxic effects~ of the superoxide radicals which form during the applica-tion of resuscitation techniques with oxygen. ~
The compositions according to the invention can also be formulated as make-up compositions such as make-up foundation, lipstick, mascara or face powder.
According to a third feature, the present invention covers a process for reducing the allergizing or irritating potential of a pharmaceutical, dermato-logical or cosmetic composition, which consists in 05 incorporating into said composition an effective amount of at least one compound of formula (I) or at least one salt thereof, as defined above.
In a currently preferred embodiment, the above-mentioned compound of formula (I) is beta-, gamma-, delta-, zeta-l- or zeta-2-, eta- or epsilon-tocopherol phosphate, gamma-tocotrienol, delta-tocotrienol or tocotrienol phosphate, or else tocol phosphate. The preferred salts are the monosodium salts and the disodium salt.
15Advantageously, the concentration of compound -- of formula (I) or salt thereof is as described above for the use.
One variant of this process involves the incorporation of a mixture of tocopherol pho~phates, at least one of which is other than alpha-tocopherol phosphate, or a salt or ester thereof, obtained~espe-cially by the phosphatiæation of a mixture of toco-pherols extracted from a plant such as soya.
According :to a fourth feature, the present invention further relatas to a process for :the manu-facture of a cosmetic or dermatological composition having a reduced allergizing or irritating potential or intended in particular~for the prevention or treatment of allergic manifestations such as skin allergy~or inflammatory manifestations, or for the prevention or treatment of the harmful effects of free radicals, said process comprising the incorporation of at::least one compound of formula~ or a salt thereof, as defined ~ ~:
above, into a cosmetically or dermatologically accep-table excipient, vehicle or carrier.
According to a fifth feature, the present invention further relates to a process for the manu-facture of a pharmaceutical composition having a reduced allergizing or irritating potential or intended - 05 for the prevention or treatment of allergic manifesta-tions such as bronchial asthma, or inflammatory mani-festations, or for the prevention or treatment of the harmful effects of free radicals, said process compri-` sing the incorporation of at least one compound of formula (I) or a salt thereof, as defined above, into a pharmaceutically acceptable excipient, vehicle or carrier.
The incorporation of the compound of formula Ior a salt thereof into said cosmetic, dermatological or pharmaceutical composition can be effected in different _ ways accessible to those skilled in the art, depending on the type of formula desired.
In one advantageous mode of carrying out said manufacturing processes, when the composition comprises an a~ueous phase, the above-mentioned compound of for-mula (I) is first dispersed, preferably in the form of a salt as already defined, in water or said aqueous phase to form small vesicles, and the resulting dis-persion is then mixed with any other constituents of 2S the composition.
According to a sixth feature, the present invention covers a ~method of preventing or treating allergic manifestations such as skin allergy or bron-chial asthma, or inflammatory manifestations, or preventing or treating the harmful effects of free radicals, said method comprising the general or topical admirlistration, to the regions of the body to be treated, of an effective amount of at least one com-pound of formula (I) or a salt thereof, as de~ined above, incorporated in a cosmetically, dermatologically "~
or pharmaceutically acceptable excipient, vehicle or carrier.
According to a seventh feature, the present invention further covers, by way of novel products, 05 tocol, tocotrienol, epsilon-tocopherol, zeta-l- or zeta-2-tocopherol or eta-tocopherol monophosphate or diphosphate and beta , gamma- or delta-tocopherol diphosphate, as well as salts and esters thereof.
The invention will now be illustrated in detail with the aid of several Examples, which are given simply by way of illustration and cannot in any way limit the scope of the invention. -The percentages are given by weight in the Examples, unless indicated otherwise.
:
__ Exam~le 1 a) Pre~aration of the disodi~m sal~t of delta-toco~herol phosphate ~ :
The reaction scheme is as follows: :
CH3 CH3 IR3 ~ C~3 = ~ClS~123 ~ ~ aH23 :
1) POCl3, Et3N, -20C, 4 h. 2) H~O, reflux~, 3 h. ;:
Use of a tocopherol phosphate or one of its deriva-tives, for the preparation of cosmetic or pharmaceuti-cal compositions and compositions so obtained The present invention relates in general terms os to the use of a tocopherol phosphate or an ester or salt thereof for the preparation of cosmetic or pharma-ceutical compositions, especially dermatological compo-sitions, having an anti-allergic or anti-inflammatory activity or intend~d for the prevention or treatment of the harmful effects of free radicals, and to the cosmetic or pharmaceutical compositions, especially dermatological compositions, having an anti-allergic or anti-inflammatory activity or intended for the preven-tion or treatment of the harmful effects of free radicals, in which said compound is incorporated.
-- Vitamin E is known especially by the common name alpha-tocopherol (see Merck Index, 11th edition, reference 9832, page ~1437). `
alpha-Tocopherol is found in the natural state in a large number of plants, usually together with other compounds such as beta-tocopherolj gamma-toco~
phero} or delta-tocopherol. `.
It is also known that tocopherols occur in both the dl and d forms.
alpha-Tocopherol is essentially used for com~
bating vitamin E deficiencies or as a nutritional factor, especially for combating muscular degensration.
It is also used as an antioxidant, but at very ~ --specific doses.
~-Tocopherol esters, in particular the succi-nate, nicotinate or acetate, have also been described (Merck Index, lOth~edition, references 9832l 9833, page 1437). The~synthesis of alpha-tocopherol acetate is also described in~the document US-A-2 723 278 and the s synthesis of other esters is described in the document .
,~
. Amer. Chem. Soc. (1943) 65, 918-924.
dl-alpha-Tocopherol phosphate is also known (see P. KARRER et al., Helv. Chim. Acta (1940) 23, 1137-8), as is its action on muscle metabolism (see J.
05 Biol. Chem. 1942, 146, pages 309-321). Another docu-ment describes its biological role as an antioxidant on brain tissue (Biol. Antioxidants Trans., 1st Conf., 1946, pages 61-62). Its anticoagulant effect by acting on the polymerization of fibrin has al50 been described (Can. J. Biochem. and Physiol. 1959, 37, pages 501-505). Its in vitro antimicrobial action on B. subtilis and S. aureus has also been described (Naturwissen-schaften 1960, 47, page 17).
It has now been discovered, totally surpri-singly and unexpectedly, that tocopherol phosphates -~ other than alpha-tocopherol phosphate, especially in their dl or d form, or of an ester or salt thereof possess an anti-ailergic, anti-inflammatoxy and anti-free-radical activity, enabling them ~ to be used advantageously for the preparation of cosmetic ;or pharmaceutical compositions, especially dexmatological compositions, having a reduced allergizing or irrita~
ting potential or intended~ for the prevention or treatment of~ allergic or anti-inflammatorv~mànifesta~
tions, or else for the prevention or treatmènt of the ; harmful effeats of ~ree radicals.
The object~o~ the present invention is thus~to solve the new technical problem which consi~ts in the ~ provision of an~active substance having~ a~good~ant ; 30 allergic activity, especially for the prevention~or~
treatment of skin~allergy or bronchial asthma,~or~ a good anti-inflammatory activityl or else a preventive or curative activity towards the harmful effects~o~
free radicals, in particular by topical or general 3s administration, there~y constituting a valuable active . ' ~' ingredient for the preparation of cosmetic or pharma-ceutical compositions, especially dermatological com-positions.
