Products for cutaneous applications with cosmetic and/or therapeutic effects

Products for cutaneous application with cosmetic and/or therapeutic effects, containing one or more active substances. This or these substances are carried by the microspheres of a polymer, dispersed in a liquid in which this polymer is not soluble.

The invention relates to new products for cutaneous application, likely to 
exert a cosmetic or therapeutic effect, or both a cosmetic and therapeutic 
effect, following a particular order in time. These products represent a 
marked advance in the field of action on or by the skin. In particular, 
they prevent overcharging with substances that are often of no use or even 
harmful, frequently the case with conventional treatments. An important 
advantage of the invention resides in the fact that it leads to 
chronobiological action, whose favorable effects have recently been 
recognized. According to recent studies, it appears that the effectiveness 
of a therapeutic agent depends on the precise time at which it is applied: 
it varies from one individual to another as a function of the daily 
physiological cycle of the person in question. The new products according 
to the invention are well-adapted to application allowing their effect in 
time to be determined in advance. A single application of such a product 
is enough to an ensure release of its effects at one or more moments 
during the day or night. Because of the particular properties of the 
carrier used for the active substances, a product according to the 
invention can be used in amounts less than those required in the case of 
usual products, in particular lotions, creams, solutions, powders, etc. 
The products according to the invention, which contain one or more active 
substances carried by the microspheres of a polymer, dispersed in a liquid 
in which this polymer is not soluble, are characterized in that they 
include at least two sets of microsphere-active substance releasing the 
active substance at different times. 
The microspheres of the various polymers and the technique for their 
preparation are known and there is no need to describe them here. 
Descriptions of such products and the processes for their preparation can 
be found, for example, in patents FR 1 572 106 and 2 304 326, EP 0 064 967 
or EP 0 274 961. However, they do not have the chronobiological properties 
of the products according to the present invention. 
Although the invention can relate to microscopic spheres of varying 
dimensions, the size of such spheres preferably does not exceed 1000 nm, 
preferred sizes ranging from 50 to 500 nm or, even better, from 60 to 300 
nm. 
The optimum size of particles further depends on the kind of polymer 
constituting them. 
Given the fineness of the microspheres used according to the invention, 
their specific area per unit weight is fairly substantial, thus leading to 
high adsorption, or electrostatic or covalent combination of the active 
substances of the particles contacted. This leads to the possibility, as 
mentioned above, of obtaining products that are much richer in active 
substances than conventional compositions which require high proportions 
of excipient, the first, and not least, disadvantage of which is blocking 
skin pores. As the active substance in the products according to the 
invention is bound to the microspheres, it is released progressively and, 
consequently, is not likely to lead to overcharging although it can still 
be applied in amounts that may be relatively high. 
The microparticles suitable for application of the invention can be chosen 
from various microspheres of known polymers, solid or hollow, as long as 
they are insoluble in the carrier liquid used. The latter is most often 
water. Nonetheless, it can also be an organic liquid tolerated by the skin 
and by the organism such as, for example, a polyol such as glycol or 
glycerine, a polyol ether or ester, in particular a lipid, such as a 
biologically acceptable vegetable or animal oil. 
The following microparticles of polymers are thus suitable for application 
according to the invention: polysaccharides, polyamides, polyalkylenes, 
polyaryl-alkylenes, polyalkylidenes, polysilicones and others. In each of 
the categories, a large number of derivatives and copolymers can also be 
used. For example, polysaccharides such as xanthan, scleroglucane, 
pectins, starches, celluloses, cyclodextrins and their derivatives such as 
amylose, amylopectin, carboxymethylcellulose, hydroxycellulose, 
alkylcelluloses, dextrin, etc. can also be used. Polysaccharides 
polymerized with proteins can be used when microencapsulation of active 
substances is required at the same time. 
The following can be given as examples of polyaryl-alkylenes: polystyrene 
and especially its copolymers, particularly with ethylene esters, namely 
acrylates or methacrylates of various alkyls, hydroxyalkyls with 
methacryl- or acryl-amide. Similarly, vinyl resins are also suitable, for 
example, polyvinyl acetate and its copolymers with acrylates or 
methacrylates, etc. 
Adsorption capacity and affinity for cosmetic or therapeutic active 
substances varies according to the kind of polymer making up the 
microspheres and the size of these microspheres. These properties are 
taken advantage of in the present invention to obtain products that are 
more or less charged with active substances, releasing the latter at more 
or less different times. Thus, according to a particular feature of the 
invention, products releasing active substances at different times are 
characterized by the joint presence of several kinds of microsphere having 
different sizes and/or derived from different polymers. 
