Compositions based on resveratrol

Details Compositions based on resveratrol Compositions based on resveratrol

2000-01-19

2003-06-03

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Capsules

C424S489000, C514S733000, C514S734000

Reexamination Certificate

active

06572882

ABSTRACT:

The invention relates to compositions based on derivatives of resveratrol having in particular a high stability as regards air and light.
Resveratrol (3,5,4′-trihydroxystilbene) exists in cis or trans form and is presented in monomer form or as the oligomer containing generally 2 to 4 monomer units.
In the following description and in the claims, the term “ORs” will be used to designate both the monomer and the oligomers.
Study of the properties of resveratrol has allowed the demonstration of useful biological activities. Cardiovascular and anti-carcinogenic effects have thus been reported.
The practical use of ORs is hindered by difficult access, selectively, to such extracts, from plant sources which contain them. It is also due to their instability, caused by the phenol groups which they contain, and to their hydrosoluble character, which poses miscibility problems with numerous excipients generally used in therapeutics, cosmetics and in the field of foods, which on the contrary have liposoluble properties.
In order to resolve these problems, the inventors have perfected extraction methods leading to extracts which are rich in ORs, and have used protective groups of the phenol functions, which allow both a satisfactory stability to be conferred on the resveratrol monomer and oligomer and renders them liposoluble, these groups having the advantage of being eliminable in vivo.
Therefore an aim of the invention is to provide compositions based on derivatives of resveratrol monomers and/or oligomers the protective groups of which can be easily eliminated in order to release the active ingredient when desired.
It also aims to provide a process for obtaining these compositions as well as the starting monomers and/or oligomers.
Moreover the invention relates to uses of these compositions in various fields in particular in therapeutics, in cosmetics and in agro-foodstuffs.
The compositions according to the invention are characterized in that they are essentially based on esters of resveratrol monomers and/or oligomers, the monomers comprising at least one ester group of formula —O—CO—A, and the oligomers being formed from monomer units joined by carbon-carbon bonds, or ether, and/or monomers cross-linked by
O—CO—R—CO— groups
A representing an alkyl radical with at least two carbon atoms, linear or branched, saturated or unsaturated, an aryl radical, except for the phenyl radical in the case of a composition of resveratrol monomer, aralkyl or aralkylene, and
R representing an alkylene radical with 0 to 10 carbon atoms, saturated or unsaturated, and/or 1 arylene radical having 1 to 3 rings and/or a heterocyclic radical, and the diastereoisomers of these units.
These compositions can be stored over a long period without alteration, in particular for at least 2 years under normal storage conditions (temperature of 10 to 22° C., in light protective packaging, hygrometry 40-50%).
In an embodiment of the invention, the compositions are based on monomers and/or oligomers of resveratrol comprising at least one —O—CO—A group.
In a preferred group, A represents a saturated or unsaturated fatty acid radical.
In the case of an unsaturation, the double bonds are advantageously cis, which corresponds to the most frequent case found in the natural products. With products obtained more particularly by synthesis or hemisynthesis, the bonds are trans.
Among the fatty acids which are suitable for the implementation of the invention, the following acids can be mentioned: butyric C4:O; valeric, C′5:O hexanoic, C6:O: sorbic, C6:2(n-2); lauric C12:O; palmitic C16:O; stearic, C18:O; oleic, C18:1(n-9) linoleic, C18:2(n-6); linolenic, C18:3(n-6); &agr; linolenic, C18:3(n-3); arachidonic, C20:4(n-3) eicosapentaenoic C20:5(n-3); and docosahexanoic. C22:6(n-3)
The C16 and more fatty acids are particularly appropriate as regards cosmetic uses. These fatty acids are extracted, for example, from microalgae.
In another preferred group, A represents an aryl group, except for, as specified above, the phenyl radical in the case of a composition of resveratrol monomer.
In yet another group, A represents an aralkyl or aralkylene group, the alkyl or alkylene group being more particularly C1 to C8, in particular C1 to C4. In particular the benzyl or styryl group can be mentioned.
In another embodiment of the invention, the compositions are based on monomers and/or of oligomers of resveratrol cross-linked using —O—CO—R—CO— bridges.
In this structure, R represents an alkylene radical with O to 10 carbon atoms, saturated or unsaturated, and/or an arylene radical comprising 1 to 3 rings and/or a heterocyclic radical.
The cross-linked esters advantageously include as substituent R, a radical of a diacid chosen from the following acids: malic, malonic, glutaric, phthalic, a chloride of diacids, such as terephthaloyl dichloride, succinyl dichloride, sebacoyl dichloride, and adipoyl dichloride, an anhydride, or also an isocyanate such as toluene or hexamethylene diisocyanate.
In an advantageous manner, these cross-linked compositions form microcapsules or spongy masses.
The invention also relates to a process for obtaining the esters defined above.
This process is characterized in that it comprises the reaction of monomers and/or of oligomers of resveratrol with, as acylation agents, compounds of formula A—CO—O-A1, or A1-O—CO—R—CO—O-A1, where
A represents an alkyl radical with at least two carbon atoms, linear or branched, saturated or unsaturated, an aryl, aralkyl or aralkylene radical,
R represents an alkylene radical with 0 to 10 carbon atoms, saturated or unsaturated, and/or 1 arylene radical having 1 to 3 rings and/or a heterocyclic radical, and
A1 represents a hydrogen atom, a halogen atom, a C1 to C8 alkyl radical, or aryl, a —CO—A group or isocyanate, A and A1 not being able to represent a phenyl radical and a chlorine atom in A—CO—C-A1.
The esterification reactions with acids are generally carried out at ambient temperature, in the presence of an activation agent. For example dicyclohexylcarbodiimide (DCC) or ter-butylchloroformiate can be mentioned.
The esterifications with acid derivatives are advantageously carried out according to the Schotten Baumann reaction in alkaline aqueous medium.
These reactions lead to the obtaining of esterified compositions in spongy form, which are isolated from the reaction mixture and which are purified with a view to the subsequent uses envisaged.
When diacids or their derivatives are used, an emulsion of (W/O) type is formed by dispersion, under agitation, of an alkaline aqueous solution of the monomers and/or oligomers of resveratrol in an organic solvent which is not miscible with water, then the cross-linking agent, A1-O—CO—R—CO—O-A1 in solution in said non-miscible organic solvent is added, or, as a variant, an emulsion of (O/W) type is formed by dispersion, under agitation, of an organic solution containing said cross-linking agent in an aqueous solution of monomers and/or oligomers of resveratrol, with an alkaline agent in aqueous solution added to it to adjust the pH of the dispersing phase to approximately 9-11.5.
The emulsifying agents are used at the rate of approximately 2 to 15% by weight, relative to the weight of the dispersion, in particular approximately 3 to 8%.
The appropriate agents correspond to those usually used, such as those marketed under the mark Spans® (esterified hexyl alcohols) or Tween® (esters of fatty acids and sorbitol with ethylene oxide).
Depending on the relative quantities of the aqueous and organic phases and of the emulsifying agent, an emulsion of O/W or W/O type is formed.
Agitation is carried out so as to rapidly homogenize the aqueous and organic solutions, for example by using a magnetic stirrer at 500-1000 rpm or a helix at 800-2000 rpm. The duration of this stage is generally of the order of 30 minutes.
The cross-linking occurs se product at the interface of the droplets of the emulsion.
The cross-linked esters formed are recovered, for example by centrifugation. The washed and dried products are in the form of fluid powder.
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