The present invention solves this new technical 05 problem in a satisfactory manner by means of a particu-larly simple solution which can be used on the indus-trial scale.
Thus, according to a first feature, the present invention covers the use of a tocopherol phosphate other than alpha-tocopherol phosphate, especially in its dl or:d form, or of an ester thereof, of general formula (I) below~
R2 ~ 8 R 0 ~ ~0 ~ P~ R
R"0 o in which~
R' is a hydrogen atom or an alkyl radical:;having from 1 to 4 carbon~atoms, suah as the`methyl or ethyl radical~
25 in particular,;or R~lo~ ~is a tocopheryl radic~al;~
R" is a hydrogen atom or an alkyl radical having from~
to 4 carbon:atoms~ such as the::methyl~:~or:ethyl~radical~
in particular, or R"O is an oxyethylenated chain of:the -(O-CH2-CH3~-oR5 in which R4 and R, independently are a hydrogen atom or :
a methyl radical and n is an integer greater than or equal to 1;
R1, R2 and R3 independently are a hydrogen atom or a methyl radical, it being understood that R~, R2 and R3 os cannot simultaneously be a methyl radical; and A is the group : ~::
: CH3 CIH3 . '':~
-CH2-CH- or -CH=C-, ~
: ~ 10 ", :~ :
or of a~cosmetically or pharmaceutically acceptable ~: .
salt thereof, for the preparation of a cosmetic or pharmaceutical composition, especially dermatological '~
15 composition, having a reduced allergizing or irritating .' __ potential or intended for the prevention or treatment of allergic manifestations such as skin allergy or bronchial asthma, or inflammatory manifestations, or .
for:the prevention~or treatment of the harmful e~fects . .
of free radicals.
In~the above~ formula, the pre~erred ;.compounds~
: ~ are tocol, be~a-tocopherol or 5,8-dimethyltocol, gamma- ': "~'~'' `'.-'' tocopherol or 7,~8-dimethyltocol, ~zeta-2-tocopherol ~or~
5,7-dimethyltocol,.~delta~tocophero'l or~ 8-methyltocol',~
eta-tocopherol~or ~7-methyltocol~,~tocotrlenol~l~ zeka-1-~
tocopherol: or'' 5,7,8-trimethyltocotrien-3',7',~ ol, : ::.~:':':::~':~.:
: epsilon-tocopherol :or~ 5,8-dimèthyltocotrien-3',~7',~
ol, yamma-tocotrienol and delta-~ocotrienol. .
In :one variant o~ the use according~to :~:the~
present ~invention~ e`'~x~ure~of:tocopherol(s)~ ~ sph~t~s,~
~ at least one~of'whi~ch; is ~other than ~alpha-toco~bro1 : phosphate,~or~of;~esters~or salts thereof~is::'us~d,~sald~
~- mixture being::obtained espec1ally~by:the~.phosphatiza-~
: tion of a:~mixture of tocopherols extracted~from a~plant~
such as soya.
~: :..
: ~:
~\ ~
The tocopherol phosphates can be manufactured by the well-known process for the manufacture of alpha-tocopherol phosphate. A process for the preparation of alpha-tocopherol phosphate and salts thereof is des-05 cribed in the document JP-A-37-1737 in the name of Tomoda Pharm. Manuf. Co. Limited, to which those skilled in the art may refer. ;
The products used according to the present invention will thus be tocopherol phosphates other than alpha-tocopherol phosphate, or esters thereof, it being possible for these products to take the ~orm of cos- :
metically or pharmaceutically acceptable salts, espe- ;~
cially dermatological acceptable salts, such as, for example, alkali metal salts, especially sodium salts 15 (monosodium or disodium salt), or alkaline earth metal ~2 -salts, especially magnesium salts, or else ammonium salts or salts of primary, secondary or tertiary amines such as diethylamine, diethanolamine, triethylamine or triethanolamine in pa~ticular.
In formula (I), the alkyl radicals can have a linear or branched chain. - -~
` An alkyl rad~cal having from 1 to 4 carbon atoms is for example methyl, ethyl, propyl, isopropyl or butyl, preferably methyl or ethyl.
Tocopheryl radical is understood as meaning~the radical of formula (II) below:
R2 ~ / ~ 3 ~ 1 J CH2-(CH2-A-CH2)3 H (II) -O \~ ~/
in which R1, R2 and R3 independently are a hydrogen atom or a methyl radical and A is the group ., -CH2-CH- or -CH=C-;
~ ~ ' when R"O is an oxyethylenated chain, n will generally be greater~than or equal to 1, for example between 2 and 50, preferably between 2 and 25 and in particular equal to 2 or 5.
In another advantageous embodiment according to the invention, a compound of formula I as defined above, preferably as a salt, is used in the form of small liposome-type vesicles obtained by the dispersion -- of said compound or said salt in water or an aqueous medium such as a buffer solution, especially by means of mechanical agitàtion followed by homogeni ation, for example by means of ultrasound or a homogenizer under ~ pressure.~
Preferably, the size of these vesicles ~is ad~usted to a value oP between about 6~10-2 ~m~and 2 ~m by modification of the homogenization parameters such ~:~
as the energy and duration.
~ ~ 25 In one advantageous variant~ oP the~previous~ --;~ embodiment,~the above-mentioned~aqu~eous~me~ium~contains~
a biologically active agent, sàid~agent~being at~least~
partially~encapsulated, after dispersion, in the above-mentioned vesicles~
~ The~above-mentioned active agent~ lS preferably~
; an anti-allergic ~substance such~ as an~ extract ~of ; ~Scutellaria, for example~a root extract of Scutellaria baicalensis Georgi described in the document F~-A-2 628 317, or an anti-inflammatory substance.
In one advantageous emhodiment of the use :.
J
`:
according to the invention, the concentration by weight of the above-mentioned compound of formula (I), of a salt thereof or of mixtures thereof is between 0.001 and 10%, preferably between 0.01% and 1% and particu-05 larly preferably between 0.05 and 0.5%, based on the total weight of the composition.
In a currently preferred embodiment, the above-mentioned compound of formula (I) is delta-tocopherol phosphate. The preferred salts are the monosodium salts and the disodium salt.
The compounds used according to the invention are generally available commercially and can be pre-pared especially by following procedures described in ~ ~-the literature, for example in Chem. Pharm. Bull.
(1971), 19, t4), pages 687 to 695; Khim.-Pharm. Zh.
-_ (1983), 17, (7), pages 840 to 844; Xhim.-Pharm. Zh.
(1985), 19, (1), pages 75 to 77; or else in the patents US-2 457 932 or JP`54-54 978.
The nomenalature of the tocopherols~ and~com~
pounds derived therefrom has been described in~Europ~-enne J. Biochem. (1982), 1~, 473-475. The preparation of delta-tocopherol has been described in J. ~m.~Chem.
Soc. (1947), 69, pages 869-874. Likewise, the prepaira-tion of natural alpha-, beta- and gamma-tocopherol and those esters which are of physiological value ha~s~been described in J. ~m. Chem. Soc. tl943), 65, pages 918-924. The document GB-A-900 085 desaribes~yet another process for the manufacture of delta-tocopherol. The synthesis of zeta-1-tocopherol, epsllon-tocopherol~ and the tocotrienols is described~in~the~document Hel~etica Chimica Acta (~1963)! 46,~pages~2517-2526.~ The~ synt~e-sis of eta-tocopherol or 7-methyltocol~is described~in the document Nature (1956), 177, pages 86-87.~ Other information on~the tocopherols can be ~ound in the Merck Index, which is well known to those skilled in , .
?
:
the art.
According to a second feature, the present invention covers a cosmetic or pharmaceutical compo~
sition, especially dermatological composition, having a 05 reduced allergizing or irritating potential or intended especially for the prevention or treatment of allergic `
manifestations such as skin allergy or bronchial ~`
asthma, or inflammatory manifestations, or for the prevention or treatment of the harmful effects of free ' '~
radicals,~ said composition comprising, as the active ingredient, at least one compound of formula (I) or a `
cosmetically or pharmaceutically acceptable salt there-of, as defined above. `'~ '-In one variant, the compositions of the inven- '' '~
tion comprise, as the active ingredient, a mixture of -- tocopherol phosphates, at least one of which is other than alpha tocopherol phosphate, or esters or salts thereof, obtained especially by the phosphatization of i~
a mixture o~ tocopherols extracted from~a;plant such~as soya.
In one advantàgeous embodiment, the~;cosmetic or dermatologiaaI'~composition comprises, as~thè ~active ingredient, at leaæt one compound of~formula~(I);~;as defined~above~ ~preferably; as~a salt,~in~the' f'orm of 25 small liposome-type~vesicles obtained by th~ dispersion ~' ' of~said compoùnd'or~said salt in watèr or~an~a~ùeous ;
medium such~as;'a~buffor~ solution, espec~laIly~byi~mëans~
~i of mechanical agi~atIon followed by homogeniza~ion,~for ~example by~ means ~of;;~ultrasound or~a homogen~izer~under~
~pr~essure.`~
; Preferably,~ the ~size of~ these ~vesicles is ~adjusted~to~a'~value'of'between about~6-~1O-2~ m~and 2~m~
by ~modification~of 'the~homogenization paraméters~such as the~energy~and duration.
~ In one advantageous variant of the previous :: :: . ::
~: ' `:
embodiment, the above-mentioned aqueous medium contains a biologically active agent, said agent being at least partially encapsulated, after dispersion, in the above-mentioned vesicles.
05 The above-mentioned active agent is preEerably an anti-allergic substance such as an extract of Scutellaria, Eor example a root extract of Scutellaria baicalensis Georgi described in the document FR-A-2 628 317, or an anti-inflammatory substance.
In another advantageous embodiment, said cos~
metic or dermatological compositions are prepared so as to have a reduced allergizing or irrita~ing potential or so as to be intended for the prevention and treat-ment of allergic manifestations such as skin allergy or bronchial asthma, or inflammatory manifestations, or -- for the prevention or treatment of the harmful effects of free radicals.
The aoncentration of active ingredients in these cosmetic or dermatological compositions is as described above for the use~ ~
The compositions acaording to the invention can be formulated in any form acceptable for their use in cosmetology, dermatology or pharmacy. In particular, they can be in the form of a cream for the prevention ~5 and cure of skin allergies, a soo~hing anti-allergic cream, a soothing anti-allergic oil, a preventive or curative anti-allergic lotionl an alcoholic after-shave lotion for soothing skin irritation, a hypoallergenic cream, a colloidal anti-asthmatic solution or else a solution intended for combating the toxic effects~ of the superoxide radicals which form during the applica-tion of resuscitation techniques with oxygen. ~
The compositions according to the invention can also be formulated as make-up compositions such as make-up foundation, lipstick, mascara or face powder.
According to a third feature, the present invention covers a process for reducing the allergizing or irritating potential of a pharmaceutical, dermato-logical or cosmetic composition, which consists in 05 incorporating into said composition an effective amount of at least one compound of formula (I) or at least one salt thereof, as defined above.
In a currently preferred embodiment, the above-mentioned compound of formula (I) is beta-, gamma-, delta-, zeta-l- or zeta-2-, eta- or epsilon-tocopherol phosphate, gamma-tocotrienol, delta-tocotrienol or tocotrienol phosphate, or else tocol phosphate. The preferred salts are the monosodium salts and the disodium salt.
15Advantageously, the concentration of compound -- of formula (I) or salt thereof is as described above for the use.
One variant of this process involves the incorporation of a mixture of tocopherol pho~phates, at least one of which is other than alpha-tocopherol phosphate, or a salt or ester thereof, obtained~espe-cially by the phosphatiæation of a mixture of toco-pherols extracted from a plant such as soya.
According :to a fourth feature, the present invention further relatas to a process for :the manu-facture of a cosmetic or dermatological composition having a reduced allergizing or irritating potential or intended in particular~for the prevention or treatment of allergic manifestations such as skin allergy~or inflammatory manifestations, or for the prevention or treatment of the harmful effects of free radicals, said process comprising the incorporation of at::least one compound of formula~ or a salt thereof, as defined ~ ~:
above, into a cosmetically or dermatologically accep-table excipient, vehicle or carrier.
According to a fifth feature, the present invention further relates to a process for the manu-facture of a pharmaceutical composition having a reduced allergizing or irritating potential or intended - 05 for the prevention or treatment of allergic manifesta-tions such as bronchial asthma, or inflammatory mani-festations, or for the prevention or treatment of the harmful effects of free radicals, said process compri-` sing the incorporation of at least one compound of formula (I) or a salt thereof, as defined above, into a pharmaceutically acceptable excipient, vehicle or carrier.
The incorporation of the compound of formula Ior a salt thereof into said cosmetic, dermatological or pharmaceutical composition can be effected in different _ ways accessible to those skilled in the art, depending on the type of formula desired.
In one advantageous mode of carrying out said manufacturing processes, when the composition comprises an a~ueous phase, the above-mentioned compound of for-mula (I) is first dispersed, preferably in the form of a salt as already defined, in water or said aqueous phase to form small vesicles, and the resulting dis-persion is then mixed with any other constituents of 2S the composition.
According to a sixth feature, the present invention covers a ~method of preventing or treating allergic manifestations such as skin allergy or bron-chial asthma, or inflammatory manifestations, or preventing or treating the harmful effects of free radicals, said method comprising the general or topical admirlistration, to the regions of the body to be treated, of an effective amount of at least one com-pound of formula (I) or a salt thereof, as de~ined above, incorporated in a cosmetically, dermatologically "~
or pharmaceutically acceptable excipient, vehicle or carrier.
According to a seventh feature, the present invention further covers, by way of novel products, 05 tocol, tocotrienol, epsilon-tocopherol, zeta-l- or zeta-2-tocopherol or eta-tocopherol monophosphate or diphosphate and beta , gamma- or delta-tocopherol diphosphate, as well as salts and esters thereof.
The invention will now be illustrated in detail with the aid of several Examples, which are given simply by way of illustration and cannot in any way limit the scope of the invention. -The percentages are given by weight in the Examples, unless indicated otherwise.
