CH659591A5 - MICROCAPSULES AND METHOD FOR THEIR PRODUCTION. - Google Patents

Description

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 here can e.g. B. for separation and material conversion processes in preparative and analytical chemistry and biochemistry, pharmacy and medicine as well as agriculture and food industry.

Microcapsules with a semipermeable or permeable capsule wall and a liquid core are known in a wide variety of embodiments (VD Solodovnik: Mikrokapselselung, Chimija, Moscow, 1980; JR Nixon: Microencapsulation. Marcel Dekker Inc. New York-Basel, 1976; JE Vandegaer : Microencapsulation Processes and Applications. Plenum Press, New York-London, 1974; M. Gutcho: 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 cases with regard to their permeation properties, their elasticity and mechanical stability, e.g. B. at high osmotic

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Pressure inside the capsule. The liquid core usually consists of an oily, water-immiscible organic liquid, which has a disadvantageous effect on the properties of sensitive substances to be encapsulated and on the mass transfer when the microcapsules are used in aqueous systems.

Numerous mechanical-physical and chemical processes are known for producing microcapsules. The principle of the mechanical-physical encapsulation process generally consists in atomizing the core material and encasing it in the gas space with the wall material. The wall material can already be dissolved in the core material (spray drying) or can subsequently be brought into contact with the core material particles or droplets (immersion method, multi-component nozzle method, fluidized bed coating and the like).

Disadvantages of these methods are primarily the use of higher temperatures, the use of organic solvents or the impermeability of the capsule shell. The chemical processes mostly work in the liquid phase, and the wall formation can take place by interfacial polymerization or condensation or by deposition of a predetermined polymeric wall material. The use of mostly aggressive monomers and organic solvents are major disadvantages of the encapsulation processes due to interfacial reactions.

Most of the chemical processes using a given polymeric wall material have in common that the core material is emulsified or suspended in the continuous phase and the polymer dissolved in the continuous phase precipitates at the phase boundary between the core and the continent, e.g. B. by changing the pH, the temperature, salt or solvent additives u. