Patent Application
20050175651
The present invention relates mainly to an aqueous dispersion of nanocapsules of core/shell type, to a process for preparing them and to their use especially in cosmetics and/or pharmaceuticals.
The field of the invention more particularly relates to the encapsulation of at least one oil, where appropriate combined with at least one liposoluble active material in a vector of nanocapsule type. Such vectors are particularly useful in cosmetics and pharmaceuticals since they ensure increased stability of the encapsulated active material and ensure its efficient vectorization to its site of action, which is generally the epidermis.
Many techniques have been proposed to date for preparing nanocapsules of this type.
For example, a certain number of nanocapsules are now produced by a technique known as “solvent overflow”. This technique is especially illustrated in document EP 274 961. It involves dissolution of the material to the encapsulated and of the polymer, which is to constitute the envelope of the nanocapsule, in a solvent. The formation of the nanocapsules is initiated by adding, with stirring, to this solution an intermediary solvent that is incapable of dissolving the polymer and the material to be encapsulated, but that is on the other hand miscible with the first solvent. Unfortunately, the degree of encapsulation obtained with this technique remains insufficient, since it generally does not exceed 8% by weight relative to the weight of the dispersion.
Patent application WO 01/64328 illustrates another technique, known as “phase inversion”, which involves the application to the emulsion under consideration of several cycles of raising and lowering the temperature to bring about this phase inversion. This technique is especially illustrated therein for the preparation of particles smaller than 100 nm, with an oily core coated with a wax or a lecithin, i.e. a core whose melting point may prove to be less than 20° C. This type of wall also has the drawback of being very permeable, sensitive to surfactants and chemically unstable since it is very sensitive to oxidation.
Patent U.S. Pat. No. 4,124,526 from the Monsanto Company itself proposes an alternative to this solvent overflow technique, which consists in obtaining particles by coacervation of a salt of a polycarboxylic polymer, by acidification of the suspension to a pH of between 5 and 8. This solvent-free process leads to particles of heterogeneous size, generally greater than one micrometre, and having high porosity.
Another route of access to nanocapsules of this type is based on the emulsification technique and involves the simultaneous synthesis of the polymer shell by crosslinking of the corresponding monomers.
For example, document FR 1 583 243 describes a process for manufacturing microcapsules containing oil droplets with a size ranging from 0.1 to several microns and which uses chemical crosslinking agents. This technique is also illustrated in document WO 02/09862.
Patent application WO 93/08908 uses this same technique to prepare nanocapsules whose shell is derived from the crosslinking of proteins.
Patent application WO 02/051536 itself describes suspensions of particles between 70 nm and 5 μm in size, obtained by crosslinking monomers, this crosslinking being initiated by exposing the suspension to UV irradiation.
As it turns out, this second route of access has the major drawback of requiring a crosslinking step that involves either chemical species of crosslinking agent type, which may pose problems in terms of harmlessness, or an external stimulus of UV irradiation type, which may be harmful to the biological active agents if they prove to be UV-sensitive.
Finally, patent application WO 99/43426 from Laboratoires Sérobiologiques describes lipid particles that are solid between 25 and 85° C., of between 10 nm and 5 mm in size, obtained by emulsification and without solvent. However, the particles described in the said document are particles necessarily consisting of at least one solid lipid of wax type and have no solid polymer coating, i.e. they are different from nanocapsules. When introduced into a composition containing surfactants, these particles show limited stability on account of the partial dissolution of the waxes by the surfactants, thus inducing the release of the encapsulated oily active materials.
In general, the processes described above are also dependent on the nature of the solvents used, which must be water-miscible. This imposes a large limitation in the choice of polymers that form the shell of the nanocapsule, which are by definition water-insoluble and lipophilic. Finally, these processes generally require very large volumes of solvent (water-miscible) and of water, which then need to be evaporated off in order finally only to obtain a dispersion containing not more than 8% by weight of degree of encapsulation.
Consequently, the dispersions of nanocapsules currently available are not found to be entirely satisfactory since they are not simultaneously satisfactory in terms of size, occasionally in terms of harmlessness, of stability and of general-purpose use regarding the nature of the active material to be encapsulated.
What is more, the content of encapsulated active material generally does not exceed 8% with nanocapsules of this type. However, to increase the performance of the encapsulated molecules, it would be necessary to have a degree of encapsulation that is, in any case, greater than 8% and in particular greater than 10%.