:
__ Exam~le 1 a) Pre~aration of the disodi~m sal~t of delta-toco~herol phosphate ~ :
The reaction scheme is as follows: :
CH3 CH3 IR3 ~ C~3 = ~ClS~123 ~ ~ aH23 :
1) POCl3, Et3N, -20C, 4 h. 2) H~O, reflux~, 3 h. ;:
3) NaOH/MeOH
8.53 g (55.7 mmol) of phosphorus oxychloride in 80 ml of previouæly distilled isopropyl ether are ;~
placed in a 500 ml round-bottomed flask equipped with a : :~
magnetic stirrer, a thermometer, a dropping funnel:and ~: :
an argon balloon. A solution of 20 g (49.6 mmol) of delta-tocopherol and 9.04 g (89.3 mmol) of triethyl-? `- ~ ;
amine in 200 ml of isopropyl ether is then added at -20C (the additlon takes about 2 h). Stirring is con-tinued for 2 h at -20C and 20 ml of water are then added, the mixture being allowed to warm up to room 05 temperature. It is subsequently rafluxed for 3 h and then cooled. The aqueous phase is drawn off, the reaction medium is evaporated to one-third of its volume and 50 ml of a 10% methanolic solution oE sodium hydroxide are added, with stirring. The solvent is evaporated off and the yellowish paste obtained is washed with 20 ml of methanol cooled to -20 C. The paste is then dried with a vane pump at 60 for 12 h to give 20.3 g (78%) of the disodium salt of delta-tocopherol.
Characteristics of the resulting sample:
p NMR (CDCl3) 5.9 ppm (monophosphate), -10.67 ppm (pyrophosphate) Sodium content % Na calculated ~.73%
found 5.86%
b) ~paration of a solution o~ the disodium salt o~
~elta-tocophe~o~ pho~hate 0.8 g;of the powdered disodium salt of deltà-tocopherol phosphate obtained according to` step a) above is weighed out.
This powder is poured into 96.2 g of double-distilled water, with stirring, and stirring is con-tinued for about 2 hours.
This gives a solution of the disodium salt of delta-tocopherol phosphate.
, :
c? Preparation of a suspension of delta-tocopherol acid phosphate The pH of the solution obtained in step b) is lowered to 7 by the addition of about 3 ml of 0.5 N
05 HCl, with stirring, and the pH is then adjusted to 6.0 with 0.1 N HCl, with stirring. The tocopherol phos-phate is then in the acid form at this pH.
Homogenization is then carried out by means of ultrasound for 10 min at 150 W until a clear suspension is obtained, thereby producing liposome-type vesicles of tocopherol acid phosphate.
In the case of larger volumes, it can be advan-tageous to use a homogenizer under pressure, for example a homogenizer of the Manton-Gaulin~ typP at a pressure of about 500 bar.
-- The size of the vesicles of delta-tocopherol acid phosphate obtained in this way can be determined for example by meàns of an Autosizer 2C from MALVERN.
In this Example, the measured mean size is of the order 20of 130 nm.
It will also be noted that various dilutions can be prepared by modification of the amount of com-pounds initially added or by modification of the volume of the dispersion solution, which constitutes an easy ;~
process for the preparation of various concentrations of active principle.
In the Example described, about 100 g of sus-pension were obtained which contained about 0.8% of delta-tocopherol acid phosphate in the form of lipo- ; -some-type vesicles of substantially homogeneous sizes.
d) Pre~aration o~ a gelled composition o~ delta-toco-pherol phosph~te The homogenized suspension obtained above in step c) can be gelled by mixing with a gel such as a ~;.
vinylic polymer gel, in particular that marketed under the tradename Carbopol~ 940.
In a manner known per se, this gel can be prepared for example by dispersing 1 g of Carbopol~ 940 05 in 99 g of water in the presence of a preservative, and then, after swelling, by neutralizing the dispersion to pH 7.5, for example with triethanolamine.
100 g of this gel are added to the 100 g of homogenized suspension obtained above. This gives a gelled composition in which the concentration of delta-tocopherol phosphatè is about 0.4%.
Gelled compositions containing various concen-trations of delta-tocopherol phosphate can be obtained by following the procedure indicated above.
-- Example 2 Demonstration of the inhibition of phospholipase A2 PLA2l The inhibition of phospholipase A2, which is involved in the production of allergy and inflammation mediators, especially in the inflammatory-reaction of skin allergies, is measured according to` the protocol described by H.W. Tchang, I. Kudo, M. Tomita and K~
Inoue in J. Biol. Chem. 1987, 102, 147-154.
The phospholipase A2 is isolated from the peri-toneal cavity of a rat. PLA~ hydrolyzes the ester linkage in the 2-position of the glycerol of~ a phos~
phatidylethanolam1ne, this position being occupied by a fatty acid residue labeled with carbon 14.~ The radio~
active fatty acid released wil~l be~extraoted~and then quantitatively a~alyzed by liquid scintillation~ ;In the presence o~ the ;;~PLAz inhibitor, this~ hydrolysis will be reduced and less released fatty acid~will therefore be determined. ~ ~"
In practice, the PLA2 and the test product are ' ~ ' -placed in a 0.1 M Tris-HCl buffer, pH = 9, containing 4 mmol of Ca++ and the mixture is incubated for 20 min at 37 C, with agitation. After this contac~ time, the labeled phosphatidylethanolamine is added and incuba-05 tion is continued for 20 min at 37C, with agitation,to allow the hydrolysis of this substrate. n-Heptane is then used to extract the labeled fatty acid released during the hydrolysis, the latter then being quantita-tively analyzed by liquid scintillation. The 50%
inhibitory concentration (IC50~, i.e. the concentration of test product at which the amount of labeled fatty acid released is half that obtained in the absence of product (control), is then determined.
Thus an IC50 f 10 ~g/ml is obtained with the disodium salt of delta-tocopherol phosphate prepared in -- step b) of Example 1. This concentration is low and shows that the disodium salt of delta-tocopherol phos-phate has a very good inhibitory activity.
ExamplesQ ~_~karmaceutical or cosmetic formulations containing Vitamin E phosphate Example 3 Cream for the prevention and cure of skin allergies A - Cera bellina ~5.00 g Silicone 200 1.50 g Squalane ~5.00 g Myglyol 812 5000 g Nylon 12 SP 500 3.00 g BHT 0.05 g ~
. :
~
'' ' B - Demineralized water 49.56 g EDTA 0.10 g Propylene glycol 4.00 g Carbopol~ 1342 0.45 g 05 Triethanolamine 0.54 g 0.4% dispersion o~ delta-tocopherol phosphate, pH 6.6 25.00 g C - Germaben II~ 0.80 g Procedure: Mixture A is heated, with stirring, to give a homogeneous mixture. To prepare mixture B, the Car~opol~ 1342 is dispersed in an aqueous solution containing the EDTA and the propylene glycol in 49.56 g of`distilled water and the dispersion is neutralized -- with the triethanolamine. The 0.4% dispersion (non-gelled) o~ delta-tocopherol phosphate obtained accor-ding to Example 1 is then addad.
Mixture B is then heated to 75C~and kept at this temperature, with stirring, while ~mixture~A is added. The resulting mixture is allowèd ~to cool~to~
45C, the Germaben II~ is then added and the mixture~i6 allowed to cool ~urther to room temperature, ~with stirring.
This gives A cream.
ExamPle 4 Soothing anti-allergic cream Compos~ion~
30 A - Soya lecithin 2.~00 g Vegetable~oil~ ~ 8.50 g~
::
3~
B - Demineralized water 58.85 g EDTA 0.10 g Glycerol 4.00 g Carbopol~ 940 0.35 g 05 Triethanolamine 0.40 g Germaben II~ 0.80 g C - 0.4% dispersion of delta-tocopherol phosphate, pH 6.6 25.00 g Procedure: The vegetable oil and the lecithin are heated, with stirring, until a complete solution has formed, and this solution is allowed to cool to room temperature. Mixture B is obtained by dispersing the Carbopol~ 940 in a water + EDTA ~ glycerol mixture.
