Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Cosmetic – antiperspirant – dentifrice
Reexamination Certificate
2000-07-11
2003-02-25
Padmanabhan, Sreeni (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Cosmetic, antiperspirant, dentifrice
C424S184100, C424S499000, C514S058000, C536S018700
Reexamination Certificate
active
06524595
ABSTRACT:
PRIOR ART
The use of alpha, beta or gamma cyclodextrins as cage molecules capable of trapping hydrophobic molecules has been particularly well described: trapping of vitamin E (Japanese patent JP56/139409), vitamin D3 (JP52/130904) for example, but also menthol, fragrances, essential oils, etc.
However, the use of such cyclodextrins poses a certain number of problems: in particular, their solubility in an aqueous phase is very poor (in particular beta cyclodextrin) and their solubility in a hydrophobic phase is almost zero. Faced with such a problem, a first strategy consists of producing derivatives of such cyclodextrins to increase the solubility of the molecules in aqueous phases:
using methyl, dimethyl, polymethyl derivatives,
using hydroxyalkylated derivatives (European patent EP-A1-0 636 634),
using sulfate or phosphate derivatives,
or to increase their solubility in oily phases:
using lipophilic derivatives (U.S. Pat. No. 3,565,887),
using lipophilic hydroxyalkylated derivatives (EP-A1-0 773 229),
using cyclodextrins monosubstituted exclusively on their primary face (reaction with a primary alcohol function) or cyclodextrins completely substituted exclusively on their secondary face (reaction with all of the secondary alcohol functions) (French patent FR-A-2 681 868).
Further, a second strategy has slowly been developing in which amphiphilic structures are synthesized from cyclodextrins, which structures enable the cyclodextrins to arrange themselves into micelles or nanoparticles:
the products described in French patent FR-A-2 681 868 can thus form nanoparticles,
the products described in European patent EP-A-0 773 229 can form nanoparticles,
it is also possible to produce the nanoparticies which are described in International patent application WO 93/25194 from cyclodextrins completely substituted on their secondary face, synthesized in accordance with Zhang and al. (Zhang, Ling, Coleman, Parrot-Lopez, Galons, Tetrahedron Letters 32 (24) 2769-2770, 1991).
The inventors have unexpectedly discovered that, in contrast to current wisdom, it is possible to produce nanoparticles from amphiphilic cyclodextrins which are mono- or multi-substituted, preferably on their primary face.
The skilled person will always aim to substitute the secondary face of cyclodextrins to produce nanoparticles, as the geometry of nanoparticles substituted on their secondary face is highly favorable to the formation of curved shapes (which enable such structures to organize themselves into nanoparticles), while the geometry of cyclodextrins substituted on their primary face is highly unfavorable to the formation of nanoparticles. Thus amphiphilic cyclodextrins for the production of nanoparticles are synthesized by blocking the primary alcohol functions which are chemically more reactive, then alkylating the secondary alcohol functions, and unblocking the primary alcohol functions in a third stage (Zhang et al., 1991 and also FR-A-2 681 868 and EP-A-0 773 229). This sequence of reactions causes problems with yield and with the industrialization of processes, which limits their use. Commercial use is currently non-existent.
The inventors have succeeded in producing nanoparticles from non-hydroxyalkylated cyclodextrins, mono- or di-substituted on their primary face which was completely unexpected, with many fields of application in the areas of encapsulating molecules of cosmetic, pharmaceutical, or agro-industrial interest, and of modulating the penetration of encapsulated active ingredients into tissues, cells, etc. . . .
The inventors have also discovered that the amphiphilic cyclodextrins of the invention have the capacity to promote penetration of active ingredients in a manner which is spectacularly stronger than other vectors which have been far more widely studied, namely liposomes.
For this reason, the targeting properties of these amphiphilic cyclodextrin molecules (which may or may not be in the form of nanoparticles, included in phospholipid double layers or not) have become extremely interesting, and chemical modifications of these cyclodextrins have been made to allow such targeting.
In particular, the invention enables molecules with selective affinities to be grafted onto the amphiphilic cyclodextrins of the invention, via a spacer arm which may or may not remain present in the chemical structure of the molecule formed.
The invention also renders possible the production of completely novel chemical entities of real industrial and economic significance in fields as varied as cosmetics, pharmacy, agro-industry, etc. . . .
OBJECTS AND SUMMARY OF THE INVENTION
Thus a principal aim of the invention is to solve the novel technical problem consisting of providing novel chemical entities which can be used in cosmetics, pharmacy, agro-industry and in the food industry.
A further principal aim of the present invention is to solve a novel technical problem consisting of providing a solution which can provide novel chemical cyclodextrin entities which can form nanoparticles or micelles of very small dimensions, in particular nanoparticles.
A still further principal aim of the present invention is to solve the novel technical problem consisting of providing novel chemical cyclodextrin entities which are easy to synthesize and have a good synthesis yield, thus enabling such novel chemical entities to be used on an industrial scale.
A yet still further principal aim of the present invention is to solve the novel technical problem consisting of providing novel chemical cyclodextrin entities which can trap or encapsulate molecules of cosmetic, pharmaceutical or agro-industrial interest to enable the penetration of the encapsulated active ingredients into tissue, cells etc. to be modulated.
A yet still further principal aim of the present invention is to solve the novel technical problem consisting of providing a solution which can provide novel chemical cyclodextrin entities with the capacity to promote penetration of active ingredients in a manner which is spectacularly stronger than other vectors which have been more widely studied, namely liposomes.
A yet still further principal aim of the present invention is to solve the novel technical problem consisting of providing novel chemical cyclodextrin entities which can graft molecules with selective affinities directly or via a spacer arm which remains in the chemical structure of the molecule thus formed.
All of these technical problems are solved for the first time by the present invention in a particularly simple fashion, with excellent yields, rendering the solution of the invention useful on an industrial and on a commercial scale, in fields as varied as the cosmetics industry, in pharmacy, in the agro-industry and in the food industry.
Thus in a first aspect, the invention concerns the use of non-hydroxyalkylated cyclodextrins wherein at least one primary alcohol function (CH
2
OH) is substituted, the —OH portion being replaced by a substituent with formula —O—C(═O)—R or —NR
1
R
2
, where:
R, R
1
and R
2
independently represent a linear or cyclic, saturated or unsaturated, hydroxylated or non-hydroxylated hydrocarbon radical containing 1 to 30 carbon atoms, preferably 1 to 22 carbon atoms, more preferably a fatty chain 2 to 22 carbon atoms;
to encourage tissue penetration, either for a cosmetic application or for producing pharmaceutical compositions, in particular dermopharmaceutical compositions; provided that when the substituent has formula —O—CO—R, the esterified non-hydroxyalkylated cyclodextrins are used as a vector for at least one active ingredient.
In a second aspect, the present invention concerns the use of non-hydroxyalkylated cyclodextrins in the form of micelles or nanoparticles, wherein at least one primary alcohol function (CH
2
OH) is substituted, the —OH portion being replaced by a substituent with formula —O—C(═O)—R or —NR
1
R
2
, where:
R, R
1
and R
2
independently represent a linear or cyclic, saturated or unsaturated, hydroxylated or non-hydroxylated hydrocarbon radical containing 1 to 30 carbon atoms, prefe
Coleman Anthony William
Perrier Eric
Rival Delphine
Terry Nicolas
Coletica
Merchant & Gould P.C.
Padmanabhan Sreeni
Willis Michael A.
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