The objective of the present invention is specifically to propose nanocapsules that can satisfy in these respects, i.e. that are suitable for encapsulated in high proportion a large variety of oils and/or liposoluble active agents, which can advantageously have a size ranging from 40 nm to 150 nm, which are compatible with the use of a very large number of polymers and whose preparation requires smaller amounts of solvent than those of the conventional processes.
According to one of its aspects, the present invention relates to an aqueous dispersion of nanocapsules of core/shell type, in which:
According to another of its aspects, the present invention relates to a process for preparing an aqueous dispersion of nanocapsules of core/shell type, the core of which comprises at least one oil and the shell covering the core is of polymeric nature and is water-insoluble and insoluble in the oil(s) of the said core, comprising the steps consisting in:
The process according to the invention is advantageous in several respects.
Firstly, as emerges from the text hereinbelow, it is found to be suitable for encapsulating a large diversity of plant, animal or synthetic oils.
The nanocapsules obtained according to this process may have a mean size of less than 150 nm, without this being harmful to the degree of encapsulation, which remains considerably higher than 10% by weight relative to the total weight of the aqueous dispersion.
Since preformed polymers are used, this makes it possible to effectively eliminate the problem of harmlessness more particularly posed by the use of monomers that involves that of at least one crosslinking agent.
Finally, the process of the invention is advantageously free of the two constraints posed by the nature of the solvents and by their volume of use with the processes discussed hereinabove.
Nanocapsules:
For the purposes of the present invention, the term “nanocapsules” denotes a structure of core-shell type, i.e. a structure consisting of a core forming or containing the material to be encapsulated, this core being enveloped with a continuous and water-insoluble protective shell. In other words, according to the invention, they are nanocapsules with a lipid core surrounded by a shell of polymeric nature.
The nanocapsules according to the invention may be, for example, as shown diagrammatically in
The nanocapsules shown in
The nanocapsules according to the invention differ especially from “nanospheres” consisting of a porous polymer matrix in which the active material is absorbed and/or adsorbed.
The nanocapsules according to the invention are advantageously less than or equal to 1 μm, in particular less than or equal to 500 nm and more particularly less than or equal to 250 nm in size. According to one particular embodiment, they are less than or equal to 150 nm, or even less than or equal to 125 nm, especially less than or equal to 100 nm and in particular less than or equal to 80 mn in size. The size is expressed as the medium intensity size supplied by a Brookhaven type BI 90 Plus granulometer, the measuring principle of which is based on quasi-elastic light scattering (QELS).
As mentioned previously, the dispersion according to the invention has a degree of encapsulation significantly higher than that of the conventional dispersions of nanocapsules as discussed previously.
This degree of encapsulation expressed as the weight of encapsulated material is at least 8% by weight relative to the total weight of the dispersion, in particular greater than or equal to 10% by weight, especially greater than or equal to 12.5% by weight, or even greater than or equal to 15% by weight, and more particularly greater than or equal to 17.5% by weight, relative to the total weight of the dispersion.
The shell of the nanocapsules is of non-polymeric, non-crosslinked nature, and is water-insoluble and insoluble in the oil of the core.
In general, any polymer, of natural or synthetic origin, which is soluble in a water-immiscible solvent, and especially those with a melting point lower than the boiling point of water at atmospheric pressure (100° C.), may be used according to the present invention.
These polymers may be biodegradable, for instance polyesters, or non-biodegradable.
As illustrations of polymers that are suitable for the invention, mention may especially be made of:
These polymers or copolymers may have a weight-average molecular weight of between 1000 and 500 000 and in particular between 1500 and 100 000.
Poly(alkylene adipate)s, organopolysiloxanes, polycaprolactones, cellulose acetophthalate, cellulose acetobutyrate, cellulose esters, and polystyrene and derivatives thereof, are most particularly suitable for the invention.
Needless to say, a person skilled in the art is capable, on the basis of his knowledge, of adjusting the molecular weight of the selected polymer with respect to its concentration in the solvent in order to have a viscosity of the mixture that is compatible with satisfactory emulsification.
Encapsulable Active Material:
For the purposes of the present invention, the term “oil” denotes any natural plant or animal, or synthetic, oily substance that is liquid at and above 40° C., which has one or more proven biological activities and which is water-insoluble (less than 2% by weight at room temperature).
Non-limiting illustrations of these oils that may especially be mentioned include unsaturation-rich plant oils, for instance borage oil, fish oils, sunscreens, vitamins E, F and K and esters thereof, and mixtures thereof.
One or more liposoluble active materials that will be dissolved in a solvent oil may also be encapsulated. According to this variant, it is a mixture of at least two or even more components that is encapsulated. Examples of these liposoluble active principles that may be mentioned include vitamins such as vitamin A (retinol), vitamin D, carotenes, β-carotene and salicylic acid and derivatives thereof. For example, the salicylic acid derivatives that may be used are those described in documents FR-A-2 581 542, EP-A-378 936 and EP-A-570 230, and in particular 5-n-octanoylsalicylic acid, 5-n-decanoyl-salicylic acid, 5-n-dodecanoylsalicylic acid, 5-n-octylsalicylic acid, 5-n-heptyloxysalicylic acid and 4-n-heptyloxysalicylic acid.
Moreover, any molecule with a therapeutic effect used in the pharmaceutical field may also be encapsulated, provided that it is of oily nature and/or of sufficient solubility in the oil under consideration. These molecules may thus be steroidal or non-steroidal anti-inflammatory agents, antifingal agents, antibacterial agents, antibiotics, antimitotic agents, anaesthetics, analgesics, antiseptics and anti-viral agents.
However, they may also be liposoluble compounds that are active in other fields, for instance pesticides or herbicides.
Needless to say, the content of oil(s) and, where appropriate, of liposoluble active material(s) (oil or oil+active agent) dissolved in the solvent depends on the solubility of these ingredients.
In general, it is adjusted such that the degree of encapsulation can represent more than 8% and in particular from 10% to 40% of the total weight of the aqueous dispersion.
As mentioned previously, the nanocapsules according to the invention may be prepared by the process in accordance with the invention.
This process according to the invention especially involves, successively:
The organic solvent medium, or even some of the water, is then removed, generally by evaporation under reduced pressure, so as to obtain a dispersion of nanocapsules at the desired concentration.
According to one particular embodiment, the oil/polymer weight ratio used in the organic solvent medium is less than or equal to 30/1 and especially ranges from 1/25 to 25/1.
Organic Solvent Medium:
The organic solvent media under consideration according to the invention are at least partially water-immiscible. More specifically, their solubility in water should be less than 10% by weight in water at room temperature. Their boiling point is necessarily less than that of water, generally 100° C. at atmospheric pressure. As examples of solvents that are suitable for the invention, mention may be made in particular of ethyl acetate, butyl acetate, dichloromethane, cyclohexane, heptane, 1-chlorobutane, chloroform and ethyl formate, and mixtures thereof.
The proportion of organic solvent medium may be adjusted so as to constitute from 5% to 70% by weight relative to the total weight of the pre-emulsion obtained in step c).
Surfactants:
In order to facilitate the emulsification of the organic solvent medium incorporating the oil and, where appropriate, the active material to be encapsulated, and to control the stability of the corresponding emulsion, it is generally desirable to use at least one surfactant, especially a nonionic surfactant.
This surfactant or this mixture of surfactants is generally present at from 0.05% to 25% and especially from 1% to 20% by weight relative to the weight of the organic solvent medium to be dispersed. Its HLB value (Hydrophilic-Lipophilic Balance) is generally adjusted so as to be favourable to the formation of emulsions of oil-in-water type.
The following nonionic surfactants are especially suitable for the invention:
The C8-C22 or C14-C22 fatty acids forming the fatty unit of the esters that may be used in the composition of the invention comprise at least one saturated or unsaturated linear alkyl chain, of 8 to 22 or of 14 to 22 carbon atoms, respectively. The fatty unit of the esters may be chosen especially from stearates, behenates, arachidonates, palmitates, myristates, laurates and caprates, and mixtures thereof. Stearates are especially used.
