FR3145282A1 - COMPOSITION COMPRISING HYALURONIC ACID, INCLUDING HYDROPHOBIC NANO PARTICLES - Google Patents

Abstract

COMPOSITION COMPRISING HYALURONIC ACID, INCLUDING HYDROPHOBIC NANO PARTICLES The present invention relates to a composition comprising: (a) at least one cationic polymer; (b-1) at least one first anionic polymer chosen from hyaluronic acids and their derivatives; (b-2) at least one second anionic polymer different from (b-1) first anionic polymer; (c) at least one non-polymeric acid or salt thereof; (d) at least one optional metal salt; (e) at least one fatty acid; and (f) water, under specific conditions. The composition according to the present invention may be stable, transparent or translucent. Furthermore, the composition according to the present invention can deliver hyaluronic acids and/or hyaluronic acid derivatives deeper into a keratinous substance such as the skin. Figure for the abstract: none

Description

COMPOSITION COMPRISING HYALURONIC ACID, INCLUDING HYDROPHOBIC NANO PARTICLES

The present invention relates to a composition including a nanoparticle including hyaluronic acid or salts thereof, as well as a cosmetic process using the composition.

PRIOR ART

Hyaluronic acid is a predominant glucosaminoglycan found in the skin. Thus, fibroblasts mainly synthesize collagens, non-collagen matrix glycoproteins (fibronectin, laminin), proteoglycans, and elastin. Keratinocytes, on the other hand, mainly synthesize sulfated glycosaminoglycans and hyaluronic acid. Hyaluronic acid is also called hyaluronan (HA).

Hyaluronic acid is present in the free state in the epidermis and dermis and is responsible for the turgor of the skin. This polysaccharide can actually retain a large volume of water, corresponding to 1000 times its weight. In this sense, hyaluronic acid plays an important role in increasing the amounts of bound water in tissues, as well as in the mechanical properties of the skin and in the formation of wrinkles.

Hyaluronic acid is widely used as a cosmetic ingredient due to its high moisturizing effects.

JP-A-2014-114272 discloses a complex particle including hyaluronic acid, chitosan and an anionic polymer other than hyaluronic acid.

DISCLOSURE OF THE INVENTION

It has been found that a complex particle including hyaluronic acid, such as that disclosed in JP-A-2014-114272, sometimes has difficulty penetrating a keratinous substance such as skin.

Furthermore, in some cases, a composition including such a complex particle must be stable without causing precipitation, and transparent or translucent with a lower turbidity level. In addition, it is preferable that the complex particle is small so that it has a nanometer size (less than 1000 nm), in terms of its ability to penetrate a keratinous substance such as the skin.

Thus, an objective of the present invention is to provide a stable, transparent or translucent composition, comprising a nanoparticle including hyaluronic acid, which could deliver hyaluronic acid deeper into a keratinous substance such as the skin.

The above objective of the present invention can be achieved by a composition, preferably a cosmetic composition, and more preferably a cosmetic composition for the skin, comprising

nanoparticles comprising:

(a) at least one cationic polymer;

(b-1) at least one first anionic polymer chosen from hyaluronic acids and their derivatives;

(b-2) at least one second anionic polymer which is different from (b-1) first anionic polymer;

(c) at least one non-polymeric acid or a salt thereof;

(d) at least one optional metal salt; and

(e) at least one fatty acid,

And

(f) water,

in which

the amount of nanoparticles is from 0.01% to 0.58% by weight, preferably from 0.05% to 0.57% by weight and more preferably from 0.1% to 0.56% by weight, relative to the total weight of the composition,

the weight ratio of the amount of the cationic polymer(s) to the total weight of the nanoparticles is 0.06 to 0.25,

the weight ratio of the amount of the (b-2) second anionic polymer to the total weight of the nanoparticles is 0.26 or more,

the weight ratio of the amount of the (c) non-polymeric acid(s) or salt(s) thereof to the total weight of the nanoparticles is 0.03 or more,

the weight ratio of the amount of the optional metal salt(s) to the total weight of the nanoparticles is 0.30 or less, and

the weight ratio of the amount of the fatty acid(s) to the total weight of the nanoparticles is 0.001 or more.

The (a) cationic polymer may have at least one positively chargeable and/or positively charged moiety selected from the group consisting of a primary, secondary or tertiary amino group, a quaternary ammonium group, a guanidine group, a biguanide group, an imidazole group, an imino group and a pyridyl group.

The (a) cationic polymer may be selected from the group consisting of alkyldiallylamine cyclopolymers and dialkyldiallylammonium cyclopolymers such as (co)polydiallyldialkyl ammonium chloride, (co)polyamines such as chitosans and (co)polylysines, cationic (co)polyamino acids such as collagen and arginine/lysine polypeptide, cationic cellulose polymers, and salts thereof.

The weight ratio of the amount of the (a) cationic polymer(s) relative to the total weight of the nanoparticles in the composition according to the present invention may be from 0.06 to 0.24, preferably from 0.07 to 0.22, and more preferably from 0.08 to 0.20.

The (b-1) first anionic polymer may have a molecular weight of 2,000 kDa or less, preferably 1,000 kDa or less, and more preferably 100 kDa or less.

The weight ratio of the amount of the (b-1) first anionic polymer(s) relative to the total weight of the nanoparticles in the composition according to the present invention may be from 0.01 to 0.8, preferably from 0.02 to 0.7, and more preferably from 0.03 to 0.6.

The (b-2) second anionic polymer may be selected from the group consisting of carrageenan, pectin and a mixture thereof.

The weight ratio of the amount of the (b-2) second anionic polymer(s) relative to the total weight of the nanoparticles in the composition according to the present invention may be from 0.26 to 0.9, preferably from 0.28 to 0.8, and more preferably from 0.30 to 0.7.

The (c) non-polymeric acid or salt(s) thereof may be selected from the group consisting of phytic acid, citric acid, lactic acid and a mixture thereof.

The weight ratio of the amount of the (c) non-polymeric acid(s) or salt(s) thereof relative to the total weight of the nanoparticles in the composition according to the present invention may be from 0.03 to 0.6, preferably from 0.035 to 0.5, and more preferably from 0.04 to 0.4.

The (d) optional metal salt may be selected from polyvalent metal salts, preferably divalent metal salts, more preferably calcium salts such as calcium chloride and calcium pyrrolidone carboxylate, and magnesium salts such as magnesium chloride.

The weight ratio of the amount of the (d) optional metal salt relative to the total weight of the nanoparticles in the composition according to the present invention may be from 0.001 to 0.30, preferably from 0.005 to 0.25, and more preferably from 0.01 to 0.20.

The (e) fatty acid may be chosen from saturated and unsaturated fatty acids, linear or branched in C ₄ -C ₂₂ , preferably C ₆ -C ₂₀ , more preferably C ₈ -C ₁₈ .

The weight ratio of the amount of the fatty acid relative to the total weight of the nanoparticles in the composition according to the present invention may be from 0.001 to 0.4, preferably from 0.002 to 0.3, and more preferably from 0.003 to 0.2.

The amount of (f) water in the composition according to the present invention may be from 50% to 95% by weight, preferably from 60% to 90% by weight and more preferably from 70% to 85% by weight, relative to the total weight of the composition.

The present invention also relates to a cosmetic process for a keratinous substance such as the skin, comprising: applying, to the keratinous substance, the composition according to the present invention.

After careful research, the inventors discovered that it is possible to provide a stable, transparent or translucent composition comprising a nanoparticle including hyaluronic acid, which could deliver hyaluronic acid deeper into a keratinous substance such as the skin.

Thus, the composition according to the present invention which is preferably a cosmetic composition, and more preferably a cosmetic composition for the skin, comprises

nanoparticles comprising:

(a) at least one cationic polymer;

(b-1) at least one first anionic polymer chosen from hyaluronic acids and their derivatives;

(b-2) at least one second anionic polymer which is different from (b-1) first anionic polymer;

(c) at least one non-polymeric acid or a salt thereof;

(d) at least one optional metal salt; and

(e) at least one fatty acid,

And

(f) water,

in which

the amount of nanoparticles is from 0.01% to 0.58% by weight, preferably from 0.05% to 0.57% by weight and more preferably from 0.1% to 0.56% by weight, relative to the total weight of the composition,

the weight ratio of the amount of the cationic polymer(s) to the total weight of the nanoparticles is 0.06 to 0.25,

the weight ratio of the amount of the (b-2) second anionic polymer to the total weight of the nanoparticles is 0.26 or more,

the weight ratio of the amount of the (c) non-polymeric acid(s) or salt(s) thereof to the total weight of the nanoparticles is 0.03 or more,

the weight ratio of the amount of the optional metal salt(s) to the total weight of the nanoparticles is 0.30 or less, and

the weight ratio of the amount of the fatty acid(s) to the total weight of the nanoparticles is 0.001 or more.

The term “nanoparticle” refers to a particle with a size or diameter less than 1000 nm. The size or diameter of the nanoparticle can be measured by a dynamic light scattering method. This particle diameter can be based on a volume average diameter.

The composition according to the present invention may include nanoparticles comprising the (a) cationic polymer(s), the (b-1) first anionic polymer(s), the (b-2) second anionic polymer(s), the (c) non-polymeric acid(s) or salt(s) thereof, the (d) optional metal salt(s) and the (e) fatty acid(s). The (b-1) first anionic polymer is selected from hyaluronic acids and their derivatives. Thus, the nanoparticles include at least one hyaluronic acid and/or at least one hyaluronic acid derivative.

Nanoparticles can be polyionic complex particles which are formed by one or more polyionic complexes.

The (a) cationic polymer can be rendered hydrophobic by the (e) fatty acid. The cationic group such as a quaternary ammonium group in the (a) cationic polymer can ionically interact with the carboxylic group, which is anionic, of the (f) fatty acid. Since the (e) fatty acid has a hydrophobic moiety, the (a) cationic polymer can be rendered ionically hydrophobic and can have sufficient hydrophobicity. Thus, the nanoparticles, including the (a) cationic polymer, can be rendered hydrophobic by the (e) fatty acid. Surprisingly, the hydrophobicized nanoparticles can penetrate deeper into a keratinous substance such as skin, compared with the non-hydrophobicized nanoparticles.

The nanoparticles can exert cosmetic effects based on hyaluronic acid and/or the hyaluronic acid derivative. In addition, the composition according to the present invention can provide cosmetic effects, such as moisturizing effects, based on hyaluronic acid and/or the hyaluronic acid derivative.

The composition according to the present invention may be stable, transparent or translucent. In addition, the composition according to the present invention may include nanoparticles including hyaluronic acid, with an increased ability to penetrate into a keratinous substance such as the skin. Thus, the composition according to the present invention may deliver hyaluronic acids and/or hyaluronic acid derivatives deeper into a keratinous substance such as the skin.

The composition, process and other properties according to the present invention will be described in more detail hereinafter.

[Nanoparticle]

The composition according to the present invention comprises nanoparticles including:

(a) at least one cationic polymer,

(b-1) at least one first anionic polymer chosen from hyaluronic acids and their derivatives;

(b-2) at least one second anionic polymer which is different from (b-1) first anionic polymer;

(c) at least one non-polymeric acid or a salt thereof;

(d) at least one optional metal salt; and

(e) at least one fatty acid.

The above ingredients (a) to (e), particularly ingredients (a), (b-1), (b-2) and (c) can form a polyionic complex. The polyionic complex can take the form of a nanoparticle.

Two or more different types of nanoparticles may be present in combination. Thus, a single type of a nanoparticle or a combination of different types of nanoparticles may be present in the composition according to the present invention.

The size or diameter of the nanoparticle may be from 5 nm to 500 nm, preferably from 10 nm to 400 nm, more preferably from 20 nm to 300 nm, and even more preferably from 30 nm to 200 nm. The size or diameter may be a volume-based average size or diameter.

The amount of nanoparticles in the composition according to the present invention may be from 0.01% to 0.58% by weight, preferably from 0.05% to 0.57% by weight, more preferably from 0.1% to 0.56% by weight, even more preferably from 0.2% to 0.55% by weight, relative to the total weight of the composition.

(Cationic polymer)

The composition according to the present invention may comprise (a) at least one cationic polymer. Two or more different types of cationic polymers may be used in combination. Thus, a single type of cationic polymer or a combination of different types of cationic polymers may be used.

The (a) cationic polymer has a positive charge density. The charge density of the (a) cationic polymer may be between 0.01 meq/g and 20 meq/g, preferably between 0.05 and 15 meq/g and, more preferably, between 0.1 and 10 meq/g.

It may be preferable that the molecular weight of the (a) cationic polymer is equal to or greater than 500, preferably equal to or greater than 1,000, more preferably equal to or greater than 2,000, and even more preferably equal to or greater than 3,000. Unless otherwise defined in the descriptions, "molecular weight" means a weight average molecular weight.

The (a) cationic polymer may have at least one positively chargeable and/or positively charged moiety selected from the group consisting of a primary, secondary or tertiary amino group, a quaternary ammonium group, a guanidine group, a biguanide group, an imidazole group, an imino group and a pyridyl group. The term “amino group” (primary) herein means a -NH ₂ group.

The (a) cationic polymer may be a homopolymer or a copolymer. By "copolymer" is meant both copolymers obtained from two kinds of monomers and those obtained from more than two kinds of monomers, such as terpolymers obtained from three kinds of monomers.

The (a) cationic polymer may be selected from natural and synthetic cationic polymers. Non-limiting examples of (a) cationic polymers are given below.

(1) Homopolymers and copolymers derived from acrylic or methacrylic esters and amides and comprising at least one unit chosen from the units of the following formulae:

in which:

R ₁ and R ₂ , which may be the same or different, are chosen from hydrogen and alkyl groups comprising from 1 to 6 carbon atoms, for example methyl and ethyl groups;

R ₃ , which may be the same or different, is selected from hydrogen and CH ₃ ;

the symbols A, which may be identical or different, are chosen from linear or branched alkyl groups comprising from 1 to 6 carbon atoms, for example from 2 to 3 carbon atoms and hydroxyalkyl groups comprising from 1 to 4 carbon atoms;

R ₄ , R ₅ and R ₆ , which may be the same or different, are selected from alkyl groups comprising from 1 to 18 carbon atoms and benzyl groups, and in at least one embodiment, alkyl groups comprising from 1 to 6 carbon atoms and

X is an anion derived from an inorganic or organic acid, such as methosulfate anions and halides, e.g. chloride and bromide.

