Aqueous colloidal dispersions of nanoparticles, and in particular pseudolatexes which are aqueous colloidal- dispersions containing nanoparticles of water insoluble preformed polymers, are currently offered for use as aqueous coating means or as pharmaceutical vectors.

At present, various techniques are known for preparing aqueous colloidal dispersions containing nanoparticles, and in particular pseudolatexes. These techniques include emulsification-evaporation, nanoprecipitation, salting-out and emulsification-diffusion, which have in common that they involve the use of an organic solution, containing the nanoparticle components, which functions as an internal phase during preparation, and of an aqueous solution, containing stabilizers which will constitute the dispersion medium for the nanoparticles.

The emulsification-evaporation technique is a well- established technique based on the classical procedure disclosed in US-A-4.177.177 (Vanderhoff). In this technique, a polymer solution in a water-immiscible organic solvent such as chloroform or methylene chloride is emulsified in an aqueous phase containing emulsifiers. This crude emulsion is then submitted to a high energy mixing step using a high energy source such as ultrasounds, homogen. izers, high pressure dispersers, colloid mills or microfluidizers, in order to reduce the droplet size. The

polymer emulsion resulting from such a treatment is very fine and contains very small droplets (below 0.5 m in diameter). This emulsification is followed by the removal of the solvent, by vacuum distillation, producing a fine aqueous dispersion of nanospheres. In this emulsification- evaporation method, each emulsion droplet will form one polymer particle when the solvent is removed. Consequently, the homogenization step is the determining factor in obtaining submicronic particles.

In order to avoid the problem of the homogenization step, which requires high energy, other techniques have been developed.

The nanoprecipitation technique was disclosed in EP-A-0.274.961, EP-A-0.275.796 and EP-A-0.349.428. In this method, polymer, drug and, optionally, a lipophilic stabilizer (e. g., phospholipids) are dissolved in a h semipolar water-miscible solvent, such as acetone or ethanol. This solution is poured or injected into an aqueous solution containing a stabilizer (e. g., poly (vinyl alcohol) (PVAL) or poloxamer 188) under magnetic stirring.

Nanoparticles are formed instantaneously by the rapid diffusion of the solvent, which is then eliminated from the suspension under reduced pressure.

The usefulness of this simple technique is limited to water-miscible solvents in which the diffusion rate is sufficient to produce spontaneous emulsification. Also, this technique can be used only for drugs soluble in this type of solvents. A major drawback with this technique is the difficulty to choose a drug/polymer/solvent/non-solvent system in which non-aggregated nanoparticles would be formed and the drug efficiently entrapped.

The salting-out technique was first disclosed in the International Patent Application WO 88/08011. This technique is based on the separation of a totally water-miscible solvent, in particular acetone, from aqueous solutions via a salting-out effect. Typically, the polymer and the drug are dissolved in acetone and this solution is emulsified under vigorous mechanical stirring in an aqueous gel containing the salting-out agent and a colloidal stabilizer. This oil-in-water emulsion is diluted with a sufficient volume of water or of aqueous solution, in order to enhance the diffusion of acetone into the aqueous phase, thus inducing the formation of nanospheres.

The utility of this technique is however generally limited to drugs soluble in water-miscible solvents, in particular acetone-soluble drugs, to salting-out agents that enable phase separation without precipitation and to soluble stabilizers which are compatible with saturated aqueous solutions and which do not coacervate or precipitate in the presence of the solvent. A major drawback is the use of a high quantity of salt which gives to the aqueous phase a fixed pH and which must be eliminated in a subsequent purification step. Another drawback is that it is necessary to remove the solvent and a considerable amount of water to obtain a high polymer concentration in the final dispersion. Moreover, the acetone is mixed in the water which renders recycling of acetone problematic.

The more recent technique for preparing nanoparticles is the emulsification-diffusion technique proposed in Eur. J. Pharm. Biopharm, 41 14-18 (1995). The method involves the emulsification of a partially water-soluble (partially water-miscible) solvent, previously saturated with water and containing a polymer, in an aqueous phase previously saturated with the solvent and containing a

stabilizer. The subsequent addition of water to the system causes the solvent to diffuse into the external phase, resulting in the aggregation of polymer in nanoparticles.

This method is of interest from a technological standpoint, since it does not need comminuting forces as in the emulsification-evaporation technique does, it is highly efficient, reproducible and easy to scale-up.

However, as in the salting-out technique, it is necessary to remove the solvent and a considerable amount of water to obtain a high polymer concentration in the final dispersion.

It is an object of the present invention to provide a method for producing an aqueous colloidal dispersion containing a high concentration of nanoparticles which is not affected by one or more of the above drawbacks of the known methods, and, in particular, which does not require high shear forces and which does not require the removing of toxic solvent, of stabilizer, of salting-out agent and/or of a considerable amount of water.

The object of the present invention is achieved by a method for producing an aqueous colloidal dispersion of nanoparticles, characterized in that it comprises : a) the emulsification of a partially water-soluble organic solvent, containing a water-insoluble material in a weight/volume percentage at which nanoparticles are formed in step b), in an aqueous solution containing optionally a stabilizing agent, using a low energy source; b) the distillation of the organic solvent from the oil-in-water emulsion formed in step a) to cause the formation of nanoparticles in suspension in the aqueous phase.

Thanks to the present invention, there is provided a method effective for producing aqueous colloidal dispersions containing a high concentration of nanoparticles, which is based on the emulsification-diffusion technique, which does not require the use of high energy source for homogenization, which does not require the removing of a considerable amount of water, in which pharmaceutically acceptable organic solvents may be used with a possibility of solvent reuse, in which pharmaceutically acceptable stabilizers may be used or not, and which is simple to., implement, easy to scale up, of a low cost and reproducible.

An advantage of the aqueous colloidal dispersions having a high concentration of nanoparticles obtained by the method of the present invention is that they can be used directly for coatings or as pharmaceutical vectors without additional purification step., The method of the present invention can be advantageously applied for producing aqueous colloidal dispersions of nanoparticles with ingredients entrapped therein, when the partially water-soluble organic solvent further contains additional ingredients.

It is to be noted that in the present description and claims, the terms"a partially water-soluble organic solvent"or"a partially water-miscible organic solvent" mean an organic solvent at least sparingly soluble in water in the sense of the European Pharmacopoeia or a mixture of organic solvents containing at least one organic solvent at least sparingly soluble in water in the sense of the European Pharmacopoeia.

Also, it is to be noted that in the present description and claims, the term"nanoparticles"means particles having a mean particle size not greater than 1 pm.

We will now describe the present invention in a more detailed manner.

To obtain an aqueous colloidal dispersion of nanoparticles according to the present invention, the first steps are to prepare the organic phase, also named internal phase, and the aqueous phase, also named external phase.

The organic phase is prepared by dissolving the selected water-insoluble material, and optionally additional ingredients, in a partially water-soluble organic solvent.

The aqueous phase is prepared separately, by providing water and optionally dissolving the selected stabilizing agent in water.

In a preferred embodiment of the present invention, the partially water-soluble organic solvent is previously added with a certain amount of water extending up to saturation and in a particularly preferred embodiment of the invention, the partially water-soluble organic solvent is previously saturated with water in order to ensure initial thermodynamic equilibrium in the subsequent step.

Preferably, the water is previously added with a certain amount, extending up to saturation, of the same or another partially water-soluble organic solvent, and more preferably the water is previously saturated with the same or the other partially water-soluble organic solvent in order to ensure initial thermodynamic equilibrium in the subsequent step.

This means that the partially water-soluble organic solvent added to water may be identical or different to the

partially water-soluble organic solvent in which water- insoluble material is to be dissolved.

In an other preferred embodiment of the present invention, the water is previously added with a certain amount of a water-soluble organic solvent (for example ethanol).

The water-insoluble material may be, for example, a polymer, a lipid, a wax and the like, or a mixture of two or more polymers and/or lipids and/or waxes and the like.

In a preferred embodiment of the invention, the water-" insoluble material is a polymer or a mixture of polymers, and in a particularly preferred embodiment, the water- insoluble material is a polymer selected from biodegradable polymer such as poly (D, L-lactic acid) (PLA) and poly (s- caprolactone) (PCL) and non-biodegradable polymers such as EudragittE, Eudragit@RS, Eudragit@RL, cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), and ethylene vinyl acetate copolymer (EVAC).

The partially water-soluble organic solvents should be selected on the basis of their volatility and low toxicity, in particular when a pharmaceutical application for the resulting aqueous colloidal dispersion is considered.

Examples of partially water-soluble organic solvents particularly preferred are ethyl acetate (AcEt), methyl acetate (MeAc), isopropyl acetate and 2-butanone, because of their widely recognized low toxicity, good solubilizing properties and low boiling points.

The additional ingredients may be any ingredients which can be entrapped in the nanoparticles or adsorbed at the surface of the nanoparticles, such as for example drugs, cosmetics, products for veterinary and agricultural use, food products or additives, colorants or any other

ingredients which can be useful when they are entrapped in nanoparticles or adsorbed at the surface of nanoparticles.

When used, stabilizing agents particularly preferred for the emulsification and for stabilizing the final dispersion are poly (vinyl alcohol) (PVAL) and poloxamer 407 because of their good water solubility, suitability for ingestion and compatibility with the system.

When used, the stabilizing agent is contained in the aqueous phase preferably in an amount of not more than 5 æ w/v, and more preferably in an amount of not more than 1.25 W w/v.

The above-mentioned aqueous phase is then mixed with the organic solution of the material, using a low energy source such as, for example, a propeller, a magnetic stirrer, a shaker and the like, to produce, when the addition is finished, an emulsion of the oil-in-water type.

When using a propeller, a particularly advantageous stirring rate for the propeller is from 1500 to 2000 rpm.

However, a stirring rate up to 5000 rpm may be acceptable.

The emulsification step is advantageously carried out at room temperature, but other temperatures may be used.

In accordance with the invention, distillation of the organic solvent from the oil-in-water emulsion is then carried out, to cause the displacement of the partially water-soluble organic solvent of the internal phase into the external phase and, consequently, to cause the formation of the particles in suspension in the aqueous phase.

In a particularly preferred embodiment of the present invention, the distillation is a vacuum distillation.

In the method of the present invention, the formation of nanoparticles is highly dependent on the water-insoluble material concentration in the internal phase and a transition from nano-to microparticles is observed at high water-insoluble material concentration.

For this reason, the amount of water-insoluble material in the organic phase is critical for achieving the mean particle size desired for the final particles.

Thus, in the method of the present invention, the weight/volume percentage of the water-insoluble material in the organic solvent should be not greater than the critical weight/volume percentage at which the particles formed during distillation have a mean particle size of 1 m.

This critical percentage varies depending on the material/solvent/stabilizer system or material/solvent system and on the stirring rate of the propeller, in view of the known effect of an increased stirring rate on decreasing the particle size.

The critical percentage at which the particles formed during distillation have a mean particle size of 1 pm is easily obtained by an optimization for each material/solvent/stabilizer system or material/solvent system at a specific stirring rate.

To illustrate the effect of the concentration of the water- insoluble material in the organic solvent on particle size, in the present invention, we will now explain the present invention, referring to Figures related to two examples of a non-biodegradable polymer particularly preferred of the present invention, named Eudragit@E-100 (obtained from Röhm GmbH, Darmstadt, Germany), which however is not yet commercially available as a colloidal dispersion, and to an

example of another non-biodegradable polymer, named cellulose acetate phthalate (CAP).

