ES2361311B1 - Process for the manufacture of a microencapsulate of a hydrophobic and microencapsulated active ingredient and corresponding compositions. - Google Patents

Abstract

The invention relates to a method for manufacturing a microencapsulate of a hydrophobic active ingredient and to a microencapsulate and corresponding compositions. The method for manufacturing a microencapsulate of a hydrophobic active ingredient, 90% of the particles of which are smaller than 5 micras, includes the following steps: [a] preparing a first solution of 5% or more of polyvinyl alcohol in water, [b] preparing a second solution of a hydrophobic active ingredient and 5% to 50% of a polyisocyanate, [c] preparing a third solution of a polyamine from the ethylendiamine and diethylentriamine group, [d] mixing the first solution with the second solution and agitating same to create an aqueous dispersion, and [e] mixing the aqueous dispersion from step [d] with the third solution, such that the proportion of the hydrophobic phase with respect to the aqueous phase is between 1 :1 and 1 :4, and allowing same to react.

Description

Process for the manufacture of a microencapsulate of a hydrophobic and microencapsulated active ingredient and corresponding compositions.

Field of the Invention

The invention relates to a process for the manufacture of a microencapsulate of a hydrophobic active ingredient or a hydrophobic solution of an active ingredient, wherein the microencapsulated has 90% of its particles smaller than 5 microns in size. The invention also refers to a microencapsulation comprising a polyurethane or polyurea / polyurethane shell in which there is a hydrophobic active ingredient or a hydrophobic solution of an active ingredient, and having 90% of its particles smaller than 5 microns, and a composition comprising such a microencapsulation. A subject of the invention is also a cosmetic composition

or pharmaceutical comprising a microencapsulated according to the invention.

In the present description and claims the expression "microencapsulated" and "microcapsules" has been used to refer to capsules whose size ranges from what is conventionally understood by microcapsules and nanocapsules, the sizes of which may range from 100 nm (nanometers) (or even less) and 10 or more microns.

State of the art

In the document "Preparation of Polyurea Microcapsules Containing Pyrethroid Insecticide with Hexamethylene Diisocyanate Isocyanurate", by T. Takahashi et al., Journal of Applied Polymer Science, Vol 107, p. 2000-2006 (2008) describes a process for the manufacture of polyurea microcapsules containing an insecticide, specifically pyrethroid. They are prepared by the reaction of hexamethylene diisocyanate isocyanurate with ethylenediamine in an oil / water emulsion. Microcapsules are obtained that have a bimodal particle size distribution, with a first maximum greater than 10 microns and a second maximum centered at 0.7 microns (700 nm). This distribution can be modified depending on the agitation applied during the generation of the emulsion. With agitations of 3000 rpm (revolutions per minute) a clearly bimodal distribution is achieved, with the maximum indicated. At 4500 revolutions the distribution remains bimodal although the proportion of 0.7 micron microcapsules seems to increase at the expense of microcapsules of more than 10 microns. At 6000 revolutions per minute the distribution seems to have a single peak centered at 0.7 microns, the peak of more than 10 microns disappearing. This seems to indicate that the increase in agitation affects particles of more than 10 microns but does not affect particles of 0.7 microns.

There is an interest in manufacturing similar microparticles but that include other active ingredients. Attempts have been made to repeat the tests carried out in the aforementioned document by replacing the insecticide with retinol (specifically a solution of 10% retinol in soybean oil). However, the results have not been as expected, larger microcapsules are obtained, in certain cases chafadas or malformed. In addition, the dispersions generated present stability problems. The results of said tests are shown in examples A, B and C below by way of comparison.

In the document "Simultaneous emulsification and interfacial polycondensation for the preparation of colloidal suspensions of nanocapsules", by H. Fessi et al., Materials Science and Engineering C 26 (2006) 472-480, microencapsulated manufacturing processes are described in that a hydrophobic active ingredient is dissolved in a polar organic solvent (water soluble, specifically acetone and ethanol). The solution is added to an aqueous solution where the emulsion spontaneously forms. As emulsifiers, polysorbates are used. The polar organic solvent is evaporated once the emulsion is formed. This evaporation stage makes these procedures more complex and, in addition, these procedures must work with very low concentrations of active ingredient. The polyureas described are polyureas formed from isophorondiisocyanate (IPDI) and diethylenetriamine (DETA) or dipropylenetriamine (DPTA).

Summary of the invention

The object of the invention is to overcome these drawbacks. This purpose is achieved by a process for the manufacture of a microencapsulation of a hydrophobic active ingredient or a hydrophobic solution of an active ingredient of the type indicated at the beginning, characterized in that it comprises the following steps:

[a] preparation of a first solution of polyvinyl alcohol in water, with a concentration greater than 5% by weight with respect to the total weight of the first solution,

[b] preparation of a second solution of the hydrophobic active ingredient, or of an internal solution of the hydrophobic active ingredient in an organic solvent, and a polyisocyanate of the group consisting of hexamethylene diisocyanate dimer, hexamethylene diisocyanate trimer, isophorondiisocyanate and mixtures thereof, with a concentration of polyisocyanate between 5% and 50% by weight with respect to the total weight of the second solution,

[c] preparation of a third solution of a polyamine of the group consisting of ethylenediamine (EDA) and diethylenetriamine (DETA), where the polyamine is in a concentration between 1% and 50% by weight with respect to the total weight of the third solution,

[d] mixing the first solution with the second solution, with stirring, generating an aqueous dispersion,

[e] mixing the aqueous dispersion of step [d] with the third solution, so that the proportion of the hydrophobic phase with respect to the aqueous phase (0: W) is between 1: 1 and 1: 4, and

[f] let the mixture in step [e] react.