__ The whole is neutralized with the triethanolamine, after which the Germaben II~ is added.
Mixture A is then poured into mixture B, with stirring. ~he resulting mixture is homogenized and the dispersion obtained as in Example 1 is then added.
Further homogenization gives a cream which can ~e used morning and evening by local application to soothe allergic skin reactions.
., E~ample 5 Soothing anti-allergic oil 0.1 g of powdered disodium gamma-tocopherol phosphate, prepared by a procedure similar to that of Example 1, is dissolved in 99.9 g of trioctyl citrate at 70C for 8 h, with magnetic stirring.
The resulting oily solution can be used by local application in the samP way as the cream of Example 4.
-Example 6 Alcoholic after-shave lotion Composition:
Disodium tocol phosphate 0.2 g 05 Ethanol 40 g Propylene glycol 0.5 g Pantothenol0.1 g Perfumed aqueous excipient qsp . 100 g lo Preparation: The disodium tocol phosphate, pre-pared by a procedure similar to that of Example 1, is dissolved in the absolute alcohol, and the other con-stituents are dissolved in the water in a separate operation. The two solutions obtained are mixed and the whole is homogenized by means of ultrasound.
-- This lotion can be used to soothe the irri-tation due to shaving, which is commonly known as "smarting".
~ample 7 Preventive or;curative anti-allergic lotion Com~osition:
Dispersion of the phosphate of a mixture of tocopherols extracted ~;
from soya, containing 4% of toco~
pherol phosphate~ ~ 25.00 g Ethanol ~ ~ ~lO.OO~g ~;
Propylene glycol 5.00 g Aqueous excipi.ent~qsp~ oo.ob~ g The 4~dispersion of the phosphate of toco-pherols extracted~from soya is prepared~as in;~Example lb), except that~it has a higher concentration of tocopherol phosphate.
The constituents of the above formulation are ~-mixed together and homogenized by means of ultrasound.
Example 8 Colloidal anti~asthmatic solution 05 composition:
8.53 g (55.7 mmol) of phosphorus oxychloride in 80 ml of previouæly distilled isopropyl ether are ;~
placed in a 500 ml round-bottomed flask equipped with a : :~
magnetic stirrer, a thermometer, a dropping funnel:and ~: :
an argon balloon. A solution of 20 g (49.6 mmol) of delta-tocopherol and 9.04 g (89.3 mmol) of triethyl-? `- ~ ;
amine in 200 ml of isopropyl ether is then added at -20C (the additlon takes about 2 h). Stirring is con-tinued for 2 h at -20C and 20 ml of water are then added, the mixture being allowed to warm up to room 05 temperature. It is subsequently rafluxed for 3 h and then cooled. The aqueous phase is drawn off, the reaction medium is evaporated to one-third of its volume and 50 ml of a 10% methanolic solution oE sodium hydroxide are added, with stirring. The solvent is evaporated off and the yellowish paste obtained is washed with 20 ml of methanol cooled to -20 C. The paste is then dried with a vane pump at 60 for 12 h to give 20.3 g (78%) of the disodium salt of delta-tocopherol.
Characteristics of the resulting sample:
p NMR (CDCl3) 5.9 ppm (monophosphate), -10.67 ppm (pyrophosphate) Sodium content % Na calculated ~.73%
found 5.86%
b) ~paration of a solution o~ the disodium salt o~
~elta-tocophe~o~ pho~hate 0.8 g;of the powdered disodium salt of deltà-tocopherol phosphate obtained according to` step a) above is weighed out.
This powder is poured into 96.2 g of double-distilled water, with stirring, and stirring is con-tinued for about 2 hours.
This gives a solution of the disodium salt of delta-tocopherol phosphate.
, :
c? Preparation of a suspension of delta-tocopherol acid phosphate The pH of the solution obtained in step b) is lowered to 7 by the addition of about 3 ml of 0.5 N
05 HCl, with stirring, and the pH is then adjusted to 6.0 with 0.1 N HCl, with stirring. The tocopherol phos-phate is then in the acid form at this pH.
Homogenization is then carried out by means of ultrasound for 10 min at 150 W until a clear suspension is obtained, thereby producing liposome-type vesicles of tocopherol acid phosphate.
In the case of larger volumes, it can be advan-tageous to use a homogenizer under pressure, for example a homogenizer of the Manton-Gaulin~ typP at a pressure of about 500 bar.
-- The size of the vesicles of delta-tocopherol acid phosphate obtained in this way can be determined for example by meàns of an Autosizer 2C from MALVERN.
In this Example, the measured mean size is of the order 20of 130 nm.
It will also be noted that various dilutions can be prepared by modification of the amount of com-pounds initially added or by modification of the volume of the dispersion solution, which constitutes an easy ;~
process for the preparation of various concentrations of active principle.
In the Example described, about 100 g of sus-pension were obtained which contained about 0.8% of delta-tocopherol acid phosphate in the form of lipo- ; -some-type vesicles of substantially homogeneous sizes.
d) Pre~aration o~ a gelled composition o~ delta-toco-pherol phosph~te The homogenized suspension obtained above in step c) can be gelled by mixing with a gel such as a ~;.
vinylic polymer gel, in particular that marketed under the tradename Carbopol~ 940.
In a manner known per se, this gel can be prepared for example by dispersing 1 g of Carbopol~ 940 05 in 99 g of water in the presence of a preservative, and then, after swelling, by neutralizing the dispersion to pH 7.5, for example with triethanolamine.
100 g of this gel are added to the 100 g of homogenized suspension obtained above. This gives a gelled composition in which the concentration of delta-tocopherol phosphatè is about 0.4%.
Gelled compositions containing various concen-trations of delta-tocopherol phosphate can be obtained by following the procedure indicated above.
-- Example 2 Demonstration of the inhibition of phospholipase A2 PLA2l The inhibition of phospholipase A2, which is involved in the production of allergy and inflammation mediators, especially in the inflammatory-reaction of skin allergies, is measured according to` the protocol described by H.W. Tchang, I. Kudo, M. Tomita and K~
Inoue in J. Biol. Chem. 1987, 102, 147-154.
The phospholipase A2 is isolated from the peri-toneal cavity of a rat. PLA~ hydrolyzes the ester linkage in the 2-position of the glycerol of~ a phos~
phatidylethanolam1ne, this position being occupied by a fatty acid residue labeled with carbon 14.~ The radio~
active fatty acid released wil~l be~extraoted~and then quantitatively a~alyzed by liquid scintillation~ ;In the presence o~ the ;;~PLAz inhibitor, this~ hydrolysis will be reduced and less released fatty acid~will therefore be determined. ~ ~"
In practice, the PLA2 and the test product are ' ~ ' -placed in a 0.1 M Tris-HCl buffer, pH = 9, containing 4 mmol of Ca++ and the mixture is incubated for 20 min at 37 C, with agitation. After this contac~ time, the labeled phosphatidylethanolamine is added and incuba-05 tion is continued for 20 min at 37C, with agitation,to allow the hydrolysis of this substrate. n-Heptane is then used to extract the labeled fatty acid released during the hydrolysis, the latter then being quantita-tively analyzed by liquid scintillation. The 50%
inhibitory concentration (IC50~, i.e. the concentration of test product at which the amount of labeled fatty acid released is half that obtained in the absence of product (control), is then determined.