For example, a product which, applied in the morning, has to react at three 
different times during the day is comprised of an aqueous dispersion of 
three kinds of microsphere, 90 to 160 nm in diameter: 1.degree. from 
polysiloxane 2.degree. from polyadipamide 3.degree. from styrene-methyl 
methacrylate copolymer (90/10). 
In another variant of the invention, a cosmetic product to be progressively 
reacted on the skin at different times of the day, following a single 
application, comprises for example (as microspheres of a butyl 
methacrylate-methacrylamide 70/30) 1.1% in weight of these microspheres of 
which 32% have sizes ranging from 60 to 100 nm, 45% have sizes ranging 
from 150 to 250 nm and 23% have diameters ranging from 300 to 500 nm. 
Another mode of application of the invention consists in a suspension of 
microspheres to which one or more active substances are bound by different 
binding forces. Thus, according to the invention, a suspension of the 
microscopic spheres of a polymer can be obtained onto which an active 
substance is adsorbed, another substance binding to the polymer by 
chemical bonds, with the possibility of a third substance binding to the 
spheres by electrostatic or ionic bonds. 
With some active substances and with suitable polymers, the spheres 
according to the invention can absorb the substance, thus forming a sort 
of solid solution. 
Because of this difference in bonding the times at which the substance(s) 
is released also vary, which produces a chronobiological effect on using 
the suspensions according to the invention. 
It should be noted that, in the case of covalent bonds between the active 
substance and the microspheres of a polymer, these bonds are either direct 
or indirect. Indirect bonds require an intermediate molecule providing a 
bridge between the active substance and the polymer's functional groups. 
Such intermediate molecules can, depending on the case, be compounds 
containing two functional groups such as, for example, diacids, diamines, 
amino acids, dialdehydes such as glyoxal, gluteraldehyde, glyoxime, 
carbodiimides, etc. In this case, the process for preparing the aqueous or 
organic microsphere suspension generally includes the addition of an 
intermediate compound before the adjunction of the active substance that 
is to be fixed via this intermediate compound. 
When the microspheres are hollow, they are, in conformity with the 
invention, both adsorbent and/or carriers of functional groups. They 
produce a chronobiological effect since one or more encapsulated active 
substances are released at different times by the hollows of the sphere 
via the adsorption forces and various chemical and physicochemical bonds 
between the substance and the polymer. 
In addition to the previous types of bonding, another type of bond consists 
in adsorption into any pores the spheres may have. This provides a further 
variation in the times at which the active substance is released. 
Generally speaking, the products according to the invention contain 0.1 to 
10%, more often 0.3 to 3%, in weight of the microparticles defined 
hereinabove, the content chosen depending on the type of polymer(s), the 
size of particles, their affinity for active substances and the nature and 
proportion of the dispersion liquid. 
Concerning the active substances, the amount used is preferably the maximum 
amount which can be bound by the microspheres. This binding can take place 
through adsorption, covalent bonding or other physicochemical 
combinations, and/or encapsulation in the case of hollow microspheres and 
preferably involves most of the weight of the active substance. If no 
biological or medical contraindication exists, a slight excess in this or 
these substances can be allowed in solution or in suspension in the 
product's liquid. In general and depending on the case, content in active 
substances of the product according to the invention ranges from 0.01 to 
90% in weight. This fairly wide range is justified by the fact that some 
active molecules, such as for example hormones, vitamins or enzymes, can 
be used at very low doses whereas others, such as rehydrators, 
anti-wrinkle or skin repair products gain from being used in fairly high 
doses. 
The following can be given as non-limiting examples of cosmetically active 
substances: hydrators, preventive agents, restructurers, repairers, 
slimming products, anti-free radical agents, non-enzymatic 
antiglyclosylants, anti-ultraviolet agents, tanning activators, dyes, 
deodorants. Products covered by the invention include those in which 
microspheres, defined hereinabove, include substances such as 
dimethylsilanyl hyaluronate (D.S.H.C.), combinations of proteins with a 
silanol, theophylline, caffeine, tyrosine, silanol-tyrosine, camomile 
extract, hyaluronic acid, collagen, partially hydrolyzed elastin, 
theobromine, fatty acids and many others. 