Indeed, the process according to the invention allows obtaining a stable microencapsulation and having 90% of its particles of a particle size smaller than 5 microns. It is difficult to give a theoretical justification as to why this procedure allows obtaining these results while the procedure described in the Takahashi document does not allow it. Many variables come into play in the manufacture of microencapsules and obtaining a satisfactory result depends on the combination of all of them. Thus, for example, the active ingredient must be hydrophobic or it must be dissolved in a hydrophobic solvent. However, it is very important the relative hydrophobia of all the products that form the hydrophobic part (inside the micelle) that will then be encapsulated by interfacial condensation, since it is convenient for the most reactive to reach the capsule wall, therefore, they must be less hydrophobic than the remaining components of the hydrophobic part. In fact, the polyisocyanate itself could exert the solvent function of the active ingredient but it is usually convenient to add an additional hydrophobic compound to improve the encapsulation performance since this prevents the emulsions from joining together during and after encapsulation. Sometimes, the polyisocyanate itself is too viscous and needs, for this reason, a solvent. In this case, the possible vapor pressure of this solvent must also be taken into account, which could penetrate or burst the capsule wall upon evaporation, undesirably increasing the diffusion of the active substance. The relationship between polyisocyanate and polyamines is also important. The reaction between the two is what will form the rigid wall and with a microencapsulated barrier effect. In theory, when they are in a 1: 1 ratio (that is, in stoichiometric ratio the NCO equivalents and the amine equivalents), maximum crosslinking would be achieved, but, on the one hand, the effect of water must be taken into account, since during the Water emulsion can consume some of the NCOs. Therefore, it is advantageous to work with a polyamine concentration that is below the stoichiometric value (between 70% and 85% of the NCO equivalents). In this sense, the degree of reactivity of the NCO depends on the structure of the polyisocyanate, on its hydrophobia, on the temperature, on the agitation of its own reactivity (if it is aliphatic or sterically hindered or if it is aromatic and not impeded), on the pH of water, etc. Also important is the ratio between the hydrophobic phase and the aqueous phase where it has been observed that, surprisingly, it is better to work at high concentrations than at dilute concentrations. The particle size is especially low at the indicated concentrations, in which there seems to be a better spontaneous cosolubilization.

In the present case it has been observed that, surprisingly, the first solution of polyvinyl alcohol in water has proved to be a decisive parameter. If this solution has a concentration greater than 5% by weight with respect to its total weight, this has allowed obtaining the desired microencapsulation. The higher concentration of polyvinyl alcohol has improved dispersion quality (with a smaller variety of sizes) and lowers the size of the microcapsules. Furthermore, it has been observed that agitation has not turned out to be a determining parameter. On the contrary, increasing the agitation has not improved the results obtained. Therefore the new procedure can be performed simply with mechanical agitation (even of low intensity) obtaining the desired results.

Selected polyamines are also particularly important. Effectively using cystamine, which allows a disulfide group to be present on the capsule wall, the results are not adequate. The capsules are larger, and it is necessary to increase the content of polyvinyl alcohol, but the desired result cannot be obtained that way. This may be because cystamine is of greater molecular volume and is more hydrophobic, which modifies the behavior of the entire system.

In general, the microencapsulated wall is a polyurea, corresponding to the reaction of the polyisocyanates and polyamines added. However, it is not ruled out that it also has a certain polyurethane formation, due to the reaction between polyisocyanates and polyvinyl alcohol. In any case, it should be understood that polyurea formation is the main reaction, the formation of secondary type polyurethanes being.

It should be noted that the method according to the invention does not employ the emulsification method which, in the Fessi document, has been termed "spontaneous emulsification". In the process according to the invention, the hydrophobic active ingredient is not dissolved in a solvent that is subsequently evaporated to cause emulsion to form. In the process according to the invention, the internal solution does not include (or, at least, does not include as a major component) a polar organic solvent that, on the one hand, is suitable for dissolving the active ingredient and, on the other hand, is suitable to dissolve in water.

Preferably the polyvinyl alcohol has a molecular weight between 60,000 and 140,000. Indeed, among the various possible polyvinyl alcohols, those between this molecular weight are the most suitable. Particularly suitable are those with a molecular weight between 85,000 and 124,000. Also particularly advantageous are those with a degree of hydrolysis between 80% and 97%, preferably between 87% and 89%. Examples of these polyvinyl alcohols are Celvol 523® and Celvol® E 23/88, marketed by Celanese.

Advantageously, the second solution has between 5% and 15% by weight of the polyisocyanate with respect to the weight of the second solution. It is indeed advantageous that the wall of the capsules represents between 2% and 20% by weight over the total dispersion, taking into account that average percentages of the dispersion are usually 30% oil, 10% of the wall polymeric and the rest water. Polyisocyanate is the main component (by weight) of the wall, since the polyamine is relatively small and its effect on the total weight is small.