Figure 1 represents the influence of the percentage of Eudragit E in the internal phase (ethyl acetate) on the mean particle size, when the external phase contains 5 % w/v of PVAL as stabilizer and the rate of stirring is 1500 rpm.

Figure 2 represents scanning electron micrographs (at x 4500) of EudragitOE particles, prepared at different concentrations of EudragitOE in the internal phase, namely : a) 10 % w/v in chloroform (Comparative Example hereafter); b) 40 k w/v in ethyl acetate, c) 30 % w/v in ethyl acetate; d) 20 % w/v in ethyl acetate (Example 3 hereafter); e) 10 % w/v in ethyl acetate (Example 1 hereafter) when the external phase contains 5 W w/v of PVAL as stabilizer and the stirring rate is 1500 rpm.

Figure 3 represents the influence of the percentage of cellulose acetate phthalate in the internal phase (2-butanone) on mean particle size when the external phase contains 5 W w/v of poloxamer 407 and the stirring rate is 1500 rpm.

Figure 4 represents the influence of the percentage of Eudragit E in the internal phase (methyl acetate) on mean particle size when the external phase contains no stabilizing agent and the stirring rate is 2000 rpm.

The particle sizes were determined using a Coulter@ Nanosizer (Coulter Electronics, Harpenden (UK)).

For the scanning electron microscopy (SE), a concentrated dispersion of nanoparticles was finely spread over a slab

and dried under vacuum. The sample was shadowed in a cathodic evaporator with a gold layer (-20 nm thick). The surface morphology of the nanoparticles was observed by SEM using a JSM-6400 scanning electron microscope (JEOL, Tokyo, Japan).

It is shown in Figure 1 that, for an Eudragit@E/ethyl acetate/PVAL system, when the PVAL content of the external phase is 5.00 % and the stirring rate of the propeller is 1500 rpm, the critical weight/volume percentage of Eudragit@E to ethyl acetate to obtain a mean particle size of 1000 nm is about 28 % w/v. However, in slightly different experimental conditions, this percentage varies.

The decrease of the size of the particles in relation with the diminution of the concentration of Eudragit@E in ethyl acetate is clearly apparent from Fig. 2 b) to Fig. 2 e).

Also, it is clear from Fig. 2te) that only nanoparticles are obtained when EudragittE is contained in a partially water-soluble organic solvent such as ethyl acetate at 10 k w/v or less.

Conversely, in the Comparative Example when Eudragit@E is contained in a non water-miscible solvent such as chloroform at a 10 % w/v, only microparticles are obtained, as shown in Fig. 2 a).

Another non-biodegradable polymer preferred for the present invention is cellulose acetate phthalate (CAP).

It is shown in Figure 3 an example of a CAP/2-butanone/poloxamer system when the poloxamer 407 content of the external phase is 5.00 % w/v and the stirring rate of the propeller is about 1500 rpm. In this case, the critical weight/volume percentage of CAP to 2-butanone to obtain a mean particle size of 1000 nm is

about 38 W w/v. However, in slightly different experimental conditions, this percentage varies.

It is shown is Fig. 4 an example of a Eudragit@E/methyl acetate system when the internal phase contains no stabilizing agent and the stirring rate is about 2000 rpm.

In this case, the critical weight/volume percentage of Eudragit@E to methyl acetate to obtain a mean particle size of 1000 nm is about 21 % w/v. However, in slightly different experimental conditions, this percentage varies.

As indicated above, it is pointed out that in the present invention, the water-insoluble materials are not limited to water-insoluble polymers.