As therapeutic or both therapeutic and cosmetic active substances, the 
product according to the invention can contain vitamins, hormones, 
enzymes, vasodilators or vasoconstrictors, anti-inflammatory, antiseptic, 
cholagog, diuretic, anti-allergy, neuroleptic substances, etc. In this 
way, microspheres are adsorbed or bound to substances such as, for 
example, vitamins A, B.sub.1, B.sub.2, B.sub.6, C, D.sub.3, E, K, PP, 
oestrogen, androstane, Ruscus Aculeatus extract, escine, acetylsalicylic 
acid, glafenin, esculoside, dextropropoxyphene (HCl), piperazine, 
diazepam, oxazepam, promethazine, etc. 
For the active substance(s) to bind to microparticles by at least one of 
the mechanisms described hereinabove, it is preferable for them to be in 
the liquid state, in solution or fine suspension, wetting the particles. 
This is particularly advisable when the polymer has little affinity for 
aqueous media, as is the case for polystyrene microspheres or microspheres 
in styrene-rich copolymer or when these contain little or no surfactant in 
their preparation. In another variant of the invention, at least one 
liquid secondary compound is incorporated into the product, miscible with 
the microsphere dispersion liquid, in order to improve contact between the 
active substances and the microspheres. 
When the active substances bind to the latter by adsorption, the molecular 
weight of the secondary compound should be less than that of the active 
substance. Polyols, polysaccharides and mucopolysaccharides soluble or 
swelled up by water, as well as their silicated derivatives, lecithin 
and/or surfactants such as, for example, polyoxyethylene, 
polyoxyethylenated fatty esters of sorbital and other surfactants 
tolerated by the skin are all suitable for use as secondary compounds. 
Some active substances can also act as secondary compounds. This is true 
for esters of hyaluronic acid, particularly that of dimethyl silane diol 
which, while acting as an energy rehydrator, can also facilitate the 
binding of various molecules to the microspheres. Content in the secondary 
compound can range from 0.1 to 80%. 
Preparation of the product according to the invention can be carried out by 
suspending the desired amount of microspheres in a dispersion liquid, most 
often water, glycol or an alcohol, in a liquid also acting as an active 
substance or in a mixture of these two liquids. The process is carried out 
at room temperature with moderate stirring. The secondary compound, if it 
use, can be added during the course of this process. 
The product obtained is preferably kept between room temperature and 
1.degree. C., as temperatures below 0.degree. C. may cause alterations.

The invention is illustrated in a non limiting manner by the following 
examples. 
EXAMPLE 1 
Rehydrating cosmetic product in the form of conventional nanospheres 
90 g of a dimethyl silane diol hyaluronate aqueous solution (19.5 g/kg i.e. 
0.9 g/kg in Si) are mixed with 5 g of the microspheres of a copolymer 
containing 60% in weight of styrene with 40% of methyl methacrylate, 
having diameters ranging from 65 to 125 nm (average 95 nm) in suspension 
in 9.5 g of water, stirred for 10 minutes at room temperature then left 
for 48 hours. 
It is found that the microspheres are charged with 30% of 
dimethylsilanediol hyaluronate. 
EXAMPLE 2 
Skin restructuring product based on a combination of silanol and elastin 
(silanol elastinate) 
Microspheres of a copolymer of 4 moles of styrene per 1 mole of acrylic 
acid are prepared using the known process, which consists in polymerizing 
an aqueous emulsion of these two monomers, the emulsifying agent being Na 
dodecylsulfate with K persulfate as the catalyst. After polymerization, 
neutralization of the suspension formed, its purification by aqueous 
dialysis and passage over an ion-exchange resin, 10 ml of the suspension 
contain 10.sup.16 polymer spheres (0.55 g) having an average size of 100 
nm. 10 ml of this suspension are added to 90 ml of a silanol elastinate 
aqueous solution at 46 g/kg (1.8 g of Si). After separation of 
microspheres, it is found that they have adsorbed 28% of the 
elastin-silanol combination, i.e. an amount containing 0.504 g of Si. The 
product thus obtained is used dispersed in a common cosmetic cream in 
three forms: at concentrations of 0.2, 2 and 5% in weight. In all cases, 
there is a clear restructuring effect. The elastin-Si combination is 
released by the microspheres in 8 to 15 hours (determined using a Frantz 
cell). 