Preferably the polyamine is ethylenediamine. Theoretically, a polyamine with more amines, such as diethylenetriamine should have been better, but it has not been. This may be due to an excess of cross-linking at the interface having negative effects. For example, it could negatively affect the flexibility of the capsule wall, making it too rigid to distort it and / or create steps or holes for lack of adaptability. This could have the consequence that it does not satisfactorily contain the contents of the microcapsule causing an unwanted release of it. Also an excess of initial crosslinking can lead to a difficulty in the growth of the polymer that encapsulates in the oil / water interface due to steric hindrance, with its structural defects and more fragility. Small polymers (and in this case crosslinked or branched) are more fragile.

Advantageously in step [d] both solutions are mixed for a time greater than 3 minutes and less than 150 minutes. Indeed, long agitations are not possible because the polyisocyanate begins to react with water. In this sense the water temperature can also play a role during the emulsion process. However, although colder water prevents premature reaction of the polyisocyanate with water, the possible emulsifying additive is also less soluble and less emulsifies. Therefore you have to find a compromise between all the parameters. It is normal to work below 20ºC in the case of using aromatic polyisocyanates. In the case of using aliphatic polyisocyanates, temperatures between 20 ° C and 30 ° C are suitable.

Preferably the polyisocyanate is a mixture of hexamethylene diisocyanate dimer and hexamethylene diisocyanate trimer. Indeed, this mixture of polyisocyanates allows to optimize a series of parameters. On the one hand it is not always possible to emulsify and stabilize the dispersion only with the polyvinyl alcohol but it is often necessary to add an emulsifier (such as an emulsifier of the dodecyl sulfate type). However, it seems that this mixture of self-emulsifying polyisocyanates and an external emulsifier is not necessary, which does not occur if the pure trimer is used (in which case larger and more unstable emulsions are obtained). As mentioned earlier, it is also important to take into account the degree of functionality of polyisocyanate and polyamine. An excessive degree of functionality causes the microcapsule wall to have a lower barrier effect. However, a minimum of functionality is necessary, which allows obtaining a minimum level of crosslinking that avoids water solubility and allows obtaining a barrier effect, so that this polyisocyanate mixture works better than pure diisocyanate. It is particularly advantageous that the mixture comprises between 50% and 70% by weight of hexamethylene diisocyanate dimer and between 30% and 50% by weight of hexamethylene diisocyanate trimer. The optimal results have been achieved when, in addition, the polyamine has been ethylenediamine.

Preferably in step [f] the mixture of step [e] is allowed to react for a time less than 120 minutes at a temperature below 45 ° C and for a time less than 120 minutes at a temperature greater than 45 ° C.

Advantageously, the active ingredient is an active ingredient of the group consisting of fat-soluble vitamins, preferably of the group consisting of vitamin E, vitamin D and retinol. It is particularly advantageous that the active substance is retinol. Preferably, retinol is dissolved in soybean oil in a proportion between 5% and 20% by weight.

The active substance can also be advantageously paclitaxel, preferably dissolved in caprylic capricus oil. Paclitaxel is a known anticancer and anti-fibotic agent used in various pharmaceutical applications. It is interesting to have it in the form of capsules to improve its stability and control its release, as well as to decrease its systemic toxic effects and to be able to apply it to specific areas of the organism with specific and directed release.

A subject of the invention is also a microencapsulation comprising a polyurea or polyurea / polyurethane shell, within which there is a hydrophobic active ingredient or a hydrophobic solution of an active ingredient, and having 90% of its particles of a size smaller than 5 microns, characterized in that the polyurea is formed from the reaction of a polyisocyanate of the group consisting of hexamethylene diisocyanate dimer, hexamethylene diisocyanate trimer and mixtures of the above, and of a polyamine of the group consisting of ethylenediamine and diethylenetriamine, and because particles have a bimodal particle size distribution, with a first maximum between 600 nm and 5 microns and a second maximum between 100 nm and 600 nm. Indeed, it has been found that the microcapsules obtained with the process according to the invention have said particle size distribution. This distribution is particularly interesting since it allows to obtain very stable dispersions and of small size. In general, if the capsules are of the order of several microns, they usually end up precipitating after a certain time. The fact that the distribution of particles has a second maximum between 100 and 600 nanometers seems to stabilize the dispersion, possibly by the Brownian movements of the small capsules.

Preferably the active ingredient is an active ingredient of the group consisting of fat-soluble vitamins, most preferably of the group consisting of vitamin E, vitamin D and retinol. It is particularly advantageous that the active substance is retinol.

Advantageously, the hydrophobic solution of an active ingredient is a solution of retinol in soybean oil.

Preferably the active ingredient is paclitaxel or the hydrophobic solution of an active ingredient is a solution of paclitaxel in caprylic-capric oil.

A subject of the invention is also a composition comprising a microencapsule according to the invention.

A subject of the invention is also a cosmetic or pharmaceutical composition characterized in that it comprises a microencapsulate of a hydrophobic active ingredient or a hydrophobic solution of an active ingredient, wherein the microencapsulated comprises a polyurea or polyurea / polyurethane shell, where the polyurea is formed from of the reaction of a polyisocyanate of the group consisting of hexamethylene diisocyanate dimer, hexamethylene diisocyanate trimer and mixtures of the above, and of a polyamine of the group consisting of ethylenediamine and diethylenetriamine, and where the microencapsulate has 90% of its particles of a smaller size at 5 microns. These particle sizes are particularly interesting for application in the cosmetic and pharmaceutical field.

Preferably the active ingredient of the cosmetic or pharmaceutical composition is an active ingredient of the group consisting of fat-soluble vitamins, preferably of the group consisting of vitamin E, vitamin D and retinol, and most preferably it is retinol. It is also advantageous that the retinol is dissolved in soybean oil forming a hydrophobic solution. Alternatively, the active ingredient is preferably paclitaxel, which is preferably dissolved in caprylic-capric oil forming a hydrophobic solution.

Advantageously, the particles of the cosmetic or pharmaceutical composition have a bimodal particle size distribution, with a first maximum between 600 nm and 5 microns and a second maximum between 100 nm and 600 nm.

Brief description of the drawings

Other advantages and features of the invention can be seen from the following examples, in which, without any limitation, preferred embodiments of the invention are mentioned, mentioning the accompanying drawings. The figures show:

Fig. 1, a particle size distribution graph for the microencapsulation of example 7.

Fig. 2, a particle size distribution graph for the microencapsulation of example 10.

Figs. 3 to 5, photographs with electron microscopy (SEM) of the microencapsulation of example 7.

Figs. 6 and 7, photographs with an optical microscope, at 400 and 1,000 magnifications, respectively, of the microencapsulation of example 7.

Examples

The following polyisocyanates have been used in the examples described below: Desmodur® N3300 (hexamethylene diisocyanate trimer) and Desmodur® N3400 (dimer and hexamethylene diisocyanate mixture) marketed by Bayer, and Polurene® MT100 (hexamethylene diisocyanate trimer) marketed by SAPICI. The retinol used is always a solution of retinol (10% by weight) in soybean oil.

Examples A, B and C have been aimed at encapsulating a 10% retinol solution in soybean oil (Retinol 10S®, supplied by BASF) following the procedures described in the Preparation of Polyurea Microcapsules Containing Pyrethroid Insecticide publication with Hexamethylene Diisocyanate Isocyanurate, from T. Takahashi et al, cited above.

Example A

In a beaker, 100.00 g of Retinol 10S® and 12.50 g of Desmodur® N3300 are mixed, this mixture is added to 243.00 g of water containing 4.0% polyvinyl alcohol (PVA) ( 9.7 g).

The emulsion is formed at 6000 rpm for 15 minutes. Once the O / W emulsion has been formed, it is introduced into a 700 ml reactor and 2.00 g of ethylenediamine (EDA) with 143.00 g of water are added at 300 rpm. It is allowed to react for 1 hour at 25 ° C and another hour at 60 ° C. A good emulsion is obtained but in the optical microscope large capsules of diameter ≤20 μm and parts of uncapsulated polymer are observed. In the publication of Takahashi the capsules are 0.70 μm.

Example B

In a beaker, 100.00 g of Retinol 10S® and 25.00 g of Desmodur® N3300 are mixed, this mixture is added to 243.00 g of water containing 4.0% PVA (9.7 g).

The emulsion is formed at 6000 rpm for 15 minutes. Once the O / W emulsion has been formed, it is introduced into a 700 ml reactor and 4.00 g of EDA with 128.50 g of water are added at 300 rpm. It is allowed to react for 1 hour at 25 ° C and another hour at 60 ° C. A good emulsion is obtained but in the optical microscope large capsules of diameter ≤15 μm are observed and some of the capsules are flat. In the publication of Takahashi the capsules are 0.78 μm.

Example C

In a beaker, 100.00 g of Retinol 10S® and 50.00 g of Desmodur® N3300 are mixed, this mixture is added to 243.00 g of water containing 4.0% PVA (9.7 g).

The emulsion is formed at 6000 rpm for 15 minutes. Once the O / W emulsion is formed, it is introduced into a 700 ml reactor and 8.00 g of EDA with 99.50 g of water are added at 300 rpm. It is allowed to react for 1 hour at 25 ° C and another hour at 60 ° C. A good emulsion is not obtained, in the optical microscope large and non-spherical capsules of diameter ≤20 μm are observed, many of them are flat. In the publication of Takahashi the capsules are 0.77 μm.

Examples A, B and C

Stability control

To observe the stability of the capsules over time, they are placed in an oven at 60 ° C for 16 hours. After 16 hours, it is observed that the three emulsions (example A, B and C) are not very stable since there is a characteristic yellow increase in Retinol 10S® in the upper part of the package.

Also in example C, the viscosity of the product increases by forming an almost solid layer on the top of the package.

Example 1 (comparative)

(Example following one of the examples in the publication Materials Science and Engineering C 26 (2006) 472-480,

H. Fessi et al.)

Formation of polyurethane capsules with the use of a cosolvent.

In a beaker, 0.2230 g of IPDI, 0.4232 g of 10% Retinol, 0.1045 g of SPAN® 85 (supplied by CRODA) and 40 ml of acetone (solution 1) are added. In another vessel, 3.06 g of PEG 300, 0.1076 g of Tween® 20 (supplied by CRODA) and 80 ml of water (solution 2) are added. After 10 min of magnetic stirring, solution 1 is slowly added over 2 and allowed to react for 3 h. Finally the acetone evaporates.

A good emulsion is obtained but there is a limit on the amount of retinol that can be encapsulated since it was repeated with 20% retinol instead of 0.5% and the emulsion obtained was not stable and separated into 2 phases.

Example 2

An organic phase containing 4.00 g of retinol and 0.63 g of Desmodur® N3400 (Bayer product, dimer and trimer mixture of HDI hexamethylene diisocyanate) is mixed with 12.15 g of an aqueous phase containing a 4 % polyvinyl alcohol (PVA) (type Celvol® E 23/88 from Celanese). The emulsion forms in 15 min at 300 rpm. Once formed, 0.10 g of EDA with 7.15 g of water are added, leaving 2h of reaction, one at 25 ° C and one at 60 ° C.

A good emulsion is obtained with capsules between 1 μm and 500 μm but over time it separates forming a solid at the top that is redone with manual agitation.

By repeating this product with mechanical agitation, capsules between 1 μm and 500 μm are obtained. Although the capsules are spherical and not agglomerated, their size cannot be reduced with mechanical agitation.

It seems that Retinol is encapsulated but after a few hours 3 phases are formed due to the wide particle size distribution, an upper solid, an intermediate liquid and a lower solid are formed. With little manual agitation, a homogeneous emulsion is formed again.

To see if the emulsion improves, 1% of Tween 20 emulsifier is added to a part of the product. It does not improve.

Example 3

Solution 1:

0.26 g of PVA in 8.71 g of water.

Solution 2:

1.16 g of Desmodur® N3400 and 2.72 g of retinol.

Solution 3:

0.20 g of DETA in 3.29 g of water.

At about 50 ° C, solution 2 is added over 1 and after about 2 minutes solution 3 is added. It is allowed to react for 1h30 min.

A good emulsion is obtained with capsules between 5 μm and 500 nm but over time it separates forming a solid at the top that is redone with manual agitation. By repeating this product with mechanical agitation, capsules between 1 μm and 100 μm are obtained. It has not been able to reduce its size with mechanical agitation, on the contrary it has increased. It seems that Retinol is encapsulated but after a few hours 2 phases are formed, an upper solid and a lower liquid. With little manual agitation, a homogeneous emulsion is formed again. To improve the stability of the emulsion, 1% of Tween 20 emulsifier is added to a part of the product. It does not improve. To improve the stability of the emulsion, 10% PVA is added to one part of the product, 1% HPMC (hydroxypropylmethylcellulose) to another part. In the first moment they all improve but they eventually separate.

Example 4

It is the same as Example 3 but with more PVA to decrease the capsule size. From 2% of PVA it goes to 3.6%. A good emulsion is obtained with better encapsulation performance, since fewer phases are observed than in example 3, and with a size less than 5 μm. But the emulsion also ends up separating over time.

Example 5

It is the same as Example 2 but with more PVA to decrease the capsule size. From 2.5% of PVA it goes to 3.8%. A good emulsion is obtained with better encapsulation performance, since fewer phases and more capsules are observed than in example 2 and with a size less than 5 μm. The obtained emulsion ends up separating slightly over time but with manual agitation it is remade.

Example 6

It is the same as Example 5. It is a repetition to see the repetitiveness of this experience. A good emulsion is obtained and with a size less than 5 μm similar to example 5. The obtained emulsion ends up separating a little over time but with manual agitation it is redone.

Example 7

An organic phase containing 20.52 g of retinol and 3.13 g of Desmodur® N3400 is mixed with 25.02 g of an aqueous phase containing 8.0% PVA (Celvol® 23/88). The emulsion is formed at 600 rpm and the organic phase addition time is 3 minutes. Once formed, after 7 minutes 0.51 g of EDA is added with 16.70 g of water also at 600 rpm and in 1 min, leave 1 h 30 min of reaction at room temperature, stirring is lowered to 300 rpm and leave an hour of reaction at 60 ° C.

An emulsion is formed with blue tones, capsules of approximately 1 μm at smaller sizes. It has a high oxidation stability, since it does not darken, and storage, since the dispersion is stable over time and does not separate into two phases. A particle size distribution graph is shown in Fig. 1. In Figs. 3 to 7 several photographs are shown, with an electronic and optical microscope, taken to the microencapsulation obtained.

The percentage of Retinol with respect to the total is 29.5%.

Example 8

Example 7 is repeated but with Polurene® MT100 (HDI trimer) instead of Desmodur® N3400. An organic phase containing 20.52 g of retinol and 3.10 g of Polurene® MT 100 is mixed with 34.00 g of an aqueous phase containing 8.0% PVA (Celvol® 23/88). The emulsion is formed at 600 rpm and the organic phase addition time is 3 minutes. Once formed, after 7 minutes 0.51 g of EDA are added with 7.72 g of water also at 600 rpm and in 1 min, leave 1h30min of reaction at room temperature, stirring is lowered to 300 rpm and left one hour of reaction at 60 ° C.

A good emulsion similar to that of example 7 is obtained but with capsules of a slightly larger size.

Example 9

It is Example 7 but with constant agitation at 400 rpm to verify that a good emulsion is obtained with constant agitation so as not to have to vary the agitation during the process. You get a good emulsion that is stable over time. The capsules are smaller than 2 μm.

Example 10

It is Example 7 but with constant agitation at 14500 rpm (ultraturrax) to verify that if agitation is increased, the capsule size decreases. A very good emulsion is obtained that has a high oxidation stability, since it does not darken, and storage, since the dispersion is stable over time and does not separate into two phases. The capsules are smaller than 2 μm. A particle size distribution graph is shown in Fig. 2. As can be seen, a significant decrease in capsule size is not obtained. In fact, the bimodal distribution maxima are both higher than in the distribution of example 7, but the particle size distribution is slightly more uniform.

Example 11

It is Example 7 but with stirring by means of an ultrasonic bath (Ultrasons 9L, J.P. Selecta S.A., 200 W) for 15 minutes before adding the EDA, to check if the capsule size decreases. The stirring described in Example 7 is then continued to end the encapsulation reaction. A good emulsion is not obtained, some capsules are formed but they are very agglomerated.

Example 12

The system of Example 7 is repeated but with IPDI (Isophorondiisocyanate) instead of Desmodur® N3400 and DETA (diethylenetriamine) instead of EDA. An organic phase containing 41.04 g of retinol and 3.10 g of IPDI is mixed with 80.00 g of an aqueous phase containing 7.30 g of PVA (Celvol® 23/88). The emulsion is formed at 600 rpm and the organic phase addition time is 3 minutes. Once formed, after 7 minutes 1.17 g of DETA with 3.44 g of water are also added at 600 rpm and in 1 min, leave 1h30min of reaction at room temperature, stirring is lowered to 300 rpm and left one hour of reaction at 60 ° C.

An emulsion is obtained with capsules of a size between 1 and 20 μm, they are not spherical and uniform as in Example 7.

Example 13

The system of Example 7 is repeated but with more emulsifier to see if the capsule size decreases. 2% more PVA compared to the total. In this case, an emulsion is formed with capsules of approximately 1 μm but they are not very spherical.

Capsule size / agitation time ratio

Example 7 is repeated at a constant stirring of 200 rpm. Before adding the EDA, particle size controls are performed with the optical microscope and in parallel it is checked that the isocyanate does not react with the water by means of IR controls.

Finally, at 335 minutes the amine is added and the temperature is raised to 60 ° C to end the reaction.

In the table it can be seen that increasing the agitation time decreases the size of the capsules but to a certain level since it remains stable afterwards. We begin to observe a certain qualitative decrease in NCO after 155 minutes. This indicates that it would be the maximum advisable time that this dispersion can be stirred in water before the diisocyanate begins to react clearly with the water at room temperature (approx. 20 ° C) .Therefore, encapsulation reactions are preferred at temperature ambient at the beginning and then the temperature is raised to end the reaction.

Example 14

An organic phase containing 20.52 g of capric, caprylic triglyceride and 3.13 g of Desmodur® N3400 is mixed with 75.02 g of water containing 7.30 g of PVA (Celvol® 23/88). The emulsion is formed at 600 rpm and the organic phase addition time is 3 minutes. Once formed, after 7 minutes 0.51 g of EDA is added with 8.40 g of water also at 600 rpm and in 1 min, leave 1h30min of reaction at room temperature, stirring is lowered to 300 rpm and left one hour of reaction at 60 ° C.

A good emulsion is formed with capsules from 3 μm to smaller sizes. It is very stable over time.

The percentage of Paclitaxel with respect to the total is 0.05%.

IR control

In all the examples the existence of bands between 3040-3010 of the conjugated double bonds of retinol is verified. The existence of bands between 1680-1660 is also checked due to the formation of ureas. Finally, it is checked that all isocyanate has reacted by observing if there is the NCO signal (2275-2230).

Claims (30)

1. Process for the manufacture of a microencapsulated of a hydrophobic active ingredient or of a hydrophobic solution of an active ingredient, wherein said microencapsulated has 90% of its particles smaller than 5 microns in size, characterized in that it comprises the following steps: [a] preparation of a first solution of polyvinyl alcohol in water, with a concentration greater than 5% by weight with respect to the total weight of said first solution, [b] preparation of a second solution of said hydrophobic active ingredient, or of an internal solution of said hydrophobic active ingredient in an organic solvent, and a polyisocyanate of the group consisting of hexamethylene diisocyanate dimer, hexamethylene diisocyanate trimer, isophorondiisocyanate and mixtures thereof. , with a concentration of said polyisocyanate between 5% and 50% by weight with respect to the total weight of said second solution, [c] preparation of a third solution of a polyamine of the group consisting of ethylenediamine and diethylenetriamine, wherein said polyamine is in a concentration between 1% and 50% by weight with respect to the total weight of the third solution, [d] mixing the first solution with the second solution, with stirring, generating an aqueous dispersion, [e] mixing the aqueous dispersion of step [d] with the third solution, so that the ratio of the hydrophobic phase to the aqueous phase is between 1: 1 and 1: 4, and [f] let the mixture in step [e] react.

2.

Method according to claim 1, characterized in that said polyvinyl alcohol has a molecular weight between 60,000 and 140,000.

3.

Method according to claim 2, characterized in that said polyvinyl alcohol has a molecular weight between 85,000 and 124,000.

Four.

Process according to any of claims 1 to 3, characterized in that said polyvinyl alcohol has a degree of hydrolysis between 80% and 97%.

5.

Method according to claim 4, characterized in that said polyvinyl alcohol has a degree of hydrolysis between 87% and 89%.

6.

Process according to any one of claims 1 to 5, characterized in that said second solution has between 5% and 15% by weight of said polyisocyanate with respect to the weight of said second solution.

7.

Process according to any one of claims 1 to 6, characterized in that said polyamine is ethylenediamine.

8.

Method according to any one of claims 1 to 7, characterized in that the amount of said polyamine in said third solution means between 70% and 85% of the NCO equivalents of said second solution.

9.

Method according to any of claims 1-8, characterized in that in said step [d] both solutions are mixed for a time greater than 3 minutes and less than 150 minutes.

10.

Process according to any one of claims 1 to 9, characterized in that said polyisocyanate is a mixture of hexamethylene diisocyanate dimer and hexamethylene diisocyanate trimer.

eleven.

Method according to claim 10, characterized in that said mixture comprises between 50% and 70% by weight of hexamethylene diisocyanate dimer and between 30% and 50% by weight of hexamethylene diisocyanate trimer.

12.

Method according to any one of claims 1 to 11, characterized in that in said step [f] the mixture of step [e] is allowed to react for a time less than 120 min at a temperature below 45 ° C and for a time less than 120 min at a temperature higher than 45 ° C.

13.

Method according to any of claims 1-12, characterized in that said active principle is an active principle of the group consisting of fat-soluble vitamins, preferably of the group consisting of vitamin E, vitamin D and retinol.

14.

Method according to claim 13, characterized in that said active ingredient is retinol.

fifteen.

Method according to any of claims 1-12, characterized in that said active ingredient is paclitaxel.

16.

Microencapsulated comprising a polyurea or polyurea / polyurethane shell, inside which there is a hydrophobic active ingredient or a hydrophobic solution of an active ingredient, and having 90% of its particles smaller than 5 microns in size, characterized in that said polyurea is formed from the reaction of a polyisocyanate of the group consisting of hexamethylene diisocyanate dimer, hexamethylene diisocyanate trimer and mixtures of the above, and of a polyamine of the group consisting of ethylenediamine and diethylenetriamine, and because said particles have a size distribution of bimodal particle, with a first maximum between 600 nm and 5 microns and a second maximum between 100 nm and 600 nm.

17.

Microencapsulated according to claim 16, characterized in that said active ingredient is an active ingredient of the group consisting of fat-soluble vitamins, preferably of the group consisting of vitamin E, vitamin D and retinol.

18. Microencapsulated according to claim 16, characterized in that said active ingredient is retinol.

19.

Microencapsulated according to claim 16, characterized in that said hydrophobic solution of an active ingredient is a solution of retinol in soybean oil.

20. Microencapsulated according to claim 16, characterized in that said active ingredient is paclitaxel.

twenty-one.

Microencapsulated according to claim 16, characterized in that said hydrophobic solution of an active ingredient is a solution of paclitaxel in caprylic-capric oil.

22. Composition comprising a microencapsulated according to any of claims 16 to 21.

2. 3.

Cosmetic or pharmaceutical composition characterized in that it comprises a microencapsulate of a hydrophobic active ingredient or a hydrophobic solution of an active ingredient, wherein said microencapsulated comprises a polyurea or polyurea / polyurethane shell, wherein said polyurea is formed from the reaction of a polyisocyanate of the group consisting of hexamethylene diisocyanate dimer, hexamethylene diisocyanate trimer and mixtures of the above, and of a polyamine of the group consisting of ethylenediamine and diethylenetriamine, and wherein said microencapsulate has 90% of its particles smaller than 5 microns in size.

24.

Cosmetic or pharmaceutical composition according to claim 23, characterized in that said active ingredient is an active ingredient of the group consisting of fat-soluble vitamins, preferably of the group consisting of vitamin E, vitamin D and retinol.

25.

Cosmetic or pharmaceutical composition according to claim 23, characterized in that said active ingredient is retinol.

26.

Cosmetic or pharmaceutical composition according to claim 23, characterized in that said hydrophobic solution of an active ingredient is a solution of retinol in soybean oil.

27.

Cosmetic or pharmaceutical composition according to claim 23, characterized in that said active ingredient is paclitaxel.

28.

Cosmetic or pharmaceutical composition according to claim 23, characterized in that said hydrophobic solution of an active ingredient is a solution of paclitaxel in caprylic-capric oil.

29.

Cosmetic or pharmaceutical composition according to any one of claims 23 to 28, characterized in that said particles have a bimodal particle size distribution, with a first maximum between 600 nm and 5 microns and a second maximum between 100 nm and 600 nm.

SPANISH OFFICE OF THE PATENTS AND BRAND Application no .: 201130593 SPAIN Date of submission of the application: 04.04.2011 Priority Date: REPORT ON THE STATE OF THE TECHNIQUE 51 Int. Cl.: See Additional Sheet RELEVANT DOCUMENTS

Category

Documents cited Claims Affected

TO

TAKAHASHI, TADATSUGU et al .; Preparation of polyurea microcapsules containing pyrethroid insecticide with hexamethylene diisocyanate isocyanurate; Journal of Applied Polymer Science 2008, volume 107, pages 2000-2006. 1-29

TO

EP 611253 A1 (CIBA-GEIGY AG) 17.08.1994, column 1, line 46 - column 2, line 2; column 3, line 4 - column 4, line 13; column 7, line 35 - column 8, line 22. 1-29

TO

ZHANG, QIANG et al .; Synthesis and characterization of microcapsules with chlorpyrifos cores and polyurea walls; Chem. Res. Chinese U. 2006, volume 22, number 3, pages 379-382; ISSN 1005-9040. 1-29

TO

WO 2007110383 A1 (BASF AG) 04.10.2007, (summary) [on line] [retrieved on 05.10.2011]. Recovered from WPI Database, DW200825, access number 2008-D53397. 1-29

Category of the documents cited X: of particular relevance Y: of particular relevance combined with other / s of the same category A: reflects the state of the art O: refers to unwritten disclosure P: published between the priority date and the date of priority submission of the application E: previous document, but published after the date of submission of the application

This report has been prepared • for all claims • for claims no:

Date of realization of the report 05.31.2011

Examiner N. Vera Gutiérrez Page 1/4

REPORT OF THE STATE OF THE TECHNIQUE Application number: 201130593 CLASSIFICATION OBJECT OF THE APPLICATION  B01J13 / 16 (2006.01) A61K9 / 50 (2006.01) A61K31 / 07 (2006.01) A61K31 / 337 (2006.01) Minimum documentation sought (classification system followed by classification symbols) B01J, A61K Electronic databases consulted during the search (name of the database and, if possible, search terms used) INVENES, EPODOC, CAS, WPI, EMBASE, MEDLINE, BIOSIS, NPL State of the Art Report Page 2/4  WRITTEN OPINION Application number: 201130593 Date of Completion of Written Opinion: 05.31.2011 Statement

Novelty (Art. 6.1 LP 11/1986)

Claims Claims 1-29 IF NOT

Inventive activity (Art. 8.1 LP11 / 1986)

Claims Claims 1-29 IF NOT

The application is considered to comply with the industrial application requirement. This requirement was evaluated during the formal and technical examination phase of the application (Article 31.2 Law 11/1986).  Opinion Base.- This opinion has been made on the basis of the patent application as published. State of the Art Report Page 3/4  WRITTEN OPINION Application number: 201130593 1. Documents considered.- The documents belonging to the state of the art taken into consideration for the realization of this opinion are listed below.

Document

Publication or Identification Number publication date

D01

TAKAHASHI, TADATSUGU et al .; Preparation of polyurea microcapsules containing pyrethroid insecticide with hexamethylene diisocyanate isocyanurate; Journal of Applied Polymer Science 2008, volume 107, pages 2000-2006. 2008

2. Statement motivated according to articles 29.6 and 29.7 of the Regulations for the execution of Law 11/1986, of March 20, on Patents on novelty and inventive activity; quotes and explanations in support of this statement The invention relates to a process for the manufacture of a microencapsulate of a hydrophobic active ingredient, wherein said microencapsulated has 90% of its particles of a size smaller than 5 microns, characterized in that it comprises: mixing a solution of polyvinyl alcohol (higher concentration 5%) in water, with a solution comprising the hydrophobic active ingredient and a polyisocyanate (concentration between 5 and 50%) of the group consisting of dimer or trimer of hexamethylene diisocyanate, isophorondiisocyanate and mixtures. An aqueous dispersion is generated to which a solution of a polyamine of the group consisting of ethylenediamine and diethylenetriamine is added (concentration between 1 and 50%), so that the hydrophobic phase: aqueous phase ratio is between 1: 1 and 1 : 4, and the mixture is allowed to react. Document D01 discloses the preparation of polyurea microcapsules containing a pyrethroid insecticide, by reaction between hexamethylene diisocyanate and ethylenediamine isocyanurate in an oil-in-water emulsion. Following the scheme shown in Figure 2, a dispersed phase is prepared from the insecticide and hexamethylene diisocyanate isocyanurate, which is poured into a continuous phase with 4% polyvinyl alcohol in water. After the formation of the O / W dispersion, ethylenediamine and water are added and allowed to react for one hour at 25 ° C and for one hour at 60 ° C. Unlike document D01, a solution of polyvinyl alcohol with a concentration greater than 5% by weight is used in the application. In view of the examples made in the application, it seems that this difference produces a surprising technical effect, which consists in a greater stability of the microencapsulation and a particle size distribution such that 90% of its particles are smaller than 5 microns Also, in the application retinol microcapsules (examples A, B and C) are prepared following the process described in D01. The results show that this microencapsulated has a larger particle size and less stability than that obtained according to the process of the invention. Therefore, it is considered that the invention set forth in claims 1-29 of the application meets the requirements of novelty and inventive activity (Articles 6.1 and 8.1 L.P.) State of the Art Report Page 4/4