Thus an IC50 f 10 ~g/ml is obtained with the disodium salt of delta-tocopherol phosphate prepared in -- step b) of Example 1. This concentration is low and shows that the disodium salt of delta-tocopherol phos-phate has a very good inhibitory activity.
ExamplesQ ~_~karmaceutical or cosmetic formulations containing Vitamin E phosphate Example 3 Cream for the prevention and cure of skin allergies A - Cera bellina ~5.00 g Silicone 200 1.50 g Squalane ~5.00 g Myglyol 812 5000 g Nylon 12 SP 500 3.00 g BHT 0.05 g ~
. :
~
'' ' B - Demineralized water 49.56 g EDTA 0.10 g Propylene glycol 4.00 g Carbopol~ 1342 0.45 g 05 Triethanolamine 0.54 g 0.4% dispersion o~ delta-tocopherol phosphate, pH 6.6 25.00 g C - Germaben II~ 0.80 g Procedure: Mixture A is heated, with stirring, to give a homogeneous mixture. To prepare mixture B, the Car~opol~ 1342 is dispersed in an aqueous solution containing the EDTA and the propylene glycol in 49.56 g of`distilled water and the dispersion is neutralized -- with the triethanolamine. The 0.4% dispersion (non-gelled) o~ delta-tocopherol phosphate obtained accor-ding to Example 1 is then addad.
Mixture B is then heated to 75C~and kept at this temperature, with stirring, while ~mixture~A is added. The resulting mixture is allowèd ~to cool~to~
45C, the Germaben II~ is then added and the mixture~i6 allowed to cool ~urther to room temperature, ~with stirring.
This gives A cream.
ExamPle 4 Soothing anti-allergic cream Compos~ion~
30 A - Soya lecithin 2.~00 g Vegetable~oil~ ~ 8.50 g~
::
3~
B - Demineralized water 58.85 g EDTA 0.10 g Glycerol 4.00 g Carbopol~ 940 0.35 g 05 Triethanolamine 0.40 g Germaben II~ 0.80 g C - 0.4% dispersion of delta-tocopherol phosphate, pH 6.6 25.00 g Procedure: The vegetable oil and the lecithin are heated, with stirring, until a complete solution has formed, and this solution is allowed to cool to room temperature. Mixture B is obtained by dispersing the Carbopol~ 940 in a water + EDTA ~ glycerol mixture.
__ The whole is neutralized with the triethanolamine, after which the Germaben II~ is added.
Mixture A is then poured into mixture B, with stirring. ~he resulting mixture is homogenized and the dispersion obtained as in Example 1 is then added.
Further homogenization gives a cream which can ~e used morning and evening by local application to soothe allergic skin reactions.
., E~ample 5 Soothing anti-allergic oil 0.1 g of powdered disodium gamma-tocopherol phosphate, prepared by a procedure similar to that of Example 1, is dissolved in 99.9 g of trioctyl citrate at 70C for 8 h, with magnetic stirring.
The resulting oily solution can be used by local application in the samP way as the cream of Example 4.
-Example 6 Alcoholic after-shave lotion Composition:
Disodium tocol phosphate 0.2 g 05 Ethanol 40 g Propylene glycol 0.5 g Pantothenol0.1 g Perfumed aqueous excipient qsp . 100 g lo Preparation: The disodium tocol phosphate, pre-pared by a procedure similar to that of Example 1, is dissolved in the absolute alcohol, and the other con-stituents are dissolved in the water in a separate operation. The two solutions obtained are mixed and the whole is homogenized by means of ultrasound.
-- This lotion can be used to soothe the irri-tation due to shaving, which is commonly known as "smarting".
~ample 7 Preventive or;curative anti-allergic lotion Com~osition:
Dispersion of the phosphate of a mixture of tocopherols extracted ~;
from soya, containing 4% of toco~
pherol phosphate~ ~ 25.00 g Ethanol ~ ~ ~lO.OO~g ~;
Propylene glycol 5.00 g Aqueous excipi.ent~qsp~ oo.ob~ g The 4~dispersion of the phosphate of toco-pherols extracted~from soya is prepared~as in;~Example lb), except that~it has a higher concentration of tocopherol phosphate.
The constituents of the above formulation are ~-mixed together and homogenized by means of ultrasound.
Example 8 Colloidal anti~asthmatic solution 05 composition:
4% dispersion of zeta-2-tocopherol phosphate 12.50 g Buffered aqueous excipient +
preservative ~sp 100.00 g , "
The dispersion of monosodium zeta-2-tocopherol phosphate is prepared as in Example 1. After homo-genization by means of ultrasound, a colloidal solution is obtained which is then incorporated into the buf-15 fered excipient. ~ ~
-- This solution can be used by spraying into the ~ -upper respiratory tract, especially for soothing asthmatic coughs.
.:: :
Example 9 Colloidal solution for resuscitation techniques Compositio~:
4% dispersion of epsilon-tocopherol phosphate 7.50 g 25 Buffered aqueous excipient +
preservative qsp : ~lOO.OO g This composition is prepared as in the previous ~ ~ -Example.
It can be used for con~ating the ~oxic effects of the superoxide~radicals which form~during~ the application of resuscitation techniques~with~oxygen.
In this~ case it is administered b~intratracheal instillation at the same time as the gaseous mixture is administered.
-Example 10 Anti-allergic make-up foundation Composition:
Disodium gamma-tocopherol phosphate 0.5 g 05 Pigmented Qmulsion for make-up foundation 99.5 g This composition is prepared by incorporating the disodium tocopherol phosphate, previously dispersed in water, into the aqueous phase of the emulsion. The pigmented emulsion is then produced by the conventional procedure. ~ -~
This make-up foundation minimi~es the risks of ~ - -allergic manifestations due to a raw material or to an ~ ~ ;
allergenic substance coming into contact with the skin.
25~ :
::
: : ~ : : : :
preservative ~sp 100.00 g , "
The dispersion of monosodium zeta-2-tocopherol phosphate is prepared as in Example 1. After homo-genization by means of ultrasound, a colloidal solution is obtained which is then incorporated into the buf-15 fered excipient. ~ ~
-- This solution can be used by spraying into the ~ -upper respiratory tract, especially for soothing asthmatic coughs.
.:: :
Example 9 Colloidal solution for resuscitation techniques Compositio~:
4% dispersion of epsilon-tocopherol phosphate 7.50 g 25 Buffered aqueous excipient +
preservative qsp : ~lOO.OO g This composition is prepared as in the previous ~ ~ -Example.
It can be used for con~ating the ~oxic effects of the superoxide~radicals which form~during~ the application of resuscitation techniques~with~oxygen.
In this~ case it is administered b~intratracheal instillation at the same time as the gaseous mixture is administered.
-Example 10 Anti-allergic make-up foundation Composition:
Disodium gamma-tocopherol phosphate 0.5 g 05 Pigmented Qmulsion for make-up foundation 99.5 g This composition is prepared by incorporating the disodium tocopherol phosphate, previously dispersed in water, into the aqueous phase of the emulsion. The pigmented emulsion is then produced by the conventional procedure. ~ -~
This make-up foundation minimi~es the risks of ~ - -allergic manifestations due to a raw material or to an ~ ~ ;
allergenic substance coming into contact with the skin.