The copolymers of family (1) above may also comprise at least one unit derived from comonomers which may be chosen from acrylamides, methacrylamides, diacetone acrylamides, acrylamides and methacrylamides substituted on the nitrogen atom with (C ₁ -C ₄ ) lower alkyl groups, groups derived from acrylic or methacrylic acids and their esters, vinyllactams such as vinylpyrrolidone and vinylcaprolactam and vinyl esters.

Here are some examples of copolymers of the family (1):

copolymers of acrylamide and dimethylaminoethyl methacrylate quaternized with dimethyl sulfate or with a dimethyl halide,

copolymers of acrylamide and methacryloyloxyethyltrimethylammonium chloride described, for example, in European Patent Application No. 0 080 976,

copolymers of acrylamide and methacryloyloxyethyltrimethylammonium methosulfate,

copolymers of vinylpyrrolidone/dialkylaminoalkyl methacrylate or acrylate, quaternized or not, described, for example, in French Patents Nos. 2,077,143 and 2,393,573,

dimethylaminoethyl methacrylate/vinylcaprolactam/vinylpyrrolidone terpolymers,

vinylpyrrolidone/methacrylamidopropyldimethylamine copolymers, quaternized vinylpyrrolidone/dimethylaminopropylmethacrylamide copolymers and

crosslinked polymers of methacryloyloxy(C ₁ -C ₄ )alkyltri(C ₁ -C ₄ )alkylammonium salts such as polymers obtained by homopolymerization of dimethylaminoethyl methacrylate quaternized with methyl chloride, or by copolymerization of acrylamide with dimethylaminoethyl methacrylate quaternized with methyl chloride, the homo- or copolymerization being followed by crosslinking with a compound containing olefinic unsaturation, in particular methylenebisacrylamide.

(2) Cationic cellulose polymers such as cellulose ether derivatives comprising one or more quaternary ammonium groups described, for example, in French patent No. 1,492,597, such as the polymers marketed under the names “JR” (JR 400, JR 125, JR 30M) or “LR” (LR 400, LR 30M) by the company Union Carbide Corporation. These polymers are also defined in the CTFA dictionary as quaternary ammoniums of hydroxyethylcellulose reacted with an epoxide substituted by a trimethylammonium group.

It is preferred that the cationic cellulose polymers have at least one quaternary ammonium group, preferably a trialkyl quaternary ammonium group and, more preferably, a trimethyl quaternary ammonium group.

The quaternary ammonium group may be present in a quaternary ammonium group which can be represented by the following chemical formula (I):
(I)

in which

each of the groups R ₁ and R ₂ denotes a C ₁ -C ₃ alkyl group, preferably a methyl or ethyl group and, more preferably, a methyl group,

R ₃ denotes a C ₁ - C ₂₄ alkyl group, preferably a methyl or ethyl group and, more preferably, a methyl group,

X- denotes an anion, preferably a halide and, more preferably, a chloride,

n denotes an integer between 0 and 30, preferably between 0 and 10 and, more preferably, equal to 0, and

R ₄ denotes a C ₁ - C ₄ alkylene group, preferably an ethylene or propylene group.

The leftmost ether bond (-O-) in the above chemical formula (I) can attach to the sugar ring of the polysaccharide.

It is preferred that the group containing the quaternary ammonium is -O-CH ₂ -CH(OH)-CH ₂ -N ⁺ (CH ₃ ) ₃ .

(3) Cationic cellulose polymers such as cellulose copolymers and cellulose derivatives grafted with a water-soluble quaternary ammonium monomer and described, for example, in U.S. Patent No. 4,131,576, such as hydroxyalkylcelluloses, e.g., hydroxymethyl-, hydroxyethyl-, and hydroxypropylcelluloses grafted with, for example, a salt selected from methacryloylethyltrimethylammonium, methacrylamidopropyltrimethylammonium, and dimethyldiallylammonium salts.

Commercial products corresponding to these polymers include, for example, the products marketed under the names “Celquat® L 200” and “Celquat® H 100” by the company National Starch.

(4) Non-cellulosic cationic polysaccharides described in U.S. Patent Nos. 3,589,578 and 4,031,307, such as guar gums comprising cationic trialkylammonium groups, cationic hyaluronic acid and dextran hydroxypropyl trimonium chloride. Guar gums modified with a salt, e.g., chloride, of 2,3-epoxypropyltrimethylammonium (guar hydroxypropyltrimonium chloride) may also be used.

These products are marketed, for example, under the trade names JAGUAR® C13 S, JAGUAR® C15, JAGUAR® C17 and JAGUAR® C162 by the company MEYHALL.

(5) Polymers comprising piperazinyl units and divalent alkylene or hydroxyalkylene groups comprising straight or branched chains, optionally interrupted with at least one entity selected from oxygen, sulfur, nitrogen, aromatic and heterocyclic rings, as well as the oxidation and/or quaternization products of these polymers. These polymers are described, for example, in French patents Nos. 2,162,025 and 2,280,361.

(6) Water-soluble polyamino amides prepared, for example, by polycondensation of an acidic compound with a polyamine; these polyamino amides being optionally crosslinked with a moiety selected from epihalohydrins; diepoxides; dianhydrides; unsaturated dianhydrides; biunsaturated derivatives; bishalohydrins; bisazetidiniums; bishaloacydiamines; bisalkyl halides; oligomers resulting from the reaction of a difunctional compound which is reactive with a moiety selected from bishalohydrins; bisazetidiniums, bishaloacyldiamines, bisalkyl halides; epihalohydrins; dihydroxides and bisunsaturated derivatives; the crosslinking agent being used in an amount ranging from 0.025 to 0.35 mole per amine group of polyamino amides; these polyaminoamides being optionally alkylated or, if they comprise at least one tertiary amine function, they can be quaternized. These polymers are described, for example, in French patents Nos. 2,252,840 and 2,368,508.

(7) Polyamino-amide derivatives resulting from the condensation of polyalkylene polyamines with polycarboxylic acids, followed by alkylation with difunctional agents, for example, adipic acid/dialkylaminohydroxyalkyldialkylenetriamine polymers in which the alkyl group comprises from 1 to 4 carbon atoms, such as methyl, ethyl and propyl groups, and the alkylene group comprises from 1 to 4 carbon atoms, such as an ethylene group. These polymers are described, for example, in French patent No. 1,583,363. In at least one embodiment, these derivatives may be selected from adipic acid/dimethylaminohydroxypropyldiethylenetriamine polymers.

(8) Polymers obtained by reacting a polyalkylene polyamine comprising two primary amine groups and at least one secondary amine group, with a dicarboxylic acid selected from diglycolic acid and saturated aliphatic dicarboxylic acids comprising from 3 to 8 carbon atoms. The molar ratio of the polyalkylene polyamine to the dicarboxylic acid can vary from 0.8:1 to 1.4:1; the polyamino amide resulting from this reaction with epichlorohydrin in a molar ratio of epichlorohydrin to the secondary amine group of the polyamino amide ranging from 0.5:1 to 1.8:1. These polymers are described, for example, in U.S. Patent Nos. 3,227,615 and 2,961,347.

(9) Alkyldiallylamine cyclopolymers and dialkyldiallylammonium cyclopolymers, such as homopolymers and copolymers comprising, as the main constituent of the chain, at least one unit selected from the units of formulae (Ia) and (Ib):
(Ia)
(Ib)

in which:

k and t, which may be the same or different, are equal to 0 or 1, the sum k+t being equal to 1;

R ₁₂ is selected from hydrogen and methyl groups;

R ₁₀ and R ₁₁ , which may be the same or different, are selected from alkyl groups comprising from 1 to 6 carbon atoms, hydroxyalkyl groups in which the alkyl group comprises, for example, from 1 to 5 carbon atoms and lower amidoalkyl groups (C ₁ -C ₄ ), or R ₁₀ and R ₁₁ may form, together with the nitrogen atom to which they are attached, heterocyclic groups such as piperidinyl and morpholinyl and

Y' is an anion such as bromide, chloride, acetate, borate, citrate, tartrate, bisulfate, bisulfite, sulfate and phosphate. These polymers are described, for example, in French patent No. 2,080,759 and in its certificate of addition 2,190,406.

In one embodiment, R ₁₀ and R ₁₁ , which may be the same or different, are selected from alkyl groups comprising from 1 to 4 carbon atoms.

Among these polymers, we can cite, in particular, (co)polydiallyldialkyl ammonium chloride such as the homopolymer of dimethyldiethylammonium chloride sold under the name “MERQUAT® 100” by the company CALGON (and its counterparts of low weight average molecular mass) and the copolymers of diallyldimethylammonium chloride and acrylamide sold under the name “MERQUAT® 550”.

Quaternary diammonium polymers comprising at least one repeating unit of formula (II):
(II)

in which:

R ₁₃ , R ₁₄ , R ₁₅ and R ₁₆ , which may be the same or different, are selected from aliphatic, alicyclic and aliphatic aryl groups comprising from 1 to 20 carbon atoms and lower aliphatic hydroxyalkyl groups, or R ₁₃ , R ₁₄ , R ₁₅ and R ₁₆ , together or separately, with the nitrogen atoms to which they are attached, heterocycles alternatively comprising a second heteroatom other than nitrogen, or R ₁₃ , R ₁₄ , R ₁₅ , and R ₁₆ which may be the same or different, are selected from linear or branched C ₁ -C ₆ alkyl groups substituted by at least one group selected from alkyl groups, ester groups, acyl groups, amide groups, -CO-OR ₁₇ -E groups and -CO-NH-R ₁₇ -E, where R ₁₇ is an alkylene group and E is a quaternary ammonium group;

A ₁ and B ₁ , which may be identical or different, are chosen from polymethylene groups comprising from 2 to 20 carbon atoms, which may be linear or branched, saturated or unsaturated, and which may comprise, linked or intercalated in the main chain, at least one entity chosen from aromatic rings, oxygen, sulfur, sulfoxide groups, sulfone groups, disulfide groups, amino groups, alkylamino groups, hydroxyl groups, quaternary ammonium groups, ureido groups, amide groups and ester groups, and

X ^- denotes an anion derived from an inorganic or organic acid;

it being understood that A ₁ , R ₁₃ and R ₁₅ can form, with the two nitrogen atoms to which they are attached, a piperazine ring;

if A ₁ is chosen from linear or branched, saturated or unsaturated alkylene or hydroxyalkylene groups, B ₁ may be chosen from:

-(CH ₂ ) _n -CO-E'-OC-(CH ₂ ) _n -

where E' is chosen from:

(a) glycolic residues of formula -O-Z-O-, where Z is selected from linear or branched hydrocarbon groups and groups of the following formulae:

-(CH ₂ -CH ₂ -O) _x -CH ₂ -CH ₂ -

-[CH ₂ -CH(CH ₃ )-O] _y -CH ₂ -CH(CH ₃ )-

where x and y, which may be the same or different, are chosen from integers ranging from 1 to 4, which represent a defined and unique degree of polymerization, and numbers ranging from 1 to 4, which represent an average degree of polymerization;

(b) a bis-secondary diamine residue such as piperazine derivatives;

(c) bis-primary diamine residues of formula -NH-Y-NH-, in which Y is selected from linear or branched hydrocarbon groups and the divalent group -CH ₂ -CH ₂ -SS-CH ₂ -CH 2 -CH ₂ - _; and

d) ureylene groups of formula -NH-CO-NH-.

In at least one embodiment, X ^- is an anion such as chloride or bromide.

Polymers of this type are described, for example, in French patents Nos. 2,320,330; 2,270,846; 2,316,271; 2,336,434; and 2,413,907 and in U.S. patents Nos. 2,273,780; 2,375,853; 2,388,614; 2,454,547; 3,206,462; 2,261,002; 2,271,378; 3,874,870; 4,001,432; 3,929,990; 3,966,904; 4,005,193; 4,025,617; 4,025,627; 4,025,653; 4,026,945 and 4,027,020.

Non-limiting examples of such polymers include those comprising at least one repeating unit of formula (III):
(III)

in which R ₁₃ , R ₁₄ , R ₁₅ and R ₁₆ , which may be the same or different, are selected from alkyl and hydroxyalkyl groups comprising from 1 to 4 carbon atoms, n and p, which may be the same or different, are integers ranging from 2 to 20, and X ^- is an anion derived from an inorganic or organic acid.

(11) polyquaternary ammonium polymers comprising units of formula (IV):
(IV)

in which:

R ₁₈ , R ₁₉ , R ₂₀ and R ₂₁ , which may be the same or different, are selected from hydrogen, methyl, ethyl, propyl, β-hydroxyethyl, β-hydroxypropyl, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) _p OH groups, where p is selected from integers between 0 and 6, provided that R ₁₈ , R ₁₉ , R ₂₀ and R ₂₁ are not simultaneously hydrogen,

r and s, which may be the same or different, are chosen from integers ranging from 1 to 6,

q is chosen from integers ranging from 0 to 34,

- X ^- denotes an anion, such as a halide and

A is selected from dihalide radicals and -CH ₂ -CH ₂ -O-CH ₂ -CH ₂ -.

These compounds are described, for example, in European patent application No. 0 122 324.

(12) Quaternary polymers of vinylpyrrolidone and vinylimidazole.

Other examples of suitable cationic polymers include, but are not limited to, cationic proteins and cationic protein hydrolysates, polyalkyleneimines, such as polyethyleneimines, polymers comprising units selected from vinylpyridine and vinylpyridinium, condensates of polyamines and epichlorohydrin, quaternary polyureylenes and chitin derivatives.

According to one embodiment of the present invention, the (a) at least one cationic polymer is selected from cellulose ether derivatives comprising quaternary ammonium groups, such as the products sold under the name "JR 400" by the company UNION CARBIDE CORPORATION, cationic cyclopolymers, for example, homopolymers and copolymers of dimethyldiallylammonium chloride sold under the names MERQUAT® 100, MERQUAT® 550, and MERQUAT® S by the company CALGON, guar gums modified with a 2,3-epoxypropyltrimethylammonium salt and quaternary polymers of vinylpyrrolidone and vinylimidazole.

(13) Polyamines

As (a) cationic polymer, it is also possible to use (co)polyamines, which may be homopolymers or copolymers, with a plurality of amino groups. The amino group may be a primary, secondary, tertiary or quaternary amino group. The amino group may be present in the backbone of a polymer or in a pendant group, if present, of the (co)polyamines.

Examples of (co)polyamines include chitosans, (co)polylamines, (co)polyvinylamines, (co)polyanilines, (co)polyvinylimidazoles, (co)polydimethylaminoethylenemethacrylates, (co)polyvinylpyridines such as (co)poly-1-methyl-2-vinylpyridines, (co)polyimines such as (co)polyethyleneimines, (co)polypyridines such as (co)poly(quaternary pyridines), (co)polybiguanides such as (co)polyaminopropyl biguanides, (co)polylysines, (co)polyornithines, (co)polyarginines, (co)polyhistidines, aminodextrans, aminocelluloses, amino(co)polyvinylacetals and their salts.

As (co)polyamines, it is preferable to use (co)polylysines. Polylysine is well known. Polylysine can be a natural homopolymer of L-lysine that can be produced by bacterial fermentation. For example, polylysine can be ε-Poly-L-lysine, which is commonly used as a natural preservative in food products. Polylysine is a polyelectrolyte that is soluble in polar solvents such as water, propylene glycol, and glycerol. Polylysine is commercially available in different forms, such as poly D-lysine and poly L-lysine. Polylysine can be in the form of salt and/or solution.

An arginine/lysine polypeptide can also be used.

(14) Cationic polyamino acids

As (a) a cationic polymer, it may be possible to use cationic polyamino acids, which may be cationic homopolymers or copolymers, with a plurality of amino groups and carboxyl groups. The amino group may be a primary, secondary, tertiary or quaternary amino group. The amino group may be present in the backbone of a polymer or in a pendant group, if present, of the cationic polyamino acids. The carboxyl group may be present in a pendant group, if present, of the cationic polyamino acids.

Examples of cationic polyamino acids include cationized collagen, cationized gelatin, hydroxypropyl steardimonium hydrolyzed wheat protein, hydroxypropyl cocodimonium hydrolyzed wheat protein, hydroxypropyltrimonium hydrolyzed conchiolin protein, hydroxypropyltrimonium steardimonium hydrolyzed soy protein, hydroxypropyltrimonium hydrolyzed soy protein, cocodimonium hydrolyzed soy protein, and the like.

(15) Cationic starches

As (a) cationic polymer, cationic starches can also be mentioned.

Examples of cationic starches include starches modified with a 2,3-epoxypropyltrimethylammonium salt (e.g. chloride), such as the product called starch hydroxypropyltrimonium chloride according to the INCl nomenclature and sold under the name SENSOMER Cl-50 from Ondeo or Pencare ^TM DP 1015 from Ingredion.

(16) Cationic gum

As (a) cationic polymer, cationic gums can also be mentioned.

The gums may, for example, be selected from the group consisting of cassia gum, karaya gum, konjac gum, tragacanth gum, tara gum, acacia gum and gum arabic.

Examples of cationic gums include cationic polygalactomannan derivatives such as guar gum derivatives and cassia gum derivatives, for example CTFA: Guar Hydroxypropyltrimonium Chloride, Hydroxypropyl Guar Hydroxypropyltrimonium Chloride, and Cassia Hydroxypropyltrimonium Chloride. Guar hydroxypropyltrimonium chloride is commercially available under the Jaguar™ family of trade names from Rhodia Inc. and the N-Hance family of trade names from Ashland Inc. Cassia hydroxypropyltrimonium chloride is commercially available under the brand names Sensomer™ CT-250 and Sensomer™ CT-400 from Lubrizol Advanced Materials, Inc. or ClearHance ^TM from Ashland Inc.

The following descriptions relate to preferable embodiments of the (a) cationic polymer.

It may be preferable that (a) the cationic polymer is selected from the group consisting of alkyldiallylamine cyclopolymers and dialkyldiallylammonium cyclopolymers such as (co)polydiallyldialkylammonium chloride, (co)polyamines such as (co)polylysines, cationic (co)polyamino acids such as cationized collagen and arginine/lysine polypeptide, cationic cellulose polymers, and salts thereof.

It may be more preferable that the (a) cationic polymer is selected from the group consisting of polylysines such as poly-α-lysine and poly-ε-lysine, arginine/lysine polypeptide, polyquaternium-4, polyquaternium-10, polyquaternium-24, polyquaternium-67, starch hydroxypropyl trimonium chloride, cassia hydroxypropyl trimonium chloride, chitosans such as chitosan and a mixture thereof.

It may be even more preferable that the (a) cationic polymer is selected from polylysines such as poly-α-lysine and poly-ε-lysine, an arginine/lysine polypeptide, chitosans such as chitosan, and a mixture thereof.

The weight ratio of the amount of the (a) cationic polymer(s) relative to the total weight of the nanoparticles in the composition according to the present invention is from 0.06 to 0.25.

The weight ratio of the amount of the (a) cationic polymer(s) relative to the total weight of the nanoparticles in the composition according to the present invention may be from 0.06 to 0.24, preferably from 0.07 to 0.22, and more preferably from 0.08 to 0.20.

(Anionic polymer)

The composition according to the present invention comprises:

(b-1) at least one first anionic polymer chosen from hyaluronic acids and their derivatives; and

(b-2) at least one second anionic polymer which is different from (b-1) first anionic polymer.

Two or more different types of anionic polymers may be used in combination for each of (b-1) first anionic polymer and (b-2) second anionic polymer. Thus, a single type of anionic polymer or a combination of different types of anionic polymers may be used for each of (b-1) first anionic polymer and (b-2) second anionic polymer.

The (b-1) first anionic polymer and the (b-2) second anionic polymer have a negative charge density. The charge density of each of the (b-1) first anionic polymer and (b-2) second anionic polymer may be between 0.1 meq/g and 20 meq/g, preferably between 1 and 15 meq/g, and more preferably between 4 and 10 meq/g.

First anionic polymer:

According to the present invention, the (b-1) first anionic polymer is chosen from hyaluronic acids and their derivatives.

Hyaluronic acid can be represented by the following chemical formula.

In the context of the present invention, the term "hyaluronic acid" covers in particular the basic unit of hyaluronic acid of formula:

It is the smallest fraction of hyaluronic acid comprising a dimer of disaccharide, namely D-glucuronic acid and N-acetylglucosamine.

The term “hyaluronic acid and its derivatives” also includes, in the context of the present invention, a linear polymer comprising the polymeric unit described above, linked together in the chain via alternating β(1,4) and β(1,3) glycosidic bonds, having a molecular weight (MW) which can vary between 380 and 13,000,000 daltons. Unless otherwise defined in the descriptions, “molecular weight” means a weight average molecular weight. This molecular weight depends largely on the source from which the hyaluronic acid is obtained and/or the preparation methods.

The term "hyaluronic acid and its derivatives" also includes, in the context of the present invention, salts of hyaluronic acid. As salts, mention may be made of alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as magnesium salts, ammonium salts and mixtures thereof.

In its natural state, hyaluronic acid is present in pericellular gels, in the basic substance of connective tissues of vertebrate organs such as the dermis and epithelial tissues and, in particular, in the epidermis, in the synovial fluid of joints, in the vitreous humor, in the human umbilical cord and in the crista galli apophysis.

Thus, the term “hyaluronic acid and its derivatives” includes all fractions or subunits of hyaluronic acid having a molecular weight particularly in the molecular weight range mentioned above.

In the context of the present invention, hyaluronic acid fractions which do not have inflammatory activity are preferably used.

As an illustration of the different hyaluronic acid fractions, reference may be made to the paper “Hyaluronan fragments: an information-rich system”, R. Stern et al., European Journal of Cell Biology 58 (2006) 699-715, which reviews the listed biological activities of hyaluronic acid as a function of its molecular weight.

The molecular weight of the (b-1) first anionic polymer, i.e. hyaluronic acid or a derivative thereof, may be less than or equal to 2,000 kDa, preferably less than or equal to 1,000 kDa and, more preferably, less than or equal to 100 kDa.

The molecular weight of the (b-1)first anionic polymer, i.e. hyaluronic acid or a derivative thereof, may be 0.4 kDa or more, preferably 1 kDa or more and, more preferably, 10 kDa or more.

The molecular weight of the (b-1) first anionic polymer, i.e. hyaluronic acid or a derivative thereof, may be from 0.4 to 2,000 kDa, preferably from 1 to 1,000 kDa, and more preferably from 10 to 100 kDa.

Finally, the term “hyaluronic acid and its derivatives” also includes hyaluronic acid esters, in particular those in which all or part of the carboxylic groups of the acid functions are esterified with oxyethylenated alkyls or alcohols, containing from 1 to 20 carbon atoms, in particular with a degree of substitution at the level of the D-glucuronic acid of the hyaluronic acid of between 0.5 and 50%.

Mention may in particular be made of methyl, ethyl, n-propyl, n-pentyl, benzyl and dodecyl esters of hyaluronic acid. These esters have been described in particular in D. Campoccia et al. “Semisynthetic resorbable materials from hyaluronan esterification”, Biomaterials 19 (1998) 2101-2127.

The hyaluronic acid derivative may be, for example, acetylated hyaluronic acid or a salt thereof such as sodium acetylated hyaluronate.

The molecular weights given above are also valid for hyaluronic acid esters.

The weight ratio of the amount of the (b-1) first anionic polymer(s) relative to the total weight of the nanoparticles in the composition according to the present invention may be 0.01 or more, preferably 0.02 or more, and more preferably 0.03 or more.

The weight ratio of the amount of the (b-1) first anionic polymer(s) relative to the total weight of the nanoparticles in the composition according to the present invention may be 0.8 or less, preferably 0.7 or less, and more preferably 0.6 or less.

The weight ratio of the amount of the (b-1) first anionic polymer(s) relative to the total weight of the nanoparticles in the composition according to the present invention may be from 0.01 to 0.8, preferably from 0.02 to 0.7, and more preferably from 0.03 to 0.6.

Second anionic polymer:

The (b-2) second anionic polymer is different from the (b-1) first anionic polymer.

The molecular weight of the (b-2) second cationic polymer may be equal to or greater than 1,000, preferably equal to or greater than 10,000, more preferably equal to or greater than 50,000, and even more preferably equal to or greater than 100,000. Unless otherwise defined in the descriptions, "molecular weight" means a weight average molecular weight.

The (b-2) second anionic polymer may have at least one negatively chargeable and/or negatively charged moiety selected from the group consisting of a sulfuric group, a sulfate group, a sulfonic group, a sulfonate group, a phosphoric group, a phosphate group, a phosphonic group, a phosphonate group, a carboxylic group and a carboxylate group.

The (b-2) second anionic polymer may be a homopolymer or a copolymer. By "copolymer" is meant both copolymers obtained from two kinds of monomers and those obtained from more than two kinds of monomers, such as terpolymers obtained from three kinds of monomers.

The (b-2) second anionic polymer may be selected from natural and synthetic anionic polymers.

The (b-2) second anionic polymer may comprise at least one hydrophobic chain.

The (b-2) second anionic polymer, which may comprise at least one hydrophobic chain, may be obtained by copolymerization of a monomer (a) selected from carboxylic acids comprising α,β-ethylenic unsaturation (monomer a') and a 2-acrylamido-2-methylpropanesulfonic acid (monomer a") with a non-surface-active monomer (b) comprising ethyl unsaturation other than (a) and/or a monomer (c) comprising ethyl unsaturation resulting from the reaction of an acrylic monomer comprising α,β-monoethylenic unsaturation or a monomer comprising monoethylenic unsaturation with a nonionic amphiphilic monohydric component or with a primary or secondary amine.

Thus, the anionic polymer with at least one hydrophobic chain can be obtained by two synthetic routes:

- either by copolymerization of the monomers (a') and (c), or (a'), (b) and (c), or (a") and (c), or (a""), (b) and (c),

- either by modification (and in particular by esterification or amidation) of a copolymer formed from the monomers (a') or from the monomers (a'") and (b), or (a) and (b), by an amphiphilic non-ionic monohydric compound or a primary or secondary fatty amine.

Mention may in particular be made, as copolymers of 2-acrylamido-2-methylpropanesulfonic acid, of those disclosed in the article “Micelle formation of random copolymers of sodium 2-(acrylamido)-2-methylpropanesulfonate and nonionic surfactant macromonomer in water as studied by fluorescence and dynamic light scattering – Macromolecules, 2000, Vol. 33, No. 10 – 3694-3704” and in applications EP-A-0 750 899 and EP-A-1 069 172.

The carboxylic acid comprising an α,β-monoethylenic unsaturation constituting the monomer (a') can be chosen from numerous acids and, in particular, acrylic acid, methacrylic acid, crotonic acid, itaconic acid and maleic acid. Preferably it is acrylic or methacrylic acid.

The copolymer may comprise a (b) monomer comprising monoethylenic unsaturation which has no surfactant property. Preferred monomers are those which give water-insoluble polymers when homopolymerized. They may be selected, for example, from C ₁ -C ₄ alkyl acrylates and methacrylates, such as methyl acrylate, ethyl acrylate, butyl acrylate or the corresponding methacrylates. The most preferred monomers are methyl acrylate and ethyl acrylate. Other monomers which may be used are, for example, styrene, vinyl toluene, vinyl acetate, acrylonitrile and vinylidene chloride. Non-reactive monomers are preferred, these monomers being those in which the single ethylenic group is the only reactive group under the polymerization conditions. However, monomers which include groups which react under heat, such as hydroxyethyl acrylate, may optionally be used.

Monomer (c) is obtained by reacting an acrylic monomer comprising α,β-monoethylenic unsaturation, such as (a), or an isocyanate monomer comprising monoethylenic unsaturation with a nonionic monohydric amphiphilic compound or a primary or secondary fatty amine.

Nonionic monohydric amphiphilic compounds or primary or secondary fatty amines used to produce the nonionic monomer (c) are well known. Nonionic monohydric amphiphilic compounds are generally alkoxylated hydrophobic compounds comprising an alkylene oxide forming the hydrophilic portion of the molecule. Hydrophobic compounds are generally composed of an aliphatic alcohol or an alkylphenol, in which compounds a carbon chain comprising at least six carbon atoms constitutes the hydrophobic portion of the amphiphilic compound.

Preferred nonionic monohydric amphiphilic compounds are compounds having the following formula (V):

R-(OCH ₂ CHR') _m -(OCH ₂ CH ₂ ) _n -OH (V)

wherein R is selected from alkyl or alkylene groups having from 6 to 30 carbon atoms and alkylaryl groups having alkyl radicals having from 8 to 30 carbon atoms, R' is selected from alkyl groups having from 1 to 4 carbon atoms, n is an average number ranging from about 1 to 150 and m is an average number ranging from about 0 to 50, provided that n is at least as large as m.

Preferably, in the compounds of formula (V), the group R is selected from alkyl groups comprising from 12 to 26 carbon atoms and alkylphenyl groups in which the alkyl group is C ₈ -C ₁₃ ; the group R' is the methyl group; m = 0 and n = 1 to 25.

Preferred primary and secondary fatty amines are composed of one or two alkyl chains comprising from 6 to 30 carbon atoms.

The monomer used to form the nonionic urethane monomer (c) may be chosen from a wide variety of compounds. Any compound comprising a copolymerizable unsaturation, such as an acrylic, methacrylic or allyl unsaturation, may be used. The monomer (c) may be obtained in particular from an isocyanate comprising a monoethylenic unsaturation such as, in particular, α,α-dimethyl-m-isopropenylbenzyl isocyanate.

The monomer (c) may be chosen, in particular, from acrylates, methacrylates or itaconates of oxyethylated alcohol (1 to 50 EO) C ₆ -C ₃₀ , such as steareth-20 methacrylate, oxyethylated behenyl methacrylate (25 EO), oxyethylenic monocetyl itaconate (20 EO), oxyethylethylated monostearyl itaconate (20 EO) or acrylate modified by polyoxyethylenic alcohols (25 EO) C ₁₂ -C ₂₄ and from dimethyl-m-isopropenylbenzyl isocyanates of oxyethylenated alcohol (1 to 50 EO) C ₆ -C ₃₀ , such as, in particular, dimethyl-m-isopropenylbenzyl isocyanate of behenyl alcohol oxyethylenated.

According to a specific embodiment of the present invention, the (b-2) second anionic polymer is selected from acrylic terpolymers obtained from (a) a carboxylic acid comprising α,β-ethylenic unsaturation, (b) a non-surface-active monomer comprising ethylenic unsaturation other than (a), and (c) a nonionic urethane monomer which is the reaction product of a nonionic monohydric amphiphilic compound with an isocyanate comprising monoethylenic unsaturation.

Mention may in particular be made, as anionic polymers comprising at least one hydrophobic chain, of the following compounds: acrylic acid/ethyl acrylate/alkyl acrylate terpolymer, such as the product in the form of a 30% aqueous dispersion marketed under the name Acusol 823 by Rohm &Haas; acrylate/steareth-20 methacrylate copolymer, such as the product marketed under the name Aculyn 22 by Rohm &Haas; (meth)acrylic acid/ethyl acrylate/oxyethylenated behenyl methacrylate (25 EO) terpopolymer, such as the product in the form of an aqueous emulsion marketed under the name Aculyn-28 by Rohm &Haas; acrylic acid/oxyethylenated monocetyl itaconate (20 EO) copolymer, such as the 30% aqueous dispersion product marketed under the name Structure 3001 by National Starch; acrylic acid/oxyethylenated monostearyl itaconate (20°EO) copolymer, such as the 30% aqueous dispersion product marketed under the name Structure 2001 by National Starch; acrylates/acrylate modified with polyoxyethylated alcohol (25 EO) C ₁₂ -C ₂₄ copolymer, such as the 30-32% copolymer latex marketed under the name Synthalen W2000 by 3V SA; or terpolymer of methacrylic acid/methyl acrylate/ethoxylated behenyl alcohol dimethyl-isopropenylbenzyl isocyanate, such as the product in the form of a 24% aqueous dispersion and comprising 40 ethylene oxide groups disclosed in document EP-A-0 173 109.

The (b-2) second anionic polymers may also be Polyester-5, such as the product marketed as Eastman AQ™ 55S Polymer by EASTMAN CHEMICAL having a chemical formula below.

HO-G-A-G-A-G-A-G-A-G-A-G-A-G-A-G-A-G-OH

| |

SO ₃ ^- Na ⁺ SO ₃ ^- Na ⁺

A: dicarboxylic acid moiety

G: glycol fraction

SO ₃ ^- Na ⁺ : sodium sulfo group

OH: hydroxyl group

It may be preferable that the (b-2) second anionic polymer is selected from the group consisting of polysaccharides such as carrageenan (e.g., ι-carrageenan, and Λ-carrageenan), pectin, alginic acid (algin), and cellulosic polymers (e.g., carboxymethylcellulose), anionic (co)polyamino acids such as (co)polyglutamic acids, (co)poly(meth)acrylic acids, (co)polyamic acids, (co)polystyrene sulfonate, (co)poly(vinyl sulfate), dextran sulfate, chondroitin sulfate, (co)polymaleic acids, (co)polyfumaric acids, (co)polymers of maleic acid, and salts thereof.

The maleic acid copolymer may comprise one or more maleic acid comonomers, and one or more comonomers selected from vinyl acetate, vinyl alcohol, vinylpyrrolidone, olefins comprising from 2 to 20 carbon atoms and styrene.

The term “maleic acid copolymer” means any polymer obtained by copolymerization of one or more maleic acid comonomers and one or more comonomers selected from vinyl acetate, vinyl alcohol, vinylpyrrolidone, olefins comprising from 2 to 20 carbon atoms, such as octadecene, ethylene, isobutylene, diisobutylene or isooctylene, and styrene, the maleic acid comonomers being optionally partially or completely hydrolyzed. Hydrophilic polymers will preferably be used, namely polymers having a solubility in water greater than or equal to 2 g/L.

In an advantageous aspect of the present invention, the maleic acid copolymer may have a molar fraction of maleic acid units of between 0.1 and 1, and preferably between 0.4 and 0.9.

The weight average molar mass of the maleic acid copolymer may be between 1,000 and 500,000 and, preferably, between 1,000 and 50,000.

It is preferred that the maleic acid copolymer is a styrene/maleic acid copolymer and, more preferably, a styrene/maleic acid copolymer.

A copolymer of styrene and maleic acid in a 50/50 ratio will preferably be used.

For example, styrene/maleic acid copolymer (50/50) in the form of 30% ammonium salt in water, marketed under the reference SMA1000H® by Cray Valley, or styrene/maleic acid copolymer (50/50) in the form of 40% sodium salt in water, marketed under the reference SMA1000HNa® by Cray Valley, can be used.

It may be preferable that the (b-2) second anionic polymer is selected from the group consisting of carrageenans such as ι-carrageenan and Λ-carrageenan, algin, chondroitin sulfate, pectin and a mixture thereof.

It may be preferable that the (b-2) second anionic polymer is selected from the group consisting of carrageenan, pectin and a mixture thereof.

The weight ratio of the amount of the (b-2) second anionic polymer(s) relative to the total weight of the nanoparticles in the composition according to the present invention is 0.26 or more, preferably 0.28 or more, and more preferably 0.30 or more.

The weight ratio of the amount of the (b-2) second anionic polymer(s) relative to the total weight of the nanoparticles in the composition according to the present invention may be 0.9 or less, preferably 0.8 or less, and more preferably 0.7 or less.

The weight ratio of the amount of the (b-2) second anionic polymer(s) relative to the total weight of the nanoparticles in the composition according to the present invention may be from 0.26 to 0.9, preferably from 0.28 to 0.8, and more preferably from 0.30 to 0.7.

(Non-polymeric acid)

The composition according to the present invention includes (c) at least one non-polymeric acid or salt(s) thereof. Two or more different types of non-polymeric acids or salts thereof may be used in combination. Thus, a single type of non-polymeric acid or salt thereof or a combination of different types of non-polymeric acids or salts thereof may be used.

The (c) non-polymeric acid(s) or salt(s) thereof may be selected from monovalent non-polymeric acids and their salts, polyvalent (e.g., divalent or trivalent) non-polymeric acids and their salts, and mixtures thereof.

Monovalent polymeric acids may have a single pKa value. On the other hand, polyvalent non-polymeric acids may have two or more pKa values. The pKa value (acid dissociation constant) is well known to those skilled in the art and should be determined at a constant temperature such as 25 °C.

The (c) non-polymeric acid or salt(s) thereof may be included in the nanoparticles which may be a polyionic complex. The polyvalent non-polymeric acid or salt(s) thereof may function as a crosslinker for the (a) cationic polymer, or the (a) cationic polymer and the (b-1) first anionic polymer and/or the (b-2) second anionic polymer.

The term "non-polymeric" here means that the acid is not obtained by polymerization of two or more monomers. Therefore, non-polymeric acid does not correspond to an acid obtained by polymerization of two or more monomers such as a polycarboxylic acid.

It is preferable that the molecular weight of the (c) non-polymeric acid or salt(s) thereof is less than or equal to 1,000, preferably less than or equal to 800 and, more preferably, less than or equal to 700.

Herein, the term "salt" means a salt formed by the addition of suitable base(s) to the non-polymeric acid, which can be obtained from a reaction with the non-polymeric acid with the base(s) according to methods known to those skilled in the art. As a salt, mention may be made of metal salts, for example alkali metal salts such as Na and K and alkaline earth metal salts such as Mg and Ca and ammonium salts.

The (c) non-polymeric acid or salt(s) thereof may be an organic acid or salt(s) thereof, and preferably a hydrophilic or water-soluble organic acid or salt(s) thereof.

The monovalent nonpolymeric acid has a single acid group which may be selected from the group consisting of a carboxylic group, a sulfuric group, a sulfonic group, a phosphoric group, a phosphonic group or a phenolic hydroxyl group.

The polyvalent non-polymeric acid may have at least two acid groups selected from the group consisting of a carboxylic group, a sulfuric group, a sulfonic group, a phosphoric group, a phosphonic group, a phenolic hydroxyl group, and a mixture thereof.

The monovalent non-polymeric acid may preferably be selected from monovalent carboxylic acids.

In one embodiment, the monovalent non-polymeric acid may be selected from hydroxy acids, and preferably alpha-hydroxy acids. Examples of alpha-hydroxy acids that may be mentioned include, for example, lactic acid and glycolic acid.

The polyvalent non-polymeric acid or salt thereof may be selected from the group consisting of oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, fumaric acid, maleic acid, malic acid, citric acid, aconitic acid, oxaloacetic acid, tartaric acid and their salts; aspartic acid, glutamic acid and their salts; sulfonic terephthalylidene dicamphor or their salts (Mexoryl SX), Benzophenone-9; phytic acid and its salts;Red 2 (Amaranth), Red 102 (New Coccine), Yellow 5 (Tartrazine), Yellow 6 (Sunset Yellow FCF), Green 3 (Fast Green FCF), Blue 1 (Brillant blue FCF), Blue 2 (Indigo Carmine), Red 202 (Lithol Rubine B), (Lithol Rubine BCA), Red 204 (Lake Red CBA), Red 206 (Lithol Red CA), Red 207 (Lithol Red BA), Red 208 (Lithol Red SR), Red 219 (Brilliant Lake Red R), Red 220 (Deep Maroon), Red 227 (Fast Acid Magenta), Yellow 203 (Quinoline Yellow WS), Green 201 (Alizanine Cyanine Green F), Green 204 (Pyranine Conc), Green 205 (Light Green SF Yellowish), Blue 203 (Patent Blue CA), Blue 205 (Alfazurine FG), Red 401 (Violamine R), Red 405 (Permanent Re F5R), Red 502 (Ponceau 3R), Red 503 (Ponceau R), Red 504 (Ponceau SX), Green 401 (Naphthol Green B), Green 402 (Guinea Green B), and Black 401 (Naphthol Blue Black); folic acid, ascorbic acid, erythorbic acid and their salts; cystine and its salts; EDTA and its salts; glycyrrhizin and its salts; and a mixture thereof.

It may be preferable that the polyvalent non-polymeric acid or a salt thereof is selected from the group consisting of terephthalylidene dicamphor sulfonic acid and its salts (Mexoryl SX), Yellow 6 (Sunset Yellow FCF), ascorbic acid, phytic acid and its salts, and a mixture thereof.

The (c) non-polymeric acid or a salt thereof may be selected from the group consisting of phytic acid, citric acid, lactic acid and a mixture thereof.

The weight ratio of the amount of the (c) non-polymeric acid(s) or salt(s) thereof relative to the total weight of the nanoparticles in the composition according to the present invention is 0.03 or more, preferably 0.035 or more, and more preferably 0.04 or more.

The weight ratio of the amount of the (c) non-polymeric acid(s) or salt(s) thereof relative to the total weight of the nanoparticles in the composition according to the present invention may be 0.6 or less, preferably 0.5 or less, and more preferably 0.4 or less.

The weight ratio of the amount of the (c) non-polymeric acid(s) or salt(s) thereof relative to the total weight of the nanoparticles in the composition according to the present invention may be from 0.03 to 0.6, preferably from 0.035 to 0.5, and more preferably from 0.04 to 0.4.

[Metal salt]

The composition according to the present invention may comprise (d) at least one metal salt. Two or more metal salts may be used in combination.

The (d) at least one metal salt is an optional ingredient. Thus, the nanoparticles may not include the (d) metal salt.

The term "metal salt" herein refers to a cosmetically acceptable water-soluble salt that provides cationic ions in an aqueous medium. The metal salt used in the composition of the present invention is preferably selected from polyvalent metal salts, such as divalent or trivalent metal salts, and is more preferably selected from divalent metal salts such as calcium, magnesium and zinc salts. Calcium salts, such as calcium chloride, calcium pyrrolidone carboxylate (PCA), calcium acetate, calcium aspartate, calcium lactate, are preferred. Among others, calcium chloride and calcium pyrrolidone carboxylate are most preferable.

The (d) metal salt may be selected from polyvalent metal salts, preferably divalent metal salts, more preferably calcium salts such as calcium chloride and calcium pyrrolidone carboxylate, and magnesium salts such as magnesium chloride.

The weight ratio of the amount of the (d) metal salt(s) relative to the total weight of the nanoparticles in the composition according to the present invention may be 0.001 or more, preferably 0.005 or more, and more preferably 0.01 or more.

The weight ratio of the amount of the metal salt(s) (d) relative to the total weight of the nanoparticles in the composition according to the present invention is 0.30 or less, preferably 0.25 or less, and more preferably 0.20 or less.

The weight ratio of the amount of the metal salt (d) relative to the total weight of the nanoparticles in the composition according to the present invention may be from 0.001 to 0.30, preferably from 0.005 to 0.25, and more preferably from 0.01 to 0.20.

[Fatty acid]

The composition according to the present invention comprises (e) at least one fatty acid. If two or more fatty acids are used, they may be the same or different.

The term "fatty acid" here refers to a carboxylic acid with a long aliphatic carbon chain.

The (e) fatty acid comprises at least 4 carbon atoms, preferably at least 6 carbon atoms and, more preferably, at least 8 carbon atoms. The (e) fatty acid may comprise up to 24 carbon atoms, preferably up to 22 carbon atoms and, more preferably, up to 20 carbon atoms. It is preferable that the (e) fatty acid is chosen from a C ₄ -C ₂₄ fatty acid, more preferably a C ₆ -C ₂₂ fatty acid, and even more preferably a C ₈ -C ₂₀ fatty acid.

The fatty acid may be chosen from saturated fatty acids which may be linear or branched.

Examples of saturated fatty acids include caprylic acid (C ₈ ), pelargonic acid (C ₉ ), capric acid (C ₁₀ ), lauric acid (C 12 ), myristic acid (C ₁₄ ), pentadecanoic acid (C ₁₅ ), palmitic acid (C ₁₆ ), heptadecanoic acid (C ₁₇ ), stearic acid (C ₁₈ ), isostearic acid (C ₁₈ ) _, nonadecanoic acid (C ₁₉ ), arachidic acid (C ₂₀ ), behenic acid (C ₂₂ ) and lignoceric acid (C ₂₄ ).

The (e)fatty acid can be chosen from unsaturated fatty acids which can be linear or branched.

As unsaturated fatty acids, linear or branched, monounsaturated fatty acids, linear or branched or polyunsaturated fatty acids, linear or branched may be used. As unsaturated fraction of unsaturated fatty acids, linear or branched, a carbon-carbon double bond or a carbon-carbon triple bond may be mentioned.

Examples of unsaturated fatty acids include myristoleic acid (C ₁₄ ), palmitoleic acid (C ₁₆ ), oleic acid (C ₁₈ ), linoleic acid (C 18 ), linolenic acid (C ₁₈ ), elaidic acid (C ₁₈ ), arachidonic acid (C ₂₀ ) _, eicosenoic acid (C ₂₀ ), erucic acid (C ₂₂ ) and nervonic acid (C ₂₄ ).

In a preferred embodiment, the (e) fatty acid may be selected from saturated or unsaturated, linear or branched fatty acids. Thus, the (e) fatty acid may be selected from saturated and unsaturated, linear or branched C ₄ -C ₂₂ , preferably C ₆ -C ₂₀ , more preferably C ₈ -C ₁₈ , fatty acids.

The (e) fatty acid may be selected from the group consisting of caprylic acid, capric acid, oleic acid, linoleic acid, myristic acid, stearic acid, isostearic acid, behenic acid and mixtures thereof.

The (e) fatty acid may be in the form of a free acid or a salt thereof. As the salt of the fatty acid, there may be an inorganic salt such as an alkali metal salt (a sodium salt, a potassium salt, or the like) and an alkaline earth metal salt (a magnesium salt, a salt salt, or the like); and an organic salt such as an ammonium salt (a quaternary ammonium salt or the like) and an amine salt (a triethanolamine salt, a triethylamine salt, or the like). A single type of fatty acid salt or a combination of different types of fatty acid salts may be used. In addition, a combination of one or more fatty acids in the free acid form and one or more fatty acids in the salt form may be used, in which one or more types of salts may also be used.

The weight ratio of the amount of the fatty acid(s) relative to the total weight of the nanoparticles in the composition according to the present invention is 0.001 or more, preferably 0.002 or more, and more preferably 0.003 or more.

The weight ratio of the amount of the fatty acid(s) relative to the total weight of the nanoparticles in the composition according to the present invention may be 0.4 or less, preferably 0.3 or less, and more preferably 0.2 or less.

The weight ratio of the quantity of the fatty acid(s) relative to the total weight of the nanoparticles in the composition according to the present invention may range from 0.001 to 0.4, preferably from 0.002 to 0.3, and more preferably from 0.003 to 0.2.

[Water]

The composition according to the present invention comprises (f) water.

The amount of (f) water in the composition according to the present invention may be greater than or equal to 50% by weight, preferably greater than or equal to 60% by weight and more preferably greater than or equal to 70% by weight, relative to the total weight of the composition.

Furthermore, the amount of (f) water in the composition according to the present invention may be less than or equal to 95% by weight, preferably less than or equal to 90% by weight and more preferably less than or equal to 85% by weight, relative to the total weight of the composition.

The amount of (f) water in the composition according to the present invention may be from 50% to 95% by weight, preferably from 60% to 90% by weight and more preferably from 70% to 85% by weight, relative to the total weight of the composition.

[pH]

The pH of the composition according to the present invention may be from 3 to 9, preferably from 3.3 to 8.5 and, more preferably, from 3.5 to 8.

At pH 3-9, the polyionic complex formed by ingredients (a) to (e), especially ingredients (a), (b-1), (b-2) and (c), can be very stable.

The pH of the composition according to the present invention may be corrected by adding at least one alkaline agent and/or at least one acid, other than the (c) non-polymeric acid or salt(s) thereof. The pH of the composition according to the present invention may also be corrected by adding at least one buffering agent.

(Alkaline agent)

The composition according to the present invention may comprise at least one alkaline agent. Two or more alkaline agents may be used in combination. Thus, a single type of alkaline agent or a combination of different types of alkaline agents may be used.

The alkaline agent may be an inorganic alkaline agent. The inorganic alkaline agent may be selected from the group consisting of the following elements: ammonia, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal phosphates and monohydrogen phosphates such as sodium phosphate or sodium monohydrogen phosphate.

Examples of inorganic alkali metal hydroxides include sodium hydroxide and potassium hydroxide. Examples of alkaline earth metal hydroxides include calcium hydroxide and magnesium hydroxide. As an inorganic alkali agent, sodium hydroxide is preferable.

The alkaline agent may be an organic alkaline agent. It is preferable that the organic alkaline agent is selected from the group consisting of monoamines and their derivatives; diamines and their derivatives; polyamines and their derivatives; basic amino acids and their derivatives; oligomers of basic amino acids and their derivatives; polymers of basic amino acids and their derivatives; urea and its derivatives and guanidine and its derivatives.

Examples of organic alkaline agents include alkanolamines such as mono-, di- and triethanolamine, and isopropanolamine; urea, guanidine and their derivatives; basic amino acids such as lysine, ornithine or arginine; and diamines such as those described by the structure below:

wherein R denotes an alkylene such as propylene optionally substituted by a hydroxyl or C ₁ -C ₄ alkyl radical, and R ₁ , R ₂ , R ₃ and R ₄ independently denote a hydrogen atom, an alkyl radical or a C ₁ -C ₄ hydroxyalkyl radical, as exemplified by 1,3-propanediamine and its derivatives. Arginine, urea and monoethanolamine are preferred.

The alkaline agent(s) may be used in an amount ranging from 0.01% to 15% by weight, preferably from 0.02% to 10% by weight, and more preferably from 0.03% to 5% by weight, relative to the total weight of the composition, depending on their solubility.

(Acid)

The composition according to the present invention may comprise at least one acid. Two or more acids may be used in combination. Thus, a single type of acid or a combination of different types of acids may be used.

As an acid, all inorganic or organic acids, preferably inorganic, which are commonly used in cosmetic products can be mentioned. A monovalent acid and/or a polyvalent acid can be used. A monovalent acid such as citric acid, phosphoric acid and hydrochloric acid (HCl) can be used. HCl is preferred.

The acid(s) may be used in an amount ranging from 0.01% to 15% by weight, preferably from 0.02% to 10% by weight, and more preferably from 0.03% to 5% by weight, relative to the total weight of the composition, depending on their solubility.

(Buffering agent)

The composition according to the present invention may comprise at least one buffering agent. Two or more buffering agents may be used in combination. Thus, a single type of buffering agent or a combination of different types of buffering agents may be used.

As a buffering agent, there may be mentioned an acetate buffer (e.g., acetic acid + sodium acetate), a phosphate buffer (e.g., sodium dihydrogen phosphate + disodium hydrogen phosphate), a citrate buffer (e.g., citric acid + sodium citrate), a borate buffer (e.g., boric acid + sodium borate), a tartrate buffer (e.g., tartaric acid + sodium tartrate dihydrate), a Tris buffer (e.g., tris(hydroxymethyl)aminomethane) and a Hepes buffer (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid).

[Optional ingredients]

The composition according to the present invention may comprise, in addition to the above-mentioned components, at least one optional ingredient typically used in cosmetics, which may be selected from, specifically, oils, surfactants or emulsifiers, hydrophilic or lipophilic thickeners, volatile or non-volatile organic solvents such as polyols, in particular glycerin and glycols, silicones and silicone derivatives, natural extracts derived from animals or vegetables, waxes, UV filters and the like, in a range which does not affect the effects of the present invention.

The composition according to the present invention may comprise the optional ingredient(s) in an amount of 0.01% to 50% by weight, preferably 0.05% to 30% by weight, and more preferably 0.1% to 10% by weight, relative to the total weight of the composition.

However, it is preferable that the composition according to the present invention includes a very limited amount of surfactant(s) or emulsifier(s). The amount of surfactant(s) or emulsifier(s) in the composition according to the present invention may be 1% by weight or less, preferably 0.1% by weight or less and, more preferably, 0.01% by weight or less, relative to the total weight of the composition. It is particularly preferable that the composition according to the present invention does not comprise any surfactant or emulsifier.

[Composition]

The composition according to the present invention can be prepared by mixing the essential ingredient(s) as explained above, and the optional ingredient(s), if necessary, as explained above.

The method and means for mixing the above essential and optional ingredients are not limited. Any conventional method and means can be used for mixing the above essential and optional ingredients to prepare the composition according to the present invention.

The composition according to the present invention can be used as a cosmetic composition. Thus, the cosmetic composition according to the present invention can be intended to be applied to a keratin fiber. By keratin substance is meant here a material containing keratin as a main constituent element and, by way of example, the skin, the scalp, the lips, the hair or body hair and the like. It is preferable that the cosmetic composition according to the present invention is used for a cosmetic process for the keratin fiber, in particular the skin.

The composition according to the present invention may be transparent or translucent, preferably transparent.

Transparency can be measured by measuring turbidity (turbidity can be measured for example with a 2100Q incandescent lamp (marketed by Hach Company) with a round cell (25 mm diameter and 60 mm high) and a tungsten filament lamp capable of emitting visible light (between 400 and 800 nm, preferably 400 to 500 nm). The measurement can be carried out on the undiluted composition. The blank test can be evaluated with distilled water.

The composition according to the present invention may have a turbidity of 300 NTU or less, preferably 200 NTU or less, more preferably 100 NTU or less, and even more preferably 50 NTU or less.

[Cosmetic process and use]

The present invention also relates to:

a cosmetic process for a keratinous substrate such as the skin, comprising: applying to the keratinous substrate the composition according to the present invention.

The cosmetic process here refers to a non-therapeutic cosmetic process for the care and/or makeup of the surface of a keratinous substance such as the skin.

The cosmetic process according to the present invention can provide a keratinous substance such as skin with cosmetic effects derived from hyaluronic acid and/or a hyaluronic acid derivative. For example, the cosmetic process according to the present invention can provide a keratinous substance such as skin with moisturizing effects.

The present invention may also relate to a use of (e) at least one fatty acid in a composition comprising:

(a) at least one cationic polymer;

(b-1) at least one first anionic polymer chosen from hyaluronic acids and their derivatives;

(b-2) at least one second anionic polymer which is different from (b-1) first anionic polymer;

(c) at least one non-polymeric acid or a salt thereof; and

(d) at least one optional metal salt; and

(f) water,

in which

ingredients (a), (b-1), (b-2), (c), (d) and (e) are capable of forming nanoparticles, the amount of which is between 0.01% and 0.58% by weight, preferably between 0.05% and 0.57% by weight, and more preferably between 0.1% and 0.56% by weight, relative to the total weight of the composition,

the weight ratio of the amount of the cationic polymer(s) to the total weight of the nanoparticles is 0.06 to 0.25,

the weight ratio of the amount of the (b-2) second anionic polymer to the total weight of the nanoparticles is 0.26 or more,

the weight ratio of the amount of the (c) non-polymeric acid(s) or salt(s) thereof to the total weight of the nanoparticles is 0.03 or more,

the weight ratio of the amount of the optional metal salt(s) to the total weight of the nanoparticles is 0.30 or less, and

the weight ratio of the amount of the fatty acid(s) to the total weight of the nanoparticles is 0.001 or more,

in order to enhance the penetration capacity of nanoparticles into a keratinous substance such as the skin.