Examples of esters or mixtures of esters of fatty acid and of sucrose, maltose, glucose or fructose that may be mentioned include sucrose monostearate, sucrose distearate and sucrose tristearate, and mixtures thereof, such as the products sold by the company Croda under the name Crodesta® F50, F70, F110 and F160, respectively having an HLB (Hydrophilic-Lipophilic Balance) of 5, 7, 11 and 16; and an example of esters or mixtures of esters of fatty acid and of methylglucose that may be mentioned is methylglucose polyglyceryl-3 distearate, sold by the company Goldschmidt under the name Tegocare 450®. Mention may also be made of monoesters of glucose or of maltose such as methyl O-hexadecanoyl-6-D-glucoside and O-hexadecanoyl-6-D-maltoside.
The sugar fatty alcohol ethers that may be used as surfactants in the composition according to the invention may be chosen especially from the group comprising ethers or mixtures of ethers of C8-C22 fatty alcohol and of glucose, maltose, sucrose or fructose, and ethers or mixtures of ethers of C14-C22 fatty alcohol and of methylglucose. They are especially alkylpolyglucosides.
The C8-C22 or C14-C22 fatty alcohols forming the fatty unit of the ethers that may be used according to the invention comprise a saturated or unsaturated linear alkyl chain containing, respectively, from 8 to 22 or from 14 to 22 carbon atoms. The fatty unit of the ethers may be chosen especially from decyl, cetyl, behenyl, arachidyl, stearyl, palmityl, myristyl, lauryl, capryl and hexadecanoyl, and mixtures thereof such as cetearyl.
Examples of sugar fatty alcohol ethers that may be mentioned include alkylpolyglucosides such as decyl glucoside and lauryl glucoside sold, for example, by the company Henkel under the respective names Plantaren 2000® and Plantaren. 1200®, cetostearyl glucoside optionally as a mixture with cetostearyl alcohol, sold, for example, under the name Montanov 68® by the company SEPPIC, under the name Tegocare CG90® by the company Goldschmidt and under the name Emulgade KE3302® by the company Henkel, and also arachidyl glucoside, for example in the form of the mixture of arachidyl and behenyl alcohols and of arachidyl glucoside, sold under the name Montanov 202® by the company SEPPIC,
According to one particular embodiment, in the compound of formula (I), the alkyl radical is a methyl radical, x is an integer ranging from 2 to 6 and y is an integer ranging from 4 to 30.
Examples of silicone surfactants of formula (I) that may be mentioned include the compounds of formula (II):
in which A is an integer ranging from 20 to 105, B is an integer ranging from 2 to 10 and y is an integer ranging from 10 to 20.
Examples of silicone surfactants of formula (I) that may also be mentioned include the compounds of formula (III):
HO—(CH2CH2O)y—(CH2)3—[(CH3)2SiO]A′—(CH2)3—(OCH2CH2)y—OH (III)
in which A′ and y are integers ranging from 10 to 20.
Compounds of the invention that may be used include those sold by the company Dow Corning under the names DC 5329, DC 7439-146, DC 2-5695 and Q4-3667. The compounds DC 5329, DC 7439-146 and DC 2-5695 are compounds of formula (II) in which, respectively, A is 22, B is 2 and y is 12; A is 103, B is 10 and y is 12; A is 27, B is 3 and y is 12. The compound Q4-3667 is a compound of formula (III) in which A is 15 and y is 13. But also:
These surfactants may be used alone or in combination. Their content, relative to the encapsulated oily phase (after evaporating off the solvent) may be between 0.1% and 30% by weight.
In order to improve the stability of this emulsion, or even to slightly further reduce the size of the drops of the organic solvent medium, it may be advantageous to add from 0.01% to 5% by weight, relative to the total weight of the dispersion, of at least one water-soluble ionic surfactant with an HLB value of greater than 11. This type of ionic surfactant appears to generate an electric charge that the surface of the nanocapsules and thus promotes the manifestation of electrostatic repulsions between them. This or these ionic, anionic or cationic surfactant(s) may be chosen from:
The content of ionic surfactant, when it is combined with the nonionic surfactant(s) present in the aqueous medium, is generally adjusted so as to represent from 2% to 100% by weight relative to the weight of the medium.
Step c) is performed by dispersing the organic solvent medium (a) in the aqueous medium (b). This dispersion is prepared under conditions such that a pre-emulsion is obtained.
For the purposes of the present invention, this pre-ernulsion qualifies a state in which the organic medium (a) is present in the form of droplets ranging from 500 nm to 10 μm and in particular from 1 to 5 μm in size in the aqueous medium constituting the continuous phase. The size of the droplets may especially be controlled using a light-scattering laser granulometer.