EXAMPLE 3 
After having proceeded as in example 2, 5.5 g of the microspheres separated 
are dispersed in 55 ml of an emulsion composed of: 20 ml of water, 25 ml 
of almond oil, 8 ml of polyethylene-glycol, 1 ml of glycerine and 1 ml of 
polyoxyethylene-sorbitol laurate. A single daily application is enough to 
produce marked signs of skin repair. 
EXAMPLE 4 
Product containing two active substances acting at different times 
The microspheres are constituted by a copolymer of 2 moles of styrene with 
2 moles of butadiene and 1 mole of 2-aminoethanol methacrylate. They are 
prepared in the known manner, in aqueous dispersion with Na dodecylsulfate 
as a surfactant and K persulfate as a catalyst. After polymerization, the 
microspheres are neutralized, purified by aqueous dialysis and passed over 
an ion-exchange resin. 
0.09 g of pyrrolidone carboxylic acid, which binds to the methacrylate 
--NH.sub.2 group forming a covalent amide bond, is added to 100 ml of 
suspension of 4 g of these microspheres numbering about 4.times.10.sup.4 
(average size 96 nm). Another purification is then carried out and 6.1 g 
of dimethyl silanol hyaluronate, the same as in example 1, are added to 
the suspension and adsorbed. 
The resulting suspension of 106.1 g thus contains 0.09 g of pyrrolidone 
carboxylic acid and 0.28 g of the Si contained in dimethyl silanol 
hyaluronate. Application to the skin of the product as it is, or mixed 
with a cosmetic cream, gel or lotion leads to release of the pyrrolidone 
compound in 2 to 5 hours and release of the hyaluronate compound in 10 to 
17 hours. A synergetic effect of the two active substances is also 
observed for 2 to 5 hours, followed by a longer period of hyaluronate 
action only. This is seen by signs of extremely favorable rehydration. 
EXAMPLE 5 
Product in which microspheres carry three different active substances 
The microspheres prepared in the known manner, described at the beginning 
of example 4, consist of a copolymer of 4 moles of styrene with 1 mole of 
acrylic acid. 
(A)-100 g of an aqueous suspension of 5 g of microspheres are reacted with 
0.126 g of theophylline, which binds to the acryl groups. 
(B)-The microspheres are then given functional groups using diamine 
hexamethylene, after which they are treated with a 40 g/kg elastin aqueous 
solution. 0.3 g of elastin polypeptides thus bind to the copolymer. 
(C)-The product obtained is purified and made to adsorb Ruscus Aculeatus 
glucosides, from an aqueous extract of this plant (Ruscus 1=33). 
The final product in a 20% aqueous or oily dispersion is well-adapted to 
cutaneous application and has slimming, anti-water retention, as well as 
skin firming, effects and stimulates superficial lymphatic and venous 
microcirculation 
It is suitable for incorporation into various known cosmetics such as 
creams, gels, lotions, etc., preferably at concentrations ranging from 1 
to 7% in weight. 
The three active substances act at different times: elastin in 8 to 19 
hours after application, Ruscus glucosides for 24 hours, theophylline in 2 
to 8 hours. 
EXAMPLE 6 
Microspheres were prepared from a copolymer of 2 moles of styrene, 2 moles 
of vinyl acetate and 1 mole of methacrylic acid. 0.12 g of tyrosine was 
then bound to 100 g of a 3-g aqueous suspension of these microspheres 
(average size 120 nm). 
The microspheres are then treated with diamine hexamethylene, thus binding 
an amine group. After purification, they are made to absorb two sun 
filters: 2-hydroxy-4-methoxy-5-benzophenone sulfonic acid and 2-ethylhexyl 
salicylate. Incorporated into common sun creams at a concentration of 1 to 
7%, a single daily application of these products considerably improves 
protection against UV A and B rays by prolonging the progressive diffusion 
of the two filters. 
EXAMPLE 7 
Modification in the duration of action of two active substances by their 
binding to the same nanospheres by two different mechanisms. 
100 g of an aqueous suspension of 5 g of nanospheres having a diameter of 
about 70 to 130 nm (average 100 nm) are prepared by the copolymerization 
of an emulsion of 4 moles of styrene and 1 mole of acrylic acid, according 
to the technique described in example 2. 0.126 g of theophylline, which 
binds to the acrylic acid groups of the copolymer by an electronic-type 
chemical interaction, is added to these 100 g. 