The above use can deliver hyaluronic acid and/or a hyaluronic acid derivative deeper into a keratinous substance such as skin. Therefore, the above use according to the present invention can provide a keratinous substance such as skin with cosmetic effects derived from hyaluronic acid and/or a hyaluronic acid derivative. For example, the use according to the present invention can provide a keratinous substance such as skin with moisturizing effects.

EXAMPLES

The present invention will be described in more detail with the aid of examples. However, these examples should not be construed as limiting the scope of the present invention.

[Example 1 and Comparative Example 1]

[Preparation]

Each of the compositions according to Example 1 and Comparative Example 1 was prepared by mixing the ingredients listed in Table 1. The numerical values of the amounts of ingredients in Table 1 are all based on a “% by weight” of active ingredients.

The compositions according to Example 1 and Comparative Example 1 included nanoparticles including hyaluronic acid. “NPAH” in Table 1 is an abbreviation for NanoParticle of Hyaluronic Acid. (a) to (f) in Table 1 correspond to those of the claims.

　 Ex. 1 Ex.
Ex. 1 NPAH (b-1) Fluorescently labeled sodium hyaluronate 0.05 0.05 (b-2) Carrageenan 0.1 0.1 (has) Polylysine 0.031 0.031 (c) Phytic acid 0.0215 0.0215 (d) Calcium PCA 0.038 0.038 (e) Oleic acid 0.007 - Caprylyl Glycol 0.3 0.3 Glycerin 10 10 Pentylene glycol 5 5 Propylene glycol 5 5 Polyglyceryl-2 oleate 0.05 0.05 Polyglyceryl-4 caprate 0.45 0.45 (f) Water qsp 100 qsp 100 Skin depth penetrated by hyaluronic acid (μm) 112 18 NPAH concentration (% by weight) 0.25 0.24 Weight ratio of (b-1) to total weight of NPAH 0.202 0.208 Weight ratio of (b-2) to total weight of NPAH 0.404 0.416 Weight ratio of (a) to total weight of NPAH 0.125 0.129 Weight ratio of (c) to total weight of NPAH 0.087 0.089 Weight ratio of (d) to total weight of NPAH 0.154 0.158 Weight ratio of (e) to total weight of NPAH 0.028 - Appearance Good Good Particle size (nm) 40 20 Turbidity (NTU) 35 13

[Evaluations]

(Depth of skin penetrated by hyaluronic acid)

Penetration test experiments were carried out using a Franz diffusion cell (Hanson) with dermatomal human skin provided by Biopredic International (France). This equipment consisted of a donor part and a receiver part, with dermatomal human skin interposed between the donor and receiver parts. The receiver part of a predetermined volume was filled with a receiver solution (phosphate buffer solution of pH 7) maintained at a temperature of 32 °C, which was continuously stirred with a small magnetic stir bar. Each of the compositions according to Example 1 and Comparative Example 1 was spread with a spatula on the membrane of the donor part with an amount of 30 mg/cm ² . After 24 hours, the dermatomal human skin was removed and cryosectioned, and the penetration depth of NPAH was measured by cross-sectional observation with a fluorescence microscope.

The results are shown in the row titled “Depth of skin penetrated by hyaluronic acid (μm)” in Table 1.

(Appearance)

The appearance of the compositions according to Example 1 and Comparative Example 1 was visually evaluated at room temperature (25°C) in accordance with the following criteria.

Good: Transparent

Bad: Turbid

The results are shown on the line marked “Aspect” in Table 1.

(Particle size)

The particle size or diameter of NPAH in the compositions according to Example 1 and Comparative Example 1 was measured by an ELSZ-2000 particle size analyzer by Otsuka Electronics Co., Ltd. at room temperature (25°C).

The results are shown in the row labeled “Particle size (nm)” in Table 1.

(Turbidity)

The turbidity of the compositions according to Example 1 and Comparative Example 1 was measured by a 2100Q turbidimeter (Hach Company) at room temperature (25 °C).

The results are shown on the line marked “Turbidity” in Table 1.

(Summary)

The experimental data shown in Table 1 show that NPAH hydrophobized with fatty acid penetrates deeper into the skin than non-hydrophobized NPAH.

Thus, the nanoparticles in the composition according to the present invention, including (e) at least one fatty acid, can penetrate deeper into the skin.

[Examples 2-6 and comparative example 2]

[Preparation]

Each of the compositions according to Examples 2 to 6 and Comparative Example 2 was prepared by mixing the ingredients shown in Table 2. The numerical values of the amounts of ingredients in Table 2 are all based on a “% by weight” of active ingredients.

The compositions according to Examples 2 to 6 and Comparative Example 2 included particles including hyaluronic acid. “NPAH” in Table 2 is an abbreviation for NanoParticle of Hyaluronic Acid. (a) to (f) in Table 2 correspond to those of the claims.

　 Ex. 2 Ex. 3 comp. 4 Ex. 5 Ex. 6 Ex.
comp. 2 NPAH (b-1) Sodium hyaluronate (20-50 kDa) 0.05 0.07 0.09 0.1 0.11 0.12 (b-2) Carrageenan 0.1 0.14 0.18 0.2 0.22 0.24 (has) Polylysine 0.031 0.044 0.056 0.063 0.069 0.075 (c) Phytic acid 0.021 0.030 0.038 0.043 0.047 0.051 (d) Calcium PCA 0.038 0.053 0.068 0.075 0.083 0.090 (e) Oleic acid 0.007 0.010 0.013 0.014 0.015 0.017 Caprylyl Glycol 0.3 0.3 0.3 0.3 0.3 0.3 Glycerin 10 10 10 10 10 10 Pentylene glycol 5 5 5 5 5 5 Propylene glycol 5 5 5 5 5 5 Polyglyceryl-2 oleate 0.05 0.05 0.05 0.05 0.05 0.05 Polyglyceryl-4 caprate 0.45 0.45 0.45 0.45 0.45 0.45 (f) Water qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 NPAH concentration (% by weight) 0.25 0.35 0.45 0.50 0.54 0.59 Weight ratio of (b-1) to total weight of NPAH 0.202 0.202 0.202 0.202 0.202 0.202 Weight ratio of (b-2) to total weight of NPAH 0.405 0.403 0.405 0.404 0.404 0.405 Weight ratio of (a) to total weight of NPAH 0.126 0.127 0.126 0.127 0.127 0.126 Weight ratio of (c) to total weight of NPAH 0.086 0.086 0.085 0.087 0.086 0.086 Weight ratio of (d) to total weight of NPAH 0.153 0.153 0.153 0.152 0.153 0.152 Weight ratio of (e) to total weight of NPAH 0.028 0.029 0.029 0.028 0.028 0.029 Appearance Good Good Good Good Good Bad Particle size (nm) 32.4 57.2 62.2 140.2 229.3 184.9 Turbidity (NTU) 25.8 68.8 76.6 237 257 333

[Evaluations]

(Appearance)

The appearance of the compositions according to Examples 2 to 6 and Comparative Example 2 was visually evaluated at room temperature (25°C) in accordance with the following criteria.

Good: Transparent

Bad: Precipitation was observed

The results are shown on the line marked “Aspect” in Table 2.

(Particle size)

The particle size or diameter of NPAH in the compositions according to Examples 2 to 6 and Comparative Example 2 was measured by an ELSZ-2000 particle size analyzer by Otsuka Electronics Co., Ltd. at room temperature (25°C).

The results are shown in the row labeled “Particle size (nm)” in Table 2.

(Turbidity)

The turbidity of the compositions according to Examples 2 to 6 and Comparative Example 2 was measured by a 2100Q turbidimeter (Hach Company) at room temperature (25 °C).

The results are shown on the line marked “Turbidity (NTU)” in Table 2.

(Summary)

The experimental data shown in Table 2 show that if the amount of nanoparticles is 0.59 wt% or more, relative to the total weight of the composition, precipitation occurs.

[Reference Example 1 and Examples 7-11]

[Preparation]

Each of the compositions according to Reference Example 1 and Examples 7-11 was prepared by mixing the ingredients listed in Table 3. The numerical values of the amounts of ingredients in Table 3 are all based on a “% by weight” of active ingredients.

The compositions according to Reference Example 1 and Examples 7-11 included particles including hyaluronic acid (except for Reference Example 1). “NPAH” in Table 3 is an abbreviation for NanoParticle of Hyaluronic Acid. (a) to (f) in Table 3 correspond to those of the claims.

　 Re. 1 comp. 7 Ex. 8 Ex. 9 Ex. 10 Ex. 11 NPAH (b-1) Sodium hyaluronate (20-50 kDa) - 0.01 0.03 0.05 0.1 0.2 (b-2) Carrageenan 0.1 0.1 0.1 0.1 0.1 0.1 (has) Polylysine 0.031 0.031 0.031 0.031 0.031 0.031 (c) Phytic acid 0.021 0.021 0.021 0.021 0.021 0.021 (d) Calcium PCA 0.038 0.038 0.038 0.038 0.038 0.038 (e) Oleic acid 0.007 0.007 0.007 0.007 0.007 0.007 Caprylyl Glycol 0.3 0.3 0.3 0.3 0.3 0.3 Glycerin 10 10 10 10 10 10 Pentylene glycol 5 5 5 5 5 5 Propylene glycol 5 5 5 5 5 5 Polyglyceryl-2 oleate 0.05 0.05 0.05 0.05 0.05 0.05 Polyglyceryl-4 caprate 0.45 0.45 0.45 0.45 0.45 0.45 (f) Water qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 NPAH concentration (% by weight) 0.20 0.21 0.23 0.25 0.30 0.40 Weight ratio of (b-1) to total weight of NPAH - 0.048 0.132 0.202 0.337 0.504 Weight ratio of (b-2) to total weight of NPAH 0.508 0.483 0.440 0.405 0.337 0.252 Weight ratio of (a) to total weight of NPAH 0.157 0.150 0.137 0.126 0.104 0.078 Weight ratio of (c) to total weight of NPAH 0.107 0.101 0.093 0.085 0.070 0.053 Weight ratio of (d) to total weight of NPAH 0.192 0.184 0.167 0.154 0.128 0.095 Weight ratio of (e) to total weight of NPAH 0.036 0.034 0.031 0.028 0.024 0.018 Appearance Good Good Good Good Good Good Particle size (nm) 37.2 40.8 47.1 30.3 39.6 51.2 Turbidity (NTU) 16 15.2 14.5 15 13.4 27.8

[Evaluations]

(Appearance)

The appearance of the compositions according to Reference Example 1 and Examples 7-11 was evaluated visually at room temperature (25°C) in accordance with the following criteria.

Good: Transparent

Bad: Turbid

The results are shown on the line marked “Aspect” in Table 3.

(Particle size)

The particle size or diameter of NPAH in the compositions according to Reference Example 1 and Examples 7-11 was measured by an ELSZ-2000 particle size analyzer by Otsuka Electronics Co., Ltd. at room temperature (25°C).

The results are shown in the row labeled “Particle size (nm)” in Table 3.

(Turbidity)

The turbidity of the compositions according to Reference Example 1 and Examples 7-11 was measured by a 2100Q turbidimeter (Hach Company) at room temperature (25 °C).

The results are shown on the line marked “Turbidity (NTU)” in Table 3.

(Summary)

The experimental data shown in Table 3 show that nanoparticles can be prepared without depending on the amount of the (b-1) first anionic polymer.

However, if no (b-1) first anionic polymer is used (Reference Example 1), the cosmetic effects derived from the (b-1) first anionic polymer cannot be obtained.

[Examples 12 to 15 and Comparative Examples 3 to 6]

[Preparation]

Each of the compositions according to Examples 12 to 15 and Comparative Examples 3 to 6 was prepared by mixing the ingredients listed in Table 4. The numerical values of the amounts of ingredients in Table 4 are all based on a “% by weight” of active ingredients.

The compositions according to Examples 12-15 and Comparative Examples 3-6 included particles including hyaluronic acid. “NPAH” in Table 4 is an abbreviation for NanoParticle Hyaluronic Acid. (a) to (f) in Table 4 correspond to those of the claims.

　 Ex.
comp. 3 Ex.
comp. 4 Ex.
comp. 5 Ex.
comp. 6 comp. 12 Ex. 13 Ex. 14 Ex. 15 NPAH (b-1) Sodium hyaluronate (20-50 kDa) 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 (b-2) Carrageenan - 0.01 0.03 0.05 0.1 0.15 0.2 0.3 (has) Polylysine 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031 (c) Phytic acid 0.021 0.021 0.021 0.021 0.021 0.021 0.021 0.021 (d) Calcium PCA 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038 (e) Oleic acid 0.007 0.007 0.007 0.007 0.007 0.007 0.007 0.007 Caprylyl Glycol 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 Glycerin 10 10 10 10 10 10 10 10 Pentylene glycol 5 5 5 5 5 5 5 5 Propylene glycol 5 5 5 5 5 5 5 5 Polyglyceryl-2 oleate 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 Polyglyceryl-4 caprate 0.45 0.45 0.45 0.45 0.45 0.45 0.45 0.45 (f) Water qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 NPAH concentration (% by weight) 0.15 0.16 0.18 0.20 0.25 0.30 0.35 0.45 Weight ratio of (b-1) to total weight of NPAH 0.340 0.318 0.282 0.254 0.202 0.168 0.144 0.112 Weight ratio of (b-2) to total weight of NPAH - 0.064 0.169 0.254 0.405 0.505 0.576 0.671 Weight ratio of (a) to total weight of NPAH 0.211 0.197 0.175 0.157 0.126 0.104 0.089 0.069 Weight ratio of (c) to total weight of NPAH 0.143 0.134 0.119 0.107 0.085 0.071 0.061 0.047 Weight ratio of (d) to total weight of NPAH 0.258 0.242 0.215 0.193 0.154 0.128 0.110 0.085 Weight ratio of (e) to total weight of NPAH 0.048 0.045 0.04 0.035 0.028 0.024 0.020 0.016 Appearance Bad Bad Bad Bad Good Good Good Good Particle size (nm) 193.6 129 255.1 46718 32.4 7.2 59 60.4 Turbidity (NTU) 542 368 902 >1000 25.8 8.02 12 10.7

[Evaluations]

(Appearance)

The appearance of the compositions according to Examples 12-15 and Comparative Examples 3-6 was visually evaluated at room temperature (25°C) in accordance with the following criteria.