The formation of the dispersion of the expected nanocapsules is performed during step (d) by subjecting this pre-emulsion to stiring with a shear effect, for example at at least 10 000 rpm, or agitation with a cavitation effect. According to one particular embodiment, this stirring is obtained by homogenizing the pre-emulsion in a high-pressure homogenizer, generally at a pressure of from 50 to 1500 bar, in particular from 200 to 1200 bar and especially greater than 400 bar. This shear effect may also be obtained using an ultrasound device such as the Sonitube from the company Sodeva.
The organic solvent medium contained in this emulsion is then removed, generally by evaporation according to standard techniques, for example using a rotary evaporator under reduced pressure. This evaporation may be performed until a fraction of the aqueous phase has evaporated off, which is indication of the total removal of the organic solvent medium.
After this step, a dispersion of nanocapsules in accordance with the invention is obtained.
A subject of the present invention is also the use of a dispersion of nanocapsules in accordance with the invention for the preparation of a cosmetic, dermatological or pharmaceutical composition.
The nanocapsules according to the invention may be introduced into any type of liquid, semi-solid or even solid galenical formulation. They may especially be gels, oil/water, water/oil or multiple (W/O/W or O/W/O) emulsions, sera or lotions. It is possible, for example, to introduce from 0.5% to 60% of an aqueous dispersion of nanocapsules in accordance with the invention into a cosmetic, dermatological or pharmaceutical composition.
Another aspect of the invention relates to a cosmetic, dermatological or pharmaceutical composition comprising, in a physiologically acceptable medium, at least one aqueous dispersion of nanocapsules according to the invention.
The formulations described containing nanocapsules may especially be intended for caring for and/or making up the hair, the skin and the nails.
Moreover, the nanocapsules of the present invention may be used for pharmaceutical purposes for the oral, peritoneal, intravenous, intramuscular or ophthalmic vectorization of medicinal products.
The examples given below are presented as non-limiting illustrations of the field of the invention.
All of the aqueous dispersions given in the examples below were prepared according to the following protocol:
A pre-emulsion of organic solvent medium/water type is prepared using an Ultra-Turrax mixer (IKA) for 5 minutes at 10 000 rpm, and is then homogenized using a Soavi OBL 20 high-pressure homogenizer, twice at 500 bar so as to obtain the expected dispersion of nanocapsules. The solvent is removed under reduced pressure using a rotary evaporator and a certain amount of water.
Preparation of Macadamia Oil Nanocapsules
In this example, after evaporating off the dichloromethane, 115 nm nanocapsules are obtained, which are perfectly stable after 2 months at 45° C. The final aqueous dispersion contains 5% by weight of oil and 1% by weight of polymer, relative to the total weight of the dispersion.
Preparation of Cottonseed Oil Nanocapsules
According to the procedure described above, a dispersion of nanocapsules with a mean size of 98 nm dispersed in 300 ml of water is obtained. The aqueous dispersion contains 12.5% by weight of cottonseed oil and 1% by weight of polymer. These capsules are perfectly stable for 2 months at 45° C.
Preparation of Vitamin E Nanocapsules
After evaporating off the dichloromethane, a dispersion of nanocapsules with a mean size of 124 nm that are perfectly stable for 2 months at 45° C. is obtained. The aqueous dispersion contains 20% by weight of oil and 3% by weight of polymer.
Preparation of Isocetyl Palmitate Nanocapsules
After evaporating off the dichloromethane, a dispersion of nanocapsules with a mean size of 103 nm that are perfectly stable for 2 months at 45° C. is obtained. The aqueous dispersion contains 15% by weight of oil and 2% by weight of polymer.
Preparation of Vitamin E Nanocapsules
After evaporating off the dichloromethane, an aqueous dispersion of nanocapsules with a mean size of 240 nm that are perfectly stable after 2 months at 45° C. is obtained. The aqueous dispersion contains 20% by weight of oil and 1% by weight of polymer.
| Number | Date | Country | Kind |
|---|---|---|---|
| 04 50057 | Jan 2004 | FR | national |
| Number | Date | Country | |
|---|---|---|---|
| 60538250 | Jan 2004 | US |
