DE3306259A1 - MICROCAPSULES AND METHOD FOR THEIR PRODUCTION - Google Patents

Description

Microcapsules and processes for their manufacture

The invention relates to microcapsules with a semipermeable or permeable capsule wall and a liquid core and a process for their production. With this method, sensitive substances can be encapsulated under physiological conditions. The products obtained in this way can, for. B. for separation and material transformation processes in preparative and analytical chemistry and biochemistry, pharmacy and medicine as well as agriculture and food goods are used. ;
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Microcapsules with a semi-permeable or permeable capsule wall and liquid core are known in the most varied of designs (V. D. Solodovnik: Mikrokapselung, Chimija, Moscow, 1980; J. R. Hixon: Microencapsulation. Marcel Dekker Inc. Uew York-Basel, 1976; J. E. Vandegaer: Microencapsulation Processes and Applications. Plenum Press, New York-London, 1974; M. Gulcho: Capsule Technology and Microencapsulation. Noyes Data Corp., Park Ridge, 1972-).

The polymers or polymer combinations used for the capsule wall, however, have disadvantages in many paelles their permeation properties, their elasticity and mechanical stability, e.g. B, when the osmotic pressure inside the capsule is high. The liquid core exists mostly from an oily, water-immiscible organic liquid, which is detrimental to the properties more sensitive substances to be encapsulated and the transport of substances when using microcapsules in aqueous systems affects.

Numerous mechanical-physical and chemical processes are known for the production of microcapsules. The principle the mechanical-physical encapsulation process consists in general in-i that one evaporates the core material and in Gas space enveloped with the wall material. The wall material can already be dissolved in the core material (spray drying) or subsequently with the core material particles or

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—Fcroepfchen are brought into contact (immersion process, multiple off due sen processes, fluidized bed stratification, etc.). The main disadvantages of these processes are their application higher temperatures, the use of organic solvents or the impermeability of the capsule shell. The chemical processes mostly work in the liquid phase, with the formation of veins by interfacial polymerisation or condensation or by deposition of a predetermined polymeric wall material can take place. The use of mostly Aggressive monomers and organic solvents represent major / disadvantages of the encapsulation process through interfacial reactions represent.

Most of the chemical processes using a given polymeric wall material have in common: that one emulsifies the core material in the continuous phase yed or suspended and the polymer dissolved in the continuous phase at the phase boundary between core and mid Kontinum fails, ζ. B. by changing the pH-Y / ertes, the Temperature, salt or solvent additives, etc. Such conditions easily lead to damage when encapsulating sensitive substances.

II.1 case of the very frequently used complex coacervation takes place the precipitation of the wall material due to two oppositely charged polymers (V /. Sliwka: Angew. Chem. 37 (1975) S, 556-567).

The use of non-water-miscible organic / rivers as core material and the usually still necessary strengthening of the capsule wall, which is sometimes quite drastic Reaction conditions are required, are the main disadvantages of this process. There is a relatively gentle containment process Preparation of mixtures from the material to be encapsulated ir. With an aqueous polyelectrolyte solution and entering the asr Mix in a bath containing low molecular weight ions. As a result of ion diffusion, shape-stable ones arise Structure with a continuous gel network (J. Klein, TJ. ITackel, P. "chara and H, ling: Angew. I. Iakromol. Chem. 7o / 77 (1? 77) 3. 329-350, DE-AG 19-17 738).

ORiGINALJNSPECTED

This process, too, leads to partial damage to sensitive substances as a result of necessary changes in the pIL and / or the presence of polyvalent metal ions. In addition, such networks have no permeable or semipermeable capsule wall and no liquid core. In DIi-CS 30 12 233, a further developed method for immobilizing sensitive biological systems based on such gel particles is described, in which the pearl-shaped particles are surrounded by subsequent treatment of a suitable polyelectrolyte solution with a polyelectrolyte complex membrane and the gel is surrounded by ion exchange with appropriate Buffer solutions are liquefied again. The microcapsules obtained in this way have the disadvantage that they are very sensitive to external influences during manufacture and handling, since the capsule walls have only a very low mechanical strength. The process does not exclude the possibly harmful influence of polyvalent metal ions. Also provides the necessary w ^r iederverfluessigung the gel core by ion exchange represents an additional Singriff in the entire system.