The Examples below will illustrate the method of the present invention without limiting its scope in any way. <BR> <BR> <P>EXAMPLES<BR> Materials Water insoluble polymers used in the Examples were Eudragit@E, Eudragit@RS and Eudragit@RL (obtained from Röhm (GmbH Darmstadt, Germany); poly (E-caprolactone) (PCL) ((Tonet767) obtained from Union Carbide (Danbury, USA)) ; ethylene vinyl acetate copolymer (EVAC, vinyl acetate content 40 %-) (obtained from Fluka (Buchs, Switzerland)); poly (D, L-lactic acid) (PLA) ( (Medisorb@ obtained by Medisorb (Cincinatti, OH, USA)); cellulose acetate phthalate (CAP) (obtained from Fluka (Buchs, Switzerland)); and cellulose acetate trimellitate (CAT) (obtained from Eastman (Kingsport, USA)); Stabilizing agents used in the present Examples were poly (vinyl alcohol) (PVAL) (Mw 26 000) (Mowiol@4-88, Hoechst, Frankfurt-am-Main, Germany) and poloxamer 407 (Pluronic@F-127, BASF, Ludwigshafen, Germany).

The partially water-soluble solvents used in the present Examples were ethyl acetate (EtAc) (n20 = 1.372; water solubility = 10 mg/ml), methyl acetate (n20 = 1.3614; water solubility = 243 mg/ml) and 2-butanone (n20 = 1.378; water solubility = 275 mg/ml), of HPLC and of analytical grade, respectively (Fluka).

Ethanol used in Example 12 is ethanol 96 W v/v (n20 = 1.361) (Fluka).

Distilled water used in the present examples was purified using a Milli-Q system (millipore, USA-Bedford, MO).

All other chemicals were of analytical grade and used without further purification.

Particle size analysis The average particle size and polydispersity index (scale from 0 to 9) were determined using a Coulter@ Nanosizer (Coulter Electronics, Harpenden (UK). The measurements were made in triplicate for all the batches prepared.

Example1 Ethyl acetate and water were mutually saturated for 1 min before use, in order to ensure initial thermodynamic equilibrium of both liquids. Typically, 4 g of Eudragit E were dissolved in 40 ml of water-saturated ethyl acetate and this organic solution (internal phase) was emulsified at room temperature with 80 ml of a 5 W w/v PVAL ethyl acetate saturated aqueous solution (external phase), using a propeller stirrer (Heidolph-Elektro, KG type E-60, propeller : IKA 1381, Germany) at 1500 rpm for ten minutes.

The oil-in-water emulsion formed was subjected to vacuum distillation at 35°C and 60 mmHg until complete solvent evaporation. Generally, the solvent was recovered and used to prepare new batches. The mean particle size of the

particles obtained by this method as well as the polydispersity are indicated in Table 1 below.

Example2 The method was repeated in the same manner as in Example 1, except that 1.25 % w/v of PVAL was used in the external phase, instead of 5.0 % w/v of PVAL. The mean particle size of the particles obtained by this method and the polydispersity are indicated in Table 1 below.

Example3 The method was repeated in the same manner as in Example 1, except that 8 g of Eudragit E was used instead of 4 g of Eudragit E. The mean particle size of the particles obtained by this method and the polydispersity are indicated in Table 1 below.

Example 4 The method was repeated in the same manner as in Example 1, except that PCL was used, instead of Eudragit E. The mean particle size of the particles obtained by this method and the polydispersity are indicated in Table 1 below.

Example 5 The method was repeated in the same manner as in Example 1, except that EVAC was used, instead of Eudragit E. The mean particle size of the particles obtained by this method and the polydispersity are indicated in Table 1 below.

Example6 The method was repeated in the same manner as in Example 1, except that PLA was used, instead of Eudragit E. The mean particle size of the particles obtained by this method and the polydispersity are indicated in Table 1 below.

Example7 2-butanone and water were mutually saturated for 1 min before use, in order to ensure initial thermodynamic equilibrium of both liquids. Typically, 4 g of CAP were dissolved in 40 ml of water-saturated 2-butanone and this organic solution (internal phase) was emulsified at room temperature with 80 ml of a 5 k w/v poloxamer 407 2- butanone saturated aqueous solution (external phase), using a propeller (Heidolph-Elektro, KG type E-60, propeller : IKA 1381, Germany) at 1500 rpm for ten minutes. The oil-in- water emulsion formed was subjected to vacuum distillation at 35°C and 60 mmHg until complete solvent evaporation.

Generally, the solvent was recovered and used to prepare new batches. The mean particle size of the particles obtained by this method as well as the polydispersity are indicated in Table 1 below.

Example8 The method was repeated in the same manner as in Example 7, except that 1.25 % w/v of poloxamer 407 was used, instead of 5.00 % w/v of poloxamer 407. The mean particle size of the particles obtained by this method as well as the polydispersity are indicated in Table 1 below.

Example9 The method was repeated in the same manner as in Example 7, except that 8 g of CAP was used, instead of 4 g of CAP. The mean particle size of the particles obtained by this method as well as the polydispersity are indicated in Table 1 below.

Example 10 The method was repeated in the same manner as in Example 7, except that 12 g of CAP was used, instead of 4 g of CAP.

The mean particle size of the particles obtained by this

method as well as the polydispersity are indicated in Table 1 below.

Example 11 The method was repeated in the same manner as in Example 7, except that CAT was used, instead of CAP. The mean size of the particles obtained by this method as well as the polydispersity are indicated in Table 1 below.

Example12 Ethyl acetate and water were mutually saturated for 1 min before use, in order to ensure initial thermodynamic equilibrium of both liquids. Typically, 4 g of Eudragit E were dissolved in 40 ml of water-saturated ethyl acetate and this organic solution (internal phase) was emulsified at room temperature with 100 ml of a 80 : 20 v/v water- ethanol mixture containing 0.21 % w/v of poloxamer 407 (external phase), using a propeller stirrer (Heidolph- t.

Elektro, KG type E-60, propeller : IKA 1381, Germany) at 1500 rpm for ten minutes. The oil-in-water emulsion formed was subjected to vacuum distillation at 35°C and 60 mmHg until complete solvent evaporation. Generally, the solvent was recovered and used to prepare new batches. The mean particle size of the particles obtained by this method as well as the polydispersity are indicated in Table 1 below.

Example13 2-butanone and water were mutually saturated for 1 min before use, in order to ensure initial thermodynamic equilibrium of both liquids. Typically, 4 g of Eudragit E were dissolved in 40 ml of water-saturated ethyl acetate and this organic solution (internal phase) was emulsified at room temperature with 80 ml of a 2-butanone-saturated aqueous/solution (external phase), using a propeller stirrer (Heidolph-Elektro, KG type E-60, propeller : IKA 1381, Germany) at 1500 rpm for ten minutes.

The oil-in-water emulsion formed was subjected to vacuum distillation at 35°C and 60 mmHg until complete solvent evaporation. Generally, the solvent was recovered and used to prepare new batches. The mean particle size of the particles obtained by this method as well as the polydispersity are indicated in Table 1 below.

Example 14 Water was saturated with 2-butanone before use and methyl acetate was saturated with water for 1 minute. Typically, 4 g of Eudragit E were dissolved in 40 ml of water-saturated methyl acetate and this organic solution (internal phase) was emulsified at room temperature with 80 ml of 2- butanone-saturated water (external phase), using a propeller stirrer (IKA, Eurostar; propeller : IKA 1381, Germany) at 2000 rpm for 15 minutes. The oil-in-water emulsion formed was subjected to vacuum distillation at 50°C and 150 mmHg until complete solvent evaporation. The mean particle size of the particles obtained by this method as well as the polydispersity are indicated in Table 1 below.

Example15 The method was repeated in the same manner as in Example 14, except that propeller stirrer was used at 1500 rpm instead of 2000 rpm. The mean particle size of the particles obtained by this method as well as the polydispersity are indicated in Table 1 below.

Example16 The method was repeated in the same manner as in Example 14, except that 6 g of Eudragit E was used, instead of 4 g of Eudragit. The mean particle size of the particles obtained by this method as well as the polydispersity are indicated in Table 1 below.

Example 17 The method was repeated in the same manner as in Example 14, except that 8 g of Eudragit E was used, instead of 4 g of Eudragit. The mean particle size of the particles obtained by this method as well as the polydispersity are indicated in Table 1 below.

Example18 2-butanone and water were mutually saturated for 1 min before use, in order to ensure initial thermodynamic equilibrium of both liquids. Typically, 4 g of Eudragit RS were dissolved in 40 ml of water-saturated 2-butanone and this organic solution (internal phase) was emulsified at room temperature with 80 ml of 2-butanone-saturated water (external phase), using a propeller stirrer (IKA, Eurostar; propeller : IKA 1381, Germany) at 2000 rpm for 15 minutes.

The oil-in-water emulsion formed was subjected to vacuum distillation at 50°C and 150 mmHg until complete solvent evaporation. The mean particle size of the particles obtained by this method as well as the polydispersity are indicated in Table 1 below.

Example19 The method was repeated in the same manner as in Example 18, except that Eudragit RL was used, instead of Eudragit RS. The mean particle size of the particles obtained by this method as well as the polydispersity are indicated in Table 1 below.

Comparative Example The method was repeated in the same manner as in Example 1, except that chloroform was used instead of ethyl acetate.

The mean particle size of the particles obtained was 5006 nm-and the polydispersity was 5.

TABLE 1 Examples of nanoparticles obtained by the method of the invention.

Internal phase : 40 ml External phase : 80 ml (except for Example 12 wherein external phase is 100 ml) Stirring rate : 1500 rpm (except for Examples 14,16,17, 18 and 19 wherein the stirring rate is 2000 rpm) Ex. Polymer Solvent Stabilizer Mean Size Pd* No. (% w/v) (% w/v) (nm) 1 Eudr. E (10) EtAc PVAL (5.00) 573 4 2 Eudr. E (10) EtAc PVAL (1.25) 590 4 3 Eudr. E (20) EtAc PVAL (5.00) 817 4 4 PCL (10) EtAc PVAL (5.00) 543 3 5 EVAC (10) EtAc PVAL (5.00) 435 5 6 PLA (10) EtAc PVAL (5.00) 472 2 7 CAP (10) 2-butanone Poloxamer 407 (5.00) 260 2 8 CAP (10) 2-butanone Poloxamer 407 (1.25) 308 4 9 CAP (20) 2-butanone Poloxamer 407 (5.00) 614 5 10 CAP (30) 2-butanone Poloxamer 407 (5.00) 770 5 11 CAT (10) 2-butanone Poloxamer 407 (5.00) 811 7 J2 Eudr. E (10) EtAc Poloxamer 407 (0.21) 248 5 13 Eudr. E (10) 2-butanone none 446 4 14 Eudr. E (10) MeAc none 210 4 15 Eudr. E (10) MeAc none 328 2 16 Eudr. E (15) MeAc none 390 2 17 Eudr. E (20) MeAc none 518 4 18 Eudr. RS (10) 2-butanone none 114 3 19 Eudr. RL (10) 2-butanone none 63 3 Comparative Example Eudr. E (10) CHCl3 PVAL (5.00) 5006 5

*Pd : Polydispersity (index expressed from 0 to 9)

As shown in Table 1, nanoparticles were obtained with the polymers tested, indicating that the method of the present invention also can be advantageously applied to non- biodegradable polymers commonly used in pharmaceutical coating methods and to biodegradable polymers.

The method of the present invention thus makes it possible to prepare aqueous colloidal dispersions containing high concentration of nanoparticles of water-insoluble material, for example pseudolatexes, from a conventional oil-in-water emulsion with an ordinary mechanical stirring without requiring homogenization, without requiring dilution with water, with or without stabilizing agent, by direct displacement of a partially water-soluble solvent during distillation. Further, the dispersion obtained by the method of the present invention may be used directly for coatings without additional treatments.