25~ :
::
: : ~ : : : :
Claims (23)
1. Use of a tocopherol phosphate other than alpha-tocopherol phosphate, especially in its dl or d form, or of an ester thereof, of general formula (I) below:
(I) in which:
R' is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, such as the methyl or ethyl radical in particular, or R'O is a tocopheryl radical;
R" is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, such as the methyl or ethyl radical in particular, or R"O is an oxyethylenated chain of the formula in which R4 and R5 independently are a hydrogen atom or a methyl radical and n is an integer greater than or equal to 1;
R1, R2 and R3 independently are a hydrogen atom or a methyl radical, it being understood that R1, R2 and R3 cannot simultaneously be a methyl radical; and A is the group or , or of a cosmetically or pharmaceutically acceptable salt thereof, for the preparation of a cosmetic or pharmaceutical composition, especially dermatological composition, having a reduced allergizing or irritating potential or intended for the prevention or treatment of allergic manifestations such as skin allergy or bronchial asthma, or inflammatory manifestations, or for the prevention or treatment of the harmful effects of free radicals.
(I) in which:
R' is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, such as the methyl or ethyl radical in particular, or R'O is a tocopheryl radical;
R" is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, such as the methyl or ethyl radical in particular, or R"O is an oxyethylenated chain of the formula in which R4 and R5 independently are a hydrogen atom or a methyl radical and n is an integer greater than or equal to 1;
R1, R2 and R3 independently are a hydrogen atom or a methyl radical, it being understood that R1, R2 and R3 cannot simultaneously be a methyl radical; and A is the group or , or of a cosmetically or pharmaceutically acceptable salt thereof, for the preparation of a cosmetic or pharmaceutical composition, especially dermatological composition, having a reduced allergizing or irritating potential or intended for the prevention or treatment of allergic manifestations such as skin allergy or bronchial asthma, or inflammatory manifestations, or for the prevention or treatment of the harmful effects of free radicals.
2. Use according to claim 1 wherein the above-mentioned compound of formula (I) is the phosphate of tocol, beta-tocopherol or 5,8-dimethyltocol, gamma-tocopherol or 7,8-dimethyltocol, zeta-1,2-tocopherol or 5,7-dimethyltocol, delta-tocopherol or 8-methyltocol, eta-tocopherol or 7-methyltocol, tocotrienol, zeta-1-tocopherol or 5,7,8-trimethyltocotrien-3',7',11'-ol, epsilon-tocopherol or 5,8-dimethyltocotrien-3',7',11'-ol, gamma-tocotrienol or delta-tocotrienol.
3. Use according to claim 1 or 2 wherein a mixture of tocopherol phosphates, at least one of which is other than alpha-tocopherol phosphate, or of esters or salts thereof is used, said mixture being obtained especially by the phosphatization of a mixture of tocopherols extracted from a plant such as soya.
4. Use according to one of claims 1 or 3 of a compound of formula (I) as defined above, preferably as a salt, in the form of small liposome-type vesicles obtained by the dispersion of said compound or said salt in water or an aqueous medium such as a buffer solution.
5. Use according to claim 4 wherein the size of the vesicles is between about 6?10-2 µm and 2 µm.
6. use according to one of claims 4 or 5 wherein the above-mentioned aqueous medium contains a bio-logically active agent, said agent being at least partially encapsulated, after dispersion, in the above-mentioned vesicles.
7. Use according to claim 6 wherein the biologi-cally active agent is an anti-allergic substance such as an extract of Scutellaria, for example a root extract of Scutellaria baicalensis Georgi, or an anti-inflammatory substance.
8. Use according to one of claims 1 to 7 wherein the concentration by weight of the compound of formula (I) given above, of a salt thereof or of mixtures thereof is between 0.001 and 10%, preferably between 0.01% and 1% and particularly preferably between 0.05%
and 0.5%, based on the total weight of the composition.
and 0.5%, based on the total weight of the composition.
9. Use according to one of claims 1 to 8 wherein the salt of the compound of formula (I) given above is a monosodium salt or the disodium salt.
10. A cosmetic or pharmaceutical composition, espe-cially dermatological composition, having a reduced allergizing or irritating potential or intended espe-cially for the prevention or treatment of allergic manifestations such as skin allergy or bronchial asthma, or inflammatory manifestations, or for the prevention or treatment of the harmful effects of free radicals, said composition comprising an effective amount of a tocopherol phosphate other than alpha-tocopherol phosphate, especially in its dl or d form, or of an ester thereof, of general formula (I) below:
(I) in which:
R' is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, such as the methyl or ethyl radical in particular, or R'O is a tocopheryl radical;
R" is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, such as the methyl or ethyl radical in particular, or R"O is an oxyethylenated chain of the formula in which R4 and R5 independently are a hydrogen atom or a methyl radical and n is an integer greater than or equal to 1;
R1, R2 and R3 independently are a hydrogen atom or a methyl radical, it being understood that R1, R2 and R3 cannot simultaneously be a methyl radical; and A is the group or , or of a cosmetically or pharmaceutically acceptable salt thereof.
(I) in which:
R' is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, such as the methyl or ethyl radical in particular, or R'O is a tocopheryl radical;
R" is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, such as the methyl or ethyl radical in particular, or R"O is an oxyethylenated chain of the formula in which R4 and R5 independently are a hydrogen atom or a methyl radical and n is an integer greater than or equal to 1;
R1, R2 and R3 independently are a hydrogen atom or a methyl radical, it being understood that R1, R2 and R3 cannot simultaneously be a methyl radical; and A is the group or , or of a cosmetically or pharmaceutically acceptable salt thereof.
11. A composition according to claim 10 wherein the above-mentioned compound of formula (I) is the phos-phate of tocol, beta-tocopherol or 5,8-dimethyltocol, gamma-tocopherol or 7,8-dimethyltocol, zeta-1,2-toco-pherol or 5,7-dimethyltocol, delta-tocopherol or 8-methyltocol, eta-tocopherol or 7-methyltocol, toco-trienol, zeta-1-tocopherol or 5,7,8-trimethyltocotrien-3',7',11'-ol, epsilon-tocopherol or 5,8-dimethyltoco-trien-3',7',11'-ol, gamma-tocotrienol or delta-toco-trienol.
12. A composition according to claim 10 or 11 which is a mixture of tocopherol phosphates, at least one of which is other than alpha-tocopherol phosphate, or of esters or salts thereof, obtained especially by the phosphatization of a mixture of tocopherols extracted from a plant such as soya.
13. A composition according to claim 10, 11 or 12 which comprises an effective amount of a compound of formula (I) as defined above, preferably as a salt, in the form of small lipsome-type vesicles obtained by the dispersion of said compound or said salt in water or an aqueous medium such as a buffer solution.
14. A composition according to claim 13 wherein the size of the vesicles is between about 6?10-2 µm and 2 µm.
15. A composition according to one of claims 10 to 14 wherein the above-mentioned aqueous medium contains a biologically active agent, said agent being at least partially encapsulated, after dispersion, in the above-mentioned vesicles.
16. A composition according to claim 15 wherein the biologically active agent is an anti-allergic substance such as an extract of Scutellaria, for example a root extract of Scutellaria baicalensis Georgi, or an anti-inflammatory substance.
17. A composition according to one of claims 10 to 16 wherein the concentration by weight of the compound of formula (I) given above, or of a salt thereof, is between 0.001 and 10%, preferably between 0.01% and 1%
and particularly preferably between 0.05% and 0.5%, based on the total weight of the composition.
and particularly preferably between 0.05% and 0.5%, based on the total weight of the composition.