The aim of the invention is to «microcapsules with ver to develop improved properties and a process for their production in order to open up new possibilities in terms of Llicro- encapsulation of sensitive substances and opening up new areas of application for the products obtained.

The invention is therefore based on the object of developing microcapsules and a suitable method for their production, while at the same time the encapsulation of sensitive substances must be guaranteed or sought after. The capsule production should be as gentle as possible, e.g. B. physiological conditions can be carried out and the capsule wall represent an elastic, permeable or semipermeable membrane, which should be sufficiently stable against chemical influences and mechanical stresses. The capsules roll liquid and cause no damage to the substance to be encapsulated.

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According to the invention, the object is achieved by introducing the encapsulating aqueous solution of a polyelectrolyte in the form of preformed, preferably spherical particles into the aqueous solution of an oppositely charged polyelectrolyte or an oppositely charged low molecular weight organic compound as a precipitation bath. A substance to be encapsulated can be contained in the solution of the polyelectrolyte used as core material. By mutual precipitation of the oppositely charged polyelectrolyte components or the polyelectrolyte with the oppositely charged low molecular weight organic compound, an insoluble membrane consisting of the corresponding polyelectrolyte complex immediately forms on the contact surface of the two solutions, which encloses the substance to be encapsulated in the liquid core material. When the method according to the invention is used, this source represents a very thin, but mechanically stable membrane which is impermeable to dissolved high molecular weight compounds and which includes the polyelectrolyte solution used as the core material and the substance to be encapsulated if necessary. The nature of the polyelectrolytes used or the low molecular weight organic ions, the precipitation conditions, the concentration ratios in the boundary layer and the viscosity of the solution used as the core material are essential for the design and properties of the membrane shell formed. It has been found that the capsule wall thickness in the radial direction to the interior of the capsule can be controlled by different dwell times of the polyelectrolyte solution droplets in the precipitation bath. The encapsulation conditions with regard to temperature and pH value of the polyelectrolyte solutions 121 can be varied within wide limits, however, for the most gentle encapsulation of sensitive substances, temperatures γόη 237 to 323 K and pH values of 5 to 3 are preferred.

Ala solvent for the respective polyelectrolyte components: bcv /. the low molecular weight organic ions can be pure water used v / earth.

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The use of buffer mixtures, such as B. 0.001 to 1 M phosphate buffer, or solutions of low molecular weight electrolytes also enable the specific adjustment of certain pH values and different ionic strengths. With regard to the polyelectrolytes to be used according to the invention for the core material, polysaccharides or polysaccharide derivatives containing sulfate or carbozylate groups, such as, for example, cellulose sulfate, dextran sulfate, starch sulfate, cellulose acetate sulfate, carboxymethyl cellulose sulfate, carboxymethyl cellulose sulfate, carboxymethyl cellulose in the form of sodium, alginate, cellulose or alone or in a mixture are particularly suitable. However, synthetic polymers containing carbo: xylate or sulfonate groups, such as poly- or copolyacrylates, -maleinates or polystyrene sulfonate, are suitable Polyelectrolytes and the degree of polymerisation between 0.5 and 20 % by mass can be varied.

While the degree of substitution of the polysaccharide sulfates or polysaccharide carboxylates can be varied within wide limits, e.g. 3. between 0.3 and 2.5 »the degree of polymerisation should not be too low, since it is important for the stability of the microcapsules in the stage A certain minimum viscosity is required to develop is. The viscosity of the finished core material mixture should preferably be kept within the limits of 0.1 to 10 Pa.s. and 10 to 10 times the Fellb'adviskositaet be. The viscosity of the core material mixture can be determined by the concentration and the degree of polymerization of the polyelectrolytes used, but also by adding other suitable water-soluble polymers.

According to the invention, aqueous solutions are used for the paell bath of polycations with quaternary aminonium groups, such as. B. Polydimethyldiallylammonium chloride and polyvinylbenzyltrimethylammonium chloride, or of low molecular weight organic Cations, especially cationic surfactants and / or cationic dyes with a quaternary nitrogen group are used.

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Quaternary ammonium salts were found to be of the cationic surfactants, such as B. lauiyldimethylbenzylammoniiimchlorid, Pyridiniumsalze-, such as B. Steararaidomethylenpyridiniumchlorid and imidazolium salts, such as. B, heptadecylimidazolium chloride, as suitable. The hydrophilic long-chain alkyl or arylalkyl radical of the surfactant can be replaced by heteroatoms or heteroatom groups may be interrupted, e.g. B. Diisobutylphenoxyethoxy- ethyldimethylbenzylammonium chloride, dodecylcarbamylmethylbenzyldimethylammonium chloride.

Aminotriarylmethane dyes, acridine dyes, methine dyes, thiazine dyes, oxazine dyes or azo dyes, for example, can be used as cationic dyes. The concentration of polycation, cationic surfactant and / or cationic dye in the coagulation bath should be 0.1 to 20 mass, preferably 0.2 to 10 mass. The implementation of the method according to the invention is extremely simple. First of all, the aqueous polyelectrolyte solution intended for the core material is mixed with the substance to be encapsulated, which can already be present as an aqueous solution, dispersion or in solid form, at the optimum pH value for the substance to be encapsulated and at a suitable temperature. The mixture obtained in this way is then simply drained from a capillary or the droplets formed are blown off with air or an inert gas, e.g. B, using a concentric nozzle, shaped into spherical particles and introduced into the stirred or otherwise agitated, optionally tempered and buffered precipitation bath. The capsule shell is formed immediately when the core material droplets and the falling bath come into contact with one another. For this reason, the microcapsules formed can also be separated off immediately after they have been introduced. However, the microcapsules are advantageously left in the precipitation bath for 10 s to 120 min or even longer. In this way, the thickness of the wall layer and its properties are also easily reproducible with the same material and constant encapsulation conditions.
The Vi'and thickness is in the order of magnitude of Q _? 1 to

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50 / um. When using low molecular weight counterions, however, it can be much larger. The size of the microcapsules can be varied within the limits of 50 to 5000 / un by appropriate technical design of the molding process and the viscosity of the core material solution. To achieve uniform, spherical microcapsules, a distance of 5 to 200 cm, preferably 10 to 100 cm, is maintained between the outlet opening of the capillary or nozzle and the bath surface.

The actual microcapsulation is generally followed by the separation of the microcapsules that have formed Pael bath by filtration or decanting and rinsing off the excess adhering paell bath with water or buffer. solution on.

To solidify and reduce the permeability of the capsule wall, the microcapsules can also be treated with a dilute, z. B, 0.01 to 1/3 aqueous solution de3 polyelectrolytes used as core material are carried out, to which it is advisable to repeat the case. bath treatment follows.

The microcapsules produced according to the invention are opposite Deformation and increased osmotic pressure very stable. However, if they are subjected to excessive mechanical stress, they burst open and release the liquid contents of the capsule. They can be frozen without damaging the capsule wall after thawing. Compared to chemical Influences such as B. 0.1 ITETaOH, 0.1 ITHCl, ethanol, Acetone, the capsule wall is also stable. For low molecular weight inorganic and organic substances, such as. B. protons, hydroxyl ions, water, dissolved salts, dyes and Sugar, the membrane is not an essential diffusion barrier.

With the help of the examples given below, the invention should be Proper procedures are explained in more detail.

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Execution examples

1 · Ο »5 S halellulose sulfate with a degree of substitution of 2.0 are dissolved in 10 ml 0.01 IT phosphate buffer (pH 7.0). The solution obtained is pressed through a capillary with an internal diameter of 0.2 mm at room temperature and after a fall distance of 30 cm into a stirred precipitation bath made of 2 g of polydimethyldiyllylammonium chloride (relative Molecular weight 40,000) and 100 ml of 0.01 M phosphate buffer (pH 7 »0) added dropwise. Immediately after entering the Pael bath, the drops are covered with a skin the complex of the two oppositely charged polyelectrolytes. Each 30 rain are the obtained microcapsules separated from the paell bath by decanting and washed with 0.01 IT phosphate buffer (pH 7.0). The spherical microcapsules have a diameter of 2 to 3 mm, are transparent and contain the core material used Cellulose sulfate solution.

The educated. The capsule wall is free of defects and represents a membrane permeable to low molecular weight substances. The microcapsules are suspended in phenolphthalein stained 0.01 IT ITaOH and discolored the suspension medium after approx. 3 min with 0.1 H Hol, the capsules retain their red color for a few more minutes and then slowly fade. Shrink when salt is added to the suspension medium the particles initially under deformation. When you close V / ascheii with V / ater take your spherical again Shape.

? .. 0.2 g ITa cellulose sulfate with a degree of substitution of 0.3 v / earth dissolved in 10 ml v / water. The solution obtained is pressed through a capillary with an inner diameter of 0.2 mm and blown off through a concentric nozzle with the help of a stream of nitrogen in such a way that individual drops of liquid with a diameter of 100 to 500 μm are formed.

ORIGINAL INSPECTED

At a distance of 15 cm, the spherical ones step Drops in an increased paell bath made of 2 g polydimethyl- diallylammonium chloride and 100 ml of water. Direct after contact with your paell bath, they cover each other Droplets with a skin made from the complex formed by the two oppositely charged polyelectrolytes. IJach 30 The microcapsules obtained are separated from the paell bath by decanting and washed with water. It will obtained transparent spherical particles with a diameter of 100 to 500 µm, their capsule wall thickness 1 to 5 µm.

1.5 g Ha-extran sulfate with a degree of substitution of 0.8 are dissolved in 10 ml of water. The resulting solution is tempered to 277 K and as in Example 1 in a 277 K tempered paell bath made from 10 g polydimethyldiallylammonium chloride and entered 100 ml of water. After 60 minutes, the microcapsules formed are removed by decanting The paell bath is separated, 100 ml of a 0.1% dextran sulfate solution are added, and after 10 minutes the dextran sulfate solution is removed separated and then treated with the paell bath for another 30 minutes. Ss are microcapsules with a Obtained a diameter of 3 to 4 mm, the wall thickness of which is approx. 20 μm.

0.3 g ITa-Carbozyme ethyl cellulose sulfate with a degree of substitution of carboxyl groups of 0.6 and of sulfate ester groups of 0.3 are dissolved in 10 ml of water. The solution obtained is tempered to 313 K and as in the example 1 in a paell bath made of 3 g of polyvinylbenzyltrimethylammonium chloride and heated to 313 K and entered 100 ml of water. After 60 minutes, the capsules are separated from the paell bath by decanting and washed with water. It will obtained transparent microcapsules with a diameter of about 3 mm.

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5 x 0.3 g of sodium cellulose acetate sulfate are dissolved in 100 ml of water solved. The solution obtained is as in Example 1 in dripped in a Faellbad, which by dissolving 3 g Polydimethyldiallylammonium chloride in 100 ml of dilute HCl with a pH of 4 was obtained. Bach 60 min the capsules are separated from the skin bath by decanting and washed with water. It will be transparent Obtained microcapsules with a diameter of about 3 mm. /

6. 0.3 g of sodium polystyrene sulfonate are dissolved in 100 ml of water. The solution obtained is, as in Example 1, in a precipitation bath of 3 g of polydimethyldiyallylammonium chloride and 100 ml of water were added dropwise. After 30 min, the capsules are separated from the coagulation bath by decanting and washed with water washed. White light red microcapsules with a diameter of about 2 mm and a liquid core are obtained.

7. 0.2 g Ne ^ -ölulose sulfate with a degree of substitution of 0.4 are dissolved in 9.8 ml of water. The solution obtained is at room temperature through a capillary with a Inside diameter of 0.2 mm and after a fall distance of 30 cm into a stirred coagulation bath of 1 g Methylene blue and 99 ml of water were added dropwise. Immediately after entering the coagulation bath, the drops are coated with a skin. After 30 minutes, the capsules formed are separated from the coagulation bath by decanting and rinsed with water washed. Deep blue colored spherical capsules with a diameter of 3 to 5 mm are obtained.

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8. 0.3 g of sodium carbosymethyl cellulose with a degree of substitution of 0.6 are dissolved in 9.7 ml of water. The solution obtained is pressed through a capillary with an inner diameter of 0.2 and blown off through a concentric nozzle with the aid of a stream of nitrogen in such a way that individual liquid droplets with a diameter of 100 to 300 μm are created. The droplets are placed in a stirred bath made of 2 g of dodecylcarbamylmethylbenzyldimetnylammonium chloride and 98 ml of water. After 120 minutes, the microcapsules formed are separated from the skin bath with the aid of a fine polyamide sieve and washed thoroughly with water. It becomes white, opaque, spherical particles with a diameter

. obtained from 100 to 300 / um.

9. 0.2 g la-carbosymethyl cellulose sulfate with a substitu- The degree of carboxyl groups of 0.6 and sulfate ester groups of 0.3 are dissolved in 9.8 g of water. The received As in Example 7, the solution is shaped into spherical droplets and placed in a precipitation bath of 1 g of crystal violet (C · I. Basic Violet 3) and 99 ml of water added. After 10 min the capsules formed are decanted separated from the bath and washed thoroughly with water until the water remains colorless. The capsules are Dark purple in color and 3 to 5 mm in diameter.

10.0.2 g IFa cellulose sulfate with a degree of substitution of 0.4 are dissolved in 9.8 ml of water. The solution obtained is mixed into spherical particles as in Example 8. shaped and added to a skin bath of 2 g of Safranin (C * I. Basic Red 2) and 98 ml of water. After 30 minutes, the Sieve off microcapsules from the bath and wash thoroughly with water. There are dark red spherical particles obtained with a diameter of 100 to 300 / µm.

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11. 0.2 g Na alginate are dissolved in 9.8 ml V / water and the Solution shaped into spherical particles as in Example 7. These are in a stirred bath of 1 g Safranin (C.I. Basic Red 2), 1 g of polydimethyldiallylammonium chloride and entered 98 ml of water. Awake 60 min the capsules are sieved off and washed with water.

Dark red spherical particles with a diameter of 3 to 5 mm are obtained.

12. 0.2 g Na cellulose sulfate with a degree of substitution of 0.4 are dissolved in 9.8 ml of water, the solution obtained is pressed as in Example 7 through a capillary and in a skin bath of 1 g of acridine orange (C, I. Basic Orange 14) and 99 ml Yfesser added dropwise. After 60 min the capsules are sieved and washed with water until the wash water runs off colorless. There are strong organs colored spherical capsules with a diameter of 3 to 5 mm are obtained.

13. 0.2 g of sodium polystyrene sulfonate are dissolved in 9.8 ml of Yfesser, the solution obtained, as in Example 7, is pressed through a capillary and placed in a laellbath of 2 g of benzethane. nium chloride and 98 ml of water were added dropwise. After 2 h, the capsules formed are sieved off and thoroughly washed with water washed. It becomes white, opaque, spherical Particles with a diameter of 3 to 5 mm are obtained.

14. 0.2 g of sodium cellulose sulfate are dissolved in 9.8 ml of water, the solution as in Example 7 through a capillary and poured into a paell bath of 2 g lauryldimethylbenzyl- ammonium chloride and 98 ml of water were added dropwise. After 2 h The capsules formed are sieved off and washed thoroughly with water. It becomes white, opaque spherical particles with a diameter of 3 to 5 mra are obtained.

BATH ORIGINAL

Claims (1)

Claims 1., microcapsules with a semi-permeable or permeable capsule wall and liquid core, characterized in that the capsule wall consists of a polyelectrolyte complex consisting of oppositely charged polyelectrolytes or of polyelectrolytes and low molecular weight organic counter- ions is formed, and the liquid core consists of an aqueous solution of a polyelectrolyte. 2. Microcapsules according to item 1-i, characterized in that the capsule wall consists of a complex of polysaccharides containing sulfate groups or polysaccharide derivatives or synthetic polymers and polymers containing sulfonate groups with quaternary ammonium groups, and the liquid core consists of the aqueous solution of the polysaccharide or polysaccharide derivatives containing sulfate groups used to form the capsule wall or synthetic polymer containing sulfonate groups. ■ 3. Microcapsules according to item 1, characterized in that the capsule wall consists of a complex of sulfate or carboxylate groups Polysaccharides or polysaccharide derivatives or synthetic sulfonate or carboxylate groups Polymers and cationic surfactants of the cationic dyes and the liquid core from the aqueous solution of the polysaccharide or polysaccharide derivatives containing sulfate or carboxylate groups used for the formation of the capsule wall or synthetic polymer containing sulfonate or carboxylate groups. 4. Microcapsules according to item 1 to 3, characterized in that the polysaccharides or polysaccharide derivatives containing sulfate groups Cellulose sulfate, cellulose acetate sulfate, Carboxymethyl cellulose sulfate, dextran sulfate or Gtaerke— sulfate are in the form of their sodium salts. ■ - - ^: '· copy' 5. Microcapsules after. Point 1 to 4, characterized in that that the degree of substitution of the sulfate groups Polysaccharides or polysaccharide derivatives on sulfate ester groups is 0.3 to 2.5. G. Microcapsules according to items 1 to 3, characterized in that the synthetic polymer containing sulfonate groups IT is sodium polystyrene sulfonate. 7. microcapsules according to point 1 and 3, characterized in that that the / tarboxylate-containing polysaccharides or Polysaccharide derivatives carboxymethyl cellulose, carboxymethyl cellulose sulfate or alginate in the form of their sodium salts. 8. Microcapsules according to items 1 and 2, characterized in that the polymers with quaternary ammonium groups are polydircethyldiallylammonium chloride or polyvinylbenzyl trimethyl arjaonium chloride. j. ITicrocapsules according to items 1 and 3, characterized in that the cationic surfactants are in particular quaternary ammonium, pyridinium or imidazolium salts and the cationic dyes are in particular aminotriarylmethane dyes, acridine dyes, methine dyes, phenazine dyes, thiazine dyes, oxazine dyes or azo dyes. i0. IVtL crocapsules according to items 1 to 9, characterized in that that the capsules have an outer diameter of 50 to 5000 μm. 11.J. microcapsules according to point 1 to 10, characterized in that that the capsule wall thickness is 0.1 to 50 µm, in particular 1 to 20 / im. ORIGINAL. INSPECTED 330S259 12. Microcapsules according to item 1 to 11, characterized in that the capsules contain further substances in dissolved, ewul— gated or suspended form. 13. Process for the production of microcapsules with semipermeable or permeable wall for the encapsulation of dissolved, emulsified or suspended substances by precipitation of polyelectrolytes, characterized in that the aqueous solution of a polyelectrolyte in , Form preformed particles in the aqueous solution of an oppositely charged polyelectrolyte or a oppositely charged low molecular weight organic compound enters as a precipitation bath. 14. The method according to item 13, characterized in that one Adding substances to be encapsulated to the polyelectrolyte solvent used as the core material. 15. The method according to items 13 and 14, characterized in that the pre-formation of particles by dripping from a Capillary takes place. 16. The method according to points 13 and 14, characterized in that that the pre-formation of the particles takes place by digestion. 17. The method according to items 13 to 16, characterized in that that the particles, after their pre-formation, have a path of 5 to 200 cm, preferably 10 to 100 cm, to the Faellbadoberflaeche retire. 18. The method according to items 13 to 17, characterized in that the concentrations of the to be used as core material Polyelectrolyte solution 0.5 to 20 IvIanse- $, preferably 1 to 10% by mass. 13. The method according to items 13 to 16, characterized in that that the concentration of polyelectrolyte or low molecular weight Laren organic counterion in the Faellbad 0.1 to 20 Lasse— # " COPY preferably 0.5 to 10 mass $. 20 «method according to items 13 to 19, characterized in that as a solvent for the polyelectrolytes or for polyelectrolyte and low molecular weight organic counterion water or 0.001 to 1 molar aqueous solution Solutions of low molecular weight electrolysis, preferably buffer solutions, can be used. 21. The method according to items 13 to 20, characterized in that that the encapsulation takes place at pH values of 5 to 9. 22. The method according to item 13 to 21, characterized in that the microcapsules formed are 10 s to 24 h, preferably Left in the paell bath for 5 to 120 minutes at temperatures of 273 to 323 K. ORIGINAL INSPECTED COPY '