Good: Transparent

Bad: Turbid

The results are shown on the line marked “Aspect” in Table 4.

(Particle size)

The particle size or diameter of NPAH in the compositions according to Examples 12-15 and Comparative Examples 3-6 was measured by an ELSZ-2000 particle size analyzer by Otsuka Electronics Co., Ltd. at room temperature (25°C).

The results are shown in the row labeled “Particle size (nm)” in Table 4.

(Turbidity)

The turbidity of the compositions according to Examples 12-15 and Comparative Examples 3-6 was measured by a 2100Q turbidimeter (Hach Company) at room temperature (25 °C).

The results are shown on the line marked “Turbidity (NTU)” in Table 4.

(Summary)

The experimental data shown in Table 4 show that if the weight ratio of the amount of the (b-2) second anionic polymer, relative to the total weight of the nanoparticles, is less than or equal to 0.254, the appearance of a composition including the nanoparticles becomes turbid (non-transparent).

[Examples 16 to 20 and Comparative Examples 7 to 9]

[Preparation]

Each of the compositions according to Examples 16 to 20 and Comparative Examples 7 to 9 was prepared by mixing the ingredients listed in Table 5. The numerical values of the amounts of ingredients in Table 5 are all based on a “% by weight” of active ingredients.

The compositions according to Examples 16-20 and Comparative Examples 7-9 included particles including hyaluronic acid. “NPAH” in Table 5 is an abbreviation for NanoParticle of Hyaluronic Acid. (a) to (f) in Table 5 correspond to those of the claims.

　 Ex.
comp. 7 Ex.
comp. 8 comp. 16 comp. 17 Ex. 18 Ex. 19 Ex. 20 Ex.
Ex. 9 NPAH (b-1) Sodium hyaluronate (20-50 kDa) 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 (b-2) Carrageenan 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 (has) Polylysine - 0.013 0.020 0.031 0.038 0.045 0.050 0.075 (c) Phytic acid 0.021 0.021 0.021 0.021 0.021 0.021 0.021 0.021 (d) Calcium PCA 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038 (e) Oleic acid 0.007 0.007 0.007 0.007 0.007 0.007 0.007 0.007 Caprylyl Glycol 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 Glycerin 10 10 10 10 10 10 10 10 Pentylene glycol 5 5 5 5 5 5 5 5 Propylene glycol 5 5 5 5 5 5 5 5 Polyglyceryl-2 oleate 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 Polyglyceryl-4 caprate 0.45 0.45 0.45 0.45 0.45 0.45 0.45 0.45 (f) Water qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 NPAH concentration (% by weight) 0.22 0.23 0.24 0.25 0.25 0.26 0.27 0.29 Weight ratio of (b-1) to total weight of NPAH 0.232 0.218 0.212 0.202 0.197 0.192 0.188 0.172 Weight ratio of (b-2) to total weight of NPAH 0.463 0.437 0.424 0.405 0.394 0.383 0.376 0.344 Weight ratio of (a) to total weight of NPAH - 0.057 0.085 0.126 0.149 0.172 0.188 0.258 Weight ratio of (c) to total weight of NPAH 0.097 0.092 0.090 0.085 0.083 0.080 0.079 0.072 Weight ratio of (d) to total weight of NPAH 0.176 0.166 0.159 0.154 0.149 0.146 0.143 0.130 Weight ratio of (e) to total weight of NPAH 0.032 0.030 0.030 0.028 0.028 0.027 0.026 0.024 Appearance Good Good Good Good Good Good Good Bad Particle size (nm) ND ND 107.5 53.3 95 172.3 172.3 885.7 Turbidity (NTU) 0.63 3.73 4.96 26 93.8 254 372 >1000

[Evaluations]

(Appearance)

The appearance of the compositions according to Examples 16-20 and Comparative Examples 7-9 was visually evaluated at room temperature (25°C) in accordance with the following criteria.

Good: Transparent

Bad: Precipitation was observed

The results are shown on the line marked “Aspect” in Table 5.

(Particle size)

The particle size or diameter of NPAH in the compositions according to Examples 16 to 20 and Comparative Examples 7 to 9 were measured by an ELSZ-2000 particle size analyzer by Otsuka Electronics Co., Ltd. at room temperature (25°C).

The results are shown in the row labeled “Particle size (nm)” in Table 5.

ND (not available) in Table 5 means that no nanoparticles were found.

(Turbidity)

The turbidity of the compositions according to Examples 16-20 and Comparative Examples 7-9 was measured by a 2100Q turbidimeter (Hach Company) at room temperature (25 °C).

The results are shown on the line marked “Turbidity (NTU)” in Table 5.

(Summary)

The experimental data shown in Table 5 show that if the weight ratio of the amount of the (a) cationic polymer, relative to the total weight of the particles, is 0.057 or less, the particles cannot have a nanometer size (less than 1,000 nm), and that if the weight ratio of the amount of the (a) cationic polymer, relative to the total weight of the particles, is 0.258 or more, precipitates are formed and the turbidity of a composition comprising the particles becomes too high.

[Examples 21 to 26 and Comparative Examples 10 to 11]

[Preparation]

Each of the compositions according to Examples 21 to 26 and Comparative Examples 10 to 11 was prepared by mixing the ingredients listed in Table 6. The numerical values of the amounts of ingredients in Table 6 are all based on a “% by weight” of active ingredients.

The compositions according to Examples 21-26 and Comparative Examples 10-11 included particles including hyaluronic acid. “NPAH” in Table 6 is an abbreviation for NanoParticle of Hyaluronic Acid. (a) to (f) in Table 6 correspond to those of the claims.

　 Ex.
Ex. 10 Comp.
Ex. 11 comp. 21 Ex. 22 Ex. 23 comp. 24 comp. 25 comp. 26 NPAH (b-1) Sodium hyaluronate (20-50 kDa) 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 (b-2) Carrageenan 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 (has) Polylysine 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031 (c) Phytic acid - 0.005 0.010 0.021 0.030 0.040 0.050 0.100 (d) Calcium PCA 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038 (e) Oleic acid 0.007 0.007 0.007 0.007 0.007 0.007 0.007 0.007 Caprylyl Glycol 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 Glycerin 10 10 10 10 10 10 10 10 Pentylene glycol 5 5 5 5 5 5 5 5 Propylene glycol 5 5 5 5 5 5 5 5 Polyglyceryl-2 oleate 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 Polyglyceryl-4 caprate 0.45 0.45 0.45 0.45 0.45 0.45 0.45 0.45 (f) Water qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 NPAH concentration (% by weight) 0.23 0.23 0.24 0.25 0.26 0.27 0.28 0.33 Weight ratio of (b-1) to total weight of NPAH 0.221 0.216 0.212 0.202 0.196 0.188 0.181 0.153 Weight ratio of (b-2) to total weight of NPAH 0.443 0.433 0.424 0.405 0.391 0.376 0.363 0.307 Weight ratio of (a) to total weight of NPAH 0.137 0.134 0.131 0.126 0.121 0.117 0.112 0.095 Weight ratio of (c) to total weight of NPAH - 0.022 0.042 0.085 0.117 0.150 0.181 0.307 Weight ratio of (d) to total weight of NPAH 0.168 0.165 0.161 0.154 0.148 0.143 0.138 0.117 Weight ratio of (e) to total weight of NPAH 0.031 0.030 0.030 0.028 0.027 0.026 0.025 0.021 Appearance Bad Good Good Good Good Good Good Bad Particle size (nm) ND ND 69.7 50.3 102.1 36.2 47.2 46.9 Turbidity (NTU) 12.7 24.5 16.9 21 30.9 22.9 21.8 25.6

[Evaluations]

(Appearance)

The appearance of the compositions according to Examples 21-26 and Comparative Examples 10-11 was visually evaluated at room temperature (25°C) in accordance with the following criteria.

Good: Transparent

Bad: Freeze

The results are shown on the line marked “Aspect” in Table 6.

(Particle size)

The particle size or diameter of NPAH in the compositions according to Examples 21-26 and Comparative Examples 10-11 was measured by an ELSZ-2000 particle size analyzer by Otsuka Electronics Co., Ltd. at room temperature (25°C).

The results are shown in the row labeled “Particle size (nm)” in Table 6.

ND (not available) in Table 6 means that no nanoparticles were found.

(Turbidity)

The turbidity of the compositions according to Examples 21-26 and Comparative Examples 10-11 was measured by a 2100Q turbidimeter (Hach Company) at room temperature (25 °C).

The results are shown on the line marked “Turbidity (NTU)” in Table 6.

(Summary)

The experimental data shown in Table 6 show that if the weight ratio of the amount of the (c) non-polymeric acid(s) or salt(s) thereof, relative to the total weight of the particles, is less than or equal to 0.022, the particles cannot have a nanometric size (less than 1000 nm), and that if the amount of the (c) non-polymeric acid(s) or salt(s) is equal to zero, a gel is formed.

[Examples 27 to 32 and Comparative Examples 12 to 13]

[Preparation]

Each of the compositions according to Examples 27 to 32 and Comparative Examples 12 to 13 was prepared by mixing the ingredients listed in Table 7. The numerical values of the amounts of ingredients in Table 7 are all based on a “% by weight” of active ingredients.

The compositions according to Examples 27-32 and Comparative Examples 12-13 included particles including hyaluronic acid. “NPAH” in Table 7 is an abbreviation for NanoParticle Hyaluronic Acid. (a) to (f) in Table 7 correspond to those of the claims.

　 comp. 27 comp. 28 comp. 29 comp. 30 comp. 31 comp. 32 Ex.
Ex. 12 Ex.
Ex. 13 NPAH (b-1) Sodium hyaluronate (20-50 kDa) 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 (b-2) Carrageenan 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 (has) Polylysine 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031 (c) Phytic acid 0.021 0.021 0.021 0.021 0.021 0.021 0.021 0.021 (d) Calcium PCA - 0.010 0.020 0.038 0.050 0.080 0.100 0.200 (e) Oleic acid 0.007 0.007 0.007 0.007 0.007 0.007 0.007 0.007 Caprylyl Glycol 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 Glycerin 10 10 10 10 10 10 10 10 Pentylene glycol 5 5 5 5 5 5 5 5 Propylene glycol 5 5 5 5 5 5 5 5 Polyglyceryl-2 oleate 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 Polyglyceryl-4 caprate 0.45 0.45 0.45 0.45 0.45 0.45 0.45 0.45 (f) Water qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 NPAH concentration (% by weight) 0.21 0.22 0.23 0.25 0.26 0.29 0.31 0.41 Weight ratio of (b-1) to total weight of NPAH 0.239 0.228 0.218 0.202 0.193 0.173 0.162 0.122 Weight ratio of (b-2) to total weight of NPAH 0.478 0.456 0.437 0.405 0.386 0.346 0.323 0.244 Weight ratio of (a) to total weight of NPAH 0.148 0.142 0.135 0.126 0.120 0.107 0.101 0.076 Weight ratio of (c) to total weight of NPAH 0.102 0.096 0.092 0.085 0.081 0.073 0.068 0.052 Weight ratio of (d) to total weight of NPAH - 0.046 0.087 0.154 0.193 0.277 0.323 0.489 Weight ratio of (e) to total weight of NPAH 0.033 0.032 0.031 0.028 0.027 0.024 0.023 0.017 Appearance Good Good Good Good Good Good Bad Bad Particle size (nm) 33.5 40.3 39.2 54.9 75.6 569.3 >1000 >1000 Turbidity (NTU) 2.79 3.89 5.26 18.7 51.9 161 167 185

[Evaluations]

(Appearance)

The appearance of the compositions according to Examples 27-32 and Comparative Examples 12-13 was visually evaluated at room temperature (25°C) in accordance with the following criteria.

Good: Transparent

Bad: Precipitation was observed

The results are shown on the line marked “Aspect” in Table 7.

(Particle size)

The particle size or diameter of NPAH in the compositions according to Examples 27-32 and Comparative Examples 12-13 was measured by an ELSZ-2000 particle size analyzer by Otsuka Electronics Co., Ltd. at room temperature (25°C).

The results are shown in the row labeled “Particle size (nm)” in Table 7.

(Turbidity)

The turbidity of the compositions according to Examples 27-32 and Comparative Examples 12-13 was measured by a 2100Q turbidimeter (Hach Company) at room temperature (25 °C).

The results are shown on the line marked “Turbidity (NTU)” in Table 7.

(Summary)

The experimental data shown in Table 7 show that if the weight ratio of the amount of the (d) metal salt to the total weight of the particles is 0.323 or more, the particles cannot be nanosized (less than 1000 nm), and precipitation occurs.

[Reference Example 2 and Examples 33-39]

[Preparation]

Each of the compositions according to Reference Example 2 and Examples 33-39 was prepared by mixing the ingredients listed in Table 8. The numerical values of the amounts of ingredients in Table 8 are all based on a “% by weight” of active ingredients.

The compositions according to Reference Example 2 and Examples 33-39 included nanoparticles including hyaluronic acid. “NPAH” in Table 8 is an abbreviation for NanoParticle of Hyaluronic Acid. (a) to (f) in Table 8 correspond to those of the claims.

　 Re. 2 comp. 33 comp. 34 comp. 35 comp. 36 comp. 37 comp. 38 comp. 39 NPAH (b-1) Sodium hyaluronate (20-50 kDa) 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 (b-2) Carrageenan 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 (has) Polylysine 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031 (c) Phytic acid 0.021 0.021 0.021 0.021 0.021 0.021 0.021 0.021 (d) Calcium PCA 0.038 0.038 0.038 0.038 0.038 0.038 0.038 0.038 (e) Oleic acid - 0.001 0.003 0.005 0.007 0.010 0.030 0.050 Caprylyl Glycol 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 Glycerin 10 10 10 10 10 10 10 10 Pentylene glycol 5 5 5 5 5 5 5 5 Propylene glycol 5 5 5 5 5 5 5 5 Polyglyceryl-2 oleate 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 Polyglyceryl-4 caprate 0.45 0.45 0.45 0.45 0.45 0.45 0.45 0.45 (f) Water qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 NPAH concentration (% by weight) 0.24 0.24 0.24 0.25 0.25 0.25 0.27 0.29 Weight ratio of (b-1) to total weight of NPAH 0.208 0.207 0.206 0.204 0.202 0.200 0.185 0.172 Weight ratio of (b-2) to total weight of NPAH 0.417 0.415 0.411 0.408 0.405 0.400 0.370 0.346 Weight ratio of (a) to total weight of NPAH 0.129 0.129 0.128 0.127 0.126 0.124 0.115 0.107 Weight ratio of (c) to total weight of NPAH 0.088 0.087 0.087 0.086 0.085 0.084 0.078 0.072 Weight ratio of (d) to total weight of NPAH 0.158 0.158 0.156 0.155 0.154 0.152 0.141 0.131 Weight ratio of (e) to total weight of NPAH - 0.004 0.012 0.020 0.028 0.040 0.111 0.172 Appearance Good Good Good Good Good Good Good Good Particle size (nm) 34.3 57.6 49.5 34.5 33.1 59.8 68.6 52.5 Turbidity (NTU) 18.1 34.4 19.8 12.2 16.5 23.6 31.4 22.7

[Evaluations]

(Appearance)

The appearance of the compositions according to Reference Example 2 and Examples 33 to 39 was evaluated visually at room temperature (25°C) in accordance with the following criteria.

Good: Transparent

Bad: Turbid

The results are shown on the line marked “Aspect” in Table 8.

(Particle size)

The particle size or diameter of NPAH in the compositions according to Reference Example 2 and Example 33-39 was measured by an ELSZ-2000 particle size analyzer by Otsuka Electronics Co., Ltd. at room temperature (25°C).

The results are shown in the row labeled “Particle size (nm)” in Table 8.

(Turbidity)

The turbidity of the compositions according to Reference Example 2 and Examples 33-39 was measured by a 2100Q turbidimeter (Hach Company) at room temperature (25 °C).

The results are shown on the line marked “Turbidity (NTU)” in Table 8.

(Summary)

The experimental data shown in Table 8 show that nanoparticles can be prepared, regardless of the amount of the (e) fatty acid.

However, in the absence of (e) fatty acid (Reference Example 2), the skin penetration enhancing effects derived from (e) fatty acid cannot be obtained.

[Examples 40 to 44]

[Preparation]

Each of the compositions according to Examples 40 to 44 was prepared by mixing the ingredients listed in Table 9. The numerical values of the amounts of ingredients in Table 9 are all based on a “% by weight” of active ingredients.

The compositions according to Examples 40 to 44 included nanoparticles including hyaluronic acid. “NPAH” in Table 9 is an abbreviation for NanoParticle of Hyaluronic Acid. (a) to (f) in Table 9 correspond to those of the claims.

　 comp. 40 comp. 41 comp. 42 comp. 43 comp. 44 NPAH (b-1) Sodium hyaluronate (20-50 kDa) 0.05 - - - - (b-1) Sodium hyaluronate (1,100 kDa) - 0.05 - - - (b-1) Sodium hyaluronate (< 5 kDa) - - 0.05 - - (b-1) Sodium hyaluronate (0.4-5 kDa) - - - 0.05 - (b-1) Acetylated sodium hyaluronate - - - - 0.05 (b-2) Carrageenan 0.1 0.1 0.1 0.1 0.1 (has) Polylysine 0.031 0.031 0.031 0.031 0.031 (c) Phytic acid 0.021 0.021 0.021 0.021 0.021 (d) Calcium PCA 0.038 0.038 0.038 0.038 0.038 (e) Oleic acid 0.007 0.007 0.007 0.007 0.007 Caprylyl Glycol 0.3 0.3 0.3 0.3 0.3 Glycerin 10 10 10 10 10 Pentylene glycol 5 5 5 5 5 Propylene glycol 5 5 5 5 5 Polyglyceryl-2 oleate 0.05 0.05 0.05 0.05 0.05 Polyglyceryl-4 caprate 0.45 0.45 0.45 0.45 0.45 (f) Water qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 NPAH concentration (% by weight) 0.25 0.25 0.25 0.25 0.25 Weight ratio of (b-1) to total weight of NPAH 0.202 0.202 0.202 0.202 0.202 Weight ratio of (b-2) to total weight of NPAH 0.405 0.405 0.405 0.405 0.405 Weight ratio of (a) to total weight of NPAH 0.126 0.126 0.126 0.126 0.126 Weight ratio of (c) to total weight of NPAH 0.085 0.085 0.085 0.085 0.085 Weight ratio of (d) to total weight of NPAH 0.154 0.154 0.154 0.154 0.154 Weight ratio of (e) to total weight of NPAH 0.028 0.028 0.028 0.028 0.028 Appearance Good Good Good Good Good Particle size (nm) 33.1 43.8 40.3 32.1 45.5 Turbidity (NTU) 16.5 23.2 17.7 12.4 21.8

[Evaluations]

(Appearance)

The appearance of the compositions according to Examples 40 to 44 was evaluated visually at room temperature (25°C) in accordance with the following criteria.

Good: Transparent

Bad: Turbid

The results are shown on the line marked “Aspect” in Table 9.

(Particle size)

The particle size or diameter of NPAH in the compositions according to Example 40-44 was measured by an ELSZ-2000 particle size analyzer by Otsuka Electronics Co., Ltd. at room temperature (25°C).

The results are shown in the row labeled “Particle size (nm)” in Table 9.

(Turbidity)

The turbidity of the compositions according to Examples 40 to 44 was measured using a 2100Q turbidimeter (Hach Company) at room temperature (25 °C).

The results are shown on the line marked “Turbidity (NTU)” in Table 9.

(Summary)

The experimental data shown in Table 9 show that a variety of hyaluronic acids can be used as (b-1) first anionic polymer.

[Examples 45 to 54]

[Preparation]

Each of the compositions according to Examples 45 to 54 was prepared by mixing the ingredients listed in Table 10. The numerical values of the amounts of ingredients in Table 10 are all based on a “% by weight” of active ingredients.

The compositions according to Examples 45 to 54 included nanoparticles including hyaluronic acid. “NPAH” in Table 10 is an abbreviation for NanoParticle of Hyaluronic Acid. (a) to (f) of Table 10 correspond to those of the claims.

　 comp. 45 comp. 46 comp. 47 comp. 48 comp. 49 comp. 50 comp. 51 comp. 52 comp. 53 comp. 54 NPAH (b-1) Sodium hyaluronate
(20-50 kDa) 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 (b-2) Carrageenan - 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 (b-2) Pectin 0.1 - - - - - - - - - (has) Polylysine 0.031 - 0.031 0.031 0.031 0.031 0.031 0.031 0.031 0.031 (has) Arginine/lysine polypeptide - 0.033 - - - - - - - - (c) Phytic acid 0.021 0.021 - - 0.021 0.021 0.021 0.021 0.021 0.021 (c) Lactic acid - - 0.017 - - - - - - - (c) Citric acid - - - 0.012 - - - - - - (d) Calcium PCA 0.038 0.038 0.038 0.038 - - 0.038 0.038 0.038 0.038 (d) Calcium chloride - - - - 0.038 - - - - - (d) Magnesium chloride - - - - - 0.038 - - - - (e) Oleic acid 0.007 0.007 0.007 0.007 0.007 0.007 - - - - (e) Decanoic acid - - - - - - 0.007 - - - (e) Myristic acid - - - - - - - 0.007 - - (e) Stearic acid - - - - - - - - 0.007 - (e) Behenic acid - - - - - - - - - 0.007 Caprylyl Glycol 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 Glycerin 10 10 10 10 10 10 10 10 10 10 Pentylene glycol 5 5 5 5 5 5 5 5 5 5 Propylene glycol 5 5 5 5 5 5 5 5 5 5 Polyglyceryl-2 oleate 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 Polyglyceryl-4 caprate 0.45 0.45 0.45 0.45 0.45 0.45 0.45 0.45 0.45 0.45 (f) Water qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 qsp 100 Following Following NPAH concentration (% by weight) 0.25 0.25 0.24 0.24 0.25 0.25 0.25 0.25 0.25 0.25 Weight ratio of (b-1) to total weight of NPAH 0.202 0.201 0.206 0.211 0.202 0.202 0.202 0.202 0.202 0.202 Weight ratio of (b-2) to total weight of NPAH 0.405 0.402 0.412 0.420 0.405 0.405 0.405 0.405 0.405 0.405 Weight ratio of (a) to total weight of NPAH 0.126 0.132 0.127 0.130 0.126 0.126 0.126 0.126 0.126 0.126 Weight ratio of (c) to total weight of
NPAH 0.085 0.084 0.070 0.050 0.085 0.085 0.085 0.085 0.085 0.085 Weight ratio of (d) to total weight of NPAH 0.154 0.153 0.156 0.160 0.154 0.154 0.154 0.154 0.154 0.154 Weight ratio of (e) to total weight of NPAH 0.028 0.028 0.029 0.029 0.028 0.028 0.028 0.028 0.028 0.028 Appearance Good Good Good Good Good Good Good Good Good Good Particle size (nm) 74.2 145.5 86 41.3 238.7 465.6 33.8 33.8 33.3 32.6 Turbidity (NTU) 34 80 42.6 27.4 101 140 17.6 15.4 13.4 69.4

[Evaluations]

(Appearance)

The appearance of the compositions according to Examples 45 to 54 was evaluated visually at room temperature (25°C) in accordance with the following criteria.

Good: Transparent

Bad: Turbid

The results are shown in the row labeled “Aspect” of Table 10.

(Particle size)

The particle size or diameter of NPAH in the compositions according to Example 45-55 was measured by an ELSZ-2000 particle size analyzer by Otsuka Electronics Co., Ltd. at room temperature (25°C).

The results are shown in the row labeled “Particle size (nm)” in Table 10.

(Turbidity)

The turbidity of the compositions according to Examples 45 to 55 was measured using a 2100Q turbidimeter (Hach Company) at room temperature (25 °C).

The results are shown on the line marked “Turbidity (NTU)” in Table 10.

(Summary)

The experimental data shown in Table 10 show that a variety of (a) cationic polymers, (b-2) second anionic polymers, (c) non-polymeric acid or salt(s) thereof, (d) metal salts and (e) fatty acids can be used.

Claims (10)

Composition, preferably cosmetic composition, and more preferably cosmetic composition for the skin, comprising
nanoparticles comprising:
(a) at least one cationic polymer;
(b-1) at least one first anionic polymer chosen from hyaluronic acids and their derivatives;
(b-2) at least one second anionic polymer which is different from (b-1) first anionic polymer;
(c) at least one non-polymeric acid or a salt thereof;
(d) at least one optional metal salt; and
(e) at least one fatty acid,
And
(f) water,
in which
the amount of nanoparticles is from 0.01% to 0.58% by weight, preferably from 0.05% to 0.57% by weight and more preferably from 0.1% to 0.56% by weight, relative to the total weight of the composition,
the weight ratio of the amount of the cationic polymer(s) to the total weight of the nanoparticles is 0.06 to 0.25,
the weight ratio of the amount of the (b-2) second anionic polymer to the total weight of the nanoparticles is 0.26 or more,
the weight ratio of the amount of the (c) non-polymeric acid(s) or salt(s) thereof to the total weight of the nanoparticles is 0.03 or more,
the weight ratio of the amount of the optional metal salt(s) to the total weight of the nanoparticles is 0.30 or less, and
the weight ratio of the amount of the fatty acid(s) to the total weight of the nanoparticles is 0.001 or more. The composition of claim 1, wherein the (a) cationic polymer comprises at least one positively chargeable and/or positively charged moiety selected from the group consisting of a primary, secondary or tertiary amino group, a quaternary ammonium group, a guanidine group, a biguanide group, an imidazole group, an imino group and a pyridyl group. The composition of claim 1 or 2, wherein the (a) cationic polymer is selected from the group consisting of alkyldiallylamine cyclopolymers and dialkyldiallylammonium cyclopolymers such as (co)polydiallyldialkyl ammonium chloride, (co)polyamines such as chitosans and (co)polylysines, cationic (co)polyamino acids such as collagen, and an arginine/lysine polypeptide, cationic cellulose polymers, and salts thereof. A composition according to any one of claims 1 to 3, wherein the (b-1) first anionic polymer has a molecular weight of 2,000 kDa or less, preferably 1,000 kDa or less, and more preferably 100 kDa or less. Composition according to any one of claims 1 to 4, in which the weight ratio of the quantity of the (b-1) first anionic polymer(s) relative to the total weight of the nanoparticles in the composition is from 0.01 to 0.8, preferably from 0.02 to 0.7, and more preferably from 0.03 to 0.6. A composition according to any one of claims 1 to 5, wherein the (b-2) second anionic polymer is selected from the group consisting of carrageenan, pectin and a mixture thereof. Composition according to any one of claims 1 to 6, in which the weight ratio of the quantity of the (b-2) second anionic polymer(s) relative to the total weight of the nanoparticles in the composition is from 0.26 to 0.9, preferably from 0.28 to 0.8, and more preferably from 0.30 to 0.7. A composition according to any one of claims 1 to 7, wherein the (c) non-polymeric acid or salt(s) thereof is (are) selected from the group consisting of phytic acid, citric acid, lactic acid and a mixture thereof. A composition according to any one of claims 1 to 8, wherein the (d) optional metal salt is selected from polyvalent metal salts, preferably divalent metal salts, more preferably salts such as calcium chloride and calcium pyrrolidone carboxylate, and magnesium salts such as magnesium chloride. Composition according to any one of claims 1 to 9, in which the (e) fatty acid is chosen from saturated and unsaturated fatty acids, linear or branched in C ₄ -C ₂₂ , preferably C ₆ -C ₂₀ , more preferentially C ₈ -C ₁₈ .