To this, 0.192 g of a combination of 1 mole of theophylline with 1 mole of 
CH.sub.3 Si(OH).sub.3 is added, hereafter designated by the term 
"theophyllisilane C" and having the empirical formula C.sub.7 H.sub.8 
N.sub.4 O.sub.2, CH.sub.3 --Si(OH).sub.3. After 1 hour's stirring followed 
by ultra-centrifugation, it is found that 28% of the total amount of 
theophyllisilane used has been adsorbed by the nanospheres. 
A liquid product (a-b) composed of two sets of copolymer/active substance 
nanospheres is thus obtained: 
(a)-0.126 g of theophylline chemically bound to 5 g of nanosphere in 100 g 
of aqueous liquid; 
(b)-0.0538 g of theophyllisilane C adsorbed by 5 g of the same nanospheres 
in 100 g of aqueous liquid; 
the aqueous liquid contains 0.1382 g of theophyllisilane C in solution (72% 
of the 0.192 g used). 
The liquid (a-b) is submitted to tests on an experimental model, 
reproducing diffusion phenomena in the skin. 
The proportions of each of the active substances which may have been in 
contact with the skin in 3 hours is thus determined. Further, similar 
determinations are carried out on an aqueous solution (c-d) containing, 
per 100 g, 0.126 g of theophylline and 0.192 g of theophyllisilane C 
without any polymer particles. 
Given below are the percentages of the initial amount of each of these 
active substances which, according to the tests mentioned hereinabove, may 
have been diffused into the skin from the liquid studied: 
______________________________________ 
(a-b) (c-d) 
(with nanospheres) 
(without nanospheres) 
______________________________________ 
Theophylline 
10% 25% 
Theophyllisilane C 
20% 35% 
______________________________________ 
This means that the amount of active substances available to the skin is 
much tempered when these substances are used in the (a-b) form according 
to the invention: 25:10=2.5 times for theophylline and 35: 20=1.75 times 
for theophyllisilane. Starting with the same dose, it is thus possible to 
obtain theophylline action at the end of a desired period of time (for 
example, over 3 hours) whereas theophyllisilane action has come to an end. 
EXAMPLE 8 
Nanospheres in water, similar to those described in the previous example, 
were obtained by copolymerization of 4 moles of styrene with 1 mole of 
methyl acrylate. They thus contained no --COOH groups likely to react with 
the --NH groups of theophylline. 
0.126 g of theophylline and 0.192 g of theophyllisilane were added to 100 g 
of nanosphere aqueous suspension. The two substances were adsorbed by the 
nanospheres. 
As above, the amount of active principal available to the skin in 3 hours 
was determined. The results are as follows: 
20% for theophylline 
22% for theophyllisilane 
against 10% and 20% respectively in the previous example. It can be seen 
that the ratio between the amounts of these two substances adsorbed by the 
skin has been modified by their different modes of binding to the 
nanospheres. Consequently, the relative durations of action of these 
substances are changed. The invention thus allows the chronology of action 
of the active substances to be modified when these substances are bound to 
microscopic polymer particles by different mechanisms. 
EXAMPLE 9 
Modification in the chronology of release of a single active substance from 
nanospheres through binding of the latter via two different mechanisms. 
(A)-0.126 g of theophylline, which binds ionically to the --COOH groups of 
the copolymer, is added to 100 g of an aqueous suspension of 5 g of 
nanosphere of the same copolymer as that described example 7, consisting 
of 1 mole of acrylic acid per 4 moles of styrene. The same nanospheres are 
then made to adsorb 0.5 g of theophylline. 
The proportion of theophylline which is available to the skin in 3 hours 
and in 5 hours is then determined from 100 g of an aqueous suspension of 5 
g of nanosphere charged as described above. 
(B)-Analogous determinations are carried out in parallel on 100 g of an 
aqueous suspension of 5 g of nanospheres of a similar copolymer containing 
--COOCH.sub.3 groups instead of --COOH groups. These spheres do not bind 
theophylline by ionic bonds but adsorb it. They were made to adsorb 0.626 
g, i.e. the same total amount as in A. 
The percentages of theophylline that can thus be absorbed by the skin are 
______________________________________ 
in 3 hours 
in 5 hours 
______________________________________ 
A 15% 28% 
B 18% 40% 
______________________________________ 
The result of this is that in product A, which contains both 
copolymer+theophylline combined to --COOH groups and adsorbed 
copolymer+theophylline, the chronology of action in the skin differs from 
that of product B containing the same amount of theophylline but in which 
the theophylline is only and totally adsorbed by the nanospheres.