18. A composition according to one of claims 10 to 15 wherein the salt of the compound of formula (I) given above is a monosodium salt or the disodium salt.
19. A process for reducing the allergizing or irritating potential of a cosmetic or pharmaceutical composition, especially dermatological composition, which consists in incorporating into said composition an effective amount of at least one tocopherol phos-phate other than alpha-tocopherol phosphate, especially in its dl or d form, or of an ester thereof, of general formula (I) below:
(I) in which:
R' is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, such as the methyl or ethyl radical in particular, or R'O is a tocopheryl radical;
R" is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, such as the methyl or ethyl radical in particular, or R"O is an oxyethylenated chain of the formula in which R4 and R5 independently are a hydrogen atom or a methyl radical and n is an integer greater than or equal to 1;
R1, R2 and R3 independently are a hydrogen atom or a methyl radical, it being understood that R1, R2 and R3 cannot simultaneously be a methyl radical; and A is the group or of a cosmetically or pharmaceutically acceptable salt thereof.
(I) in which:
R' is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, such as the methyl or ethyl radical in particular, or R'O is a tocopheryl radical;
R" is a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, such as the methyl or ethyl radical in particular, or R"O is an oxyethylenated chain of the formula in which R4 and R5 independently are a hydrogen atom or a methyl radical and n is an integer greater than or equal to 1;
R1, R2 and R3 independently are a hydrogen atom or a methyl radical, it being understood that R1, R2 and R3 cannot simultaneously be a methyl radical; and A is the group or of a cosmetically or pharmaceutically acceptable salt thereof.
20. A process according to claim 19 wherein the above-mentioned compound of formula (I) is the phos-phate of tocol, beta-tocopherol or 5,8-dimethyltocol, gamma-tocopherol or 7,8-dimethyltocol, zeta-1,2-toco-pherol or 5,7-dimethyltocol, delta-tocopherol or 8-methyltocol, eta-tocopherol or 7-methyltocol, toco-trienol, zeta-1-tocopherol or 5,7,8-trimethyltocotrien-3',7',11'-ol, epsilon-tocopherol or 5,8-dimethyltoco-trien-3',7',11'-ol, gamma-tocotrienol or delta-toco-trienol.
21. A process according to claim 19 or 20 wherein the salt of the compound of formula (I) given above is a monosodium salt or the disodium salt.
22. A process according to one of claims 19 to 21 wherein the concentration by weight of the compound of formula (I) given above, or of a salt thereof, is between 0.001 and 10%, preferably between 0.01% and 1%
and particularly preferably between 0.05% and 0.5%, based on the total weight of the composition.
and particularly preferably between 0.05% and 0.5%, based on the total weight of the composition.
23. A tocopherol phosphate which is selected from the group consisting of tocol, tocotrienol, epsilon-tocopherol, zeta-1-tocopherol, zeta-2-tocopherol or eta-tocopherol monophosphate or diphosphate, beta-tocopherol diphosphate and gamma-tocopherol diphos-phate, as well as salts and esters thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9109825A FR2679904A1 (en) | 1991-08-01 | 1991-08-01 | Use of a tocopherol phosphate, or of one of its derivatives, in the preparation of cosmetic or pharmaceutical compositions and compositions thus obtained |
| FR9109825 | 1991-08-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2114225A1 true CA2114225A1 (en) | 1993-02-02 |
Family
ID=9415841
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002114225A Abandoned CA2114225A1 (en) | 1991-08-01 | 1992-07-30 | Use of a tocopherol phosphate or one of its derivatives, for the preparation of cosmetic or pharmaceutical compositions and compositions so obtained |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US5603949A (en) |
| EP (1) | EP0597025B1 (en) |
| JP (1) | JPH06509351A (en) |
| CA (1) | CA2114225A1 (en) |
| DE (1) | DE69227115D1 (en) |
| FR (1) | FR2679904A1 (en) |
| WO (1) | WO1993002661A1 (en) |
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| JPS6130594A (en) * | 1984-07-21 | 1986-02-12 | Sunstar Inc | Antiallergic |
| JPS62205091A (en) * | 1986-03-04 | 1987-09-09 | Senjiyu Seiyaku Kk | Novel phosphate diester and its salt, preparation thereof and medicinal preparation containing same |
| JPH0678214B2 (en) * | 1986-12-02 | 1994-10-05 | 株式会社資生堂 | Hair cosmetics |
| JP2526059B2 (en) * | 1987-04-28 | 1996-08-21 | 千寿製薬株式会社 | Anti-ulcer agent |
| EP0382779B1 (en) * | 1987-10-19 | 1993-08-11 | The Liposome Company, Inc. | Tocopherol-based pharmaceutical systems |
| FR2628317B1 (en) * | 1988-03-09 | 1991-11-08 | Lvmh Rech | COMPOSITION BASED ON HYDRATED LIPID LAMID PHASES OR LIPOSOMES CONTAINING SCUTELLARIA EXTRACT, OR AT LEAST ONE FLAVONOID SUCH AS BAICALINE OR BAICALINE AND COSMETIC OR PHARMACEUTICAL COMPOSITION, IN PARTICULAR DERMATOLOGICAL, ANTI-ALLERGIC ANTI-ALLERGIC ACTIVITY THE INCORPORANT |
| JP2736794B2 (en) * | 1988-12-26 | 1998-04-02 | 千寿製薬株式会社 | Plaque formation inhibitor |
| US5053222A (en) | 1989-06-07 | 1991-10-01 | Shiseido Company Ltd. | Hair cosmetic composition |
| FR2657526B1 (en) * | 1990-01-31 | 1994-10-28 | Lvmh Rech | USE OF AN ALPHA-TOCOPHEROL PHOSPHATE, OR ONE OF ITS DERIVATIVES, FOR THE PREPARATION OF COSMETIC, DERMATOLOGICAL, OR PHARMACEUTICAL COMPOSITIONS; COMPOSITIONS THUS OBTAINED. |
| US5114957A (en) * | 1990-05-08 | 1992-05-19 | Biodor U.S. Holding | Tocopherol-based antiviral agents and method of using same |
-
1991
- 1991-08-01 FR FR9109825A patent/FR2679904A1/en active Granted
-
1992
- 1992-07-30 WO PCT/FR1992/000748 patent/WO1993002661A1/en active IP Right Grant
- 1992-07-30 DE DE69227115T patent/DE69227115D1/en not_active Expired - Lifetime
- 1992-07-30 JP JP5503328A patent/JPH06509351A/en active Pending
- 1992-07-30 EP EP92917637A patent/EP0597025B1/en not_active Expired - Lifetime
- 1992-07-30 CA CA002114225A patent/CA2114225A1/en not_active Abandoned
-
1995
- 1995-06-05 US US08/465,610 patent/US5603949A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| EP0597025B1 (en) | 1998-09-23 |
| JPH06509351A (en) | 1994-10-20 |
| FR2679904A1 (en) | 1993-02-05 |
| DE69227115D1 (en) | 1998-10-29 |
| US5603949A (en) | 1997-02-18 |
| WO1993002661A1 (en) | 1993-02-18 |
| FR2679904B1 (en) | 1995-03-17 |
| EP0597025A1 (en) | 1994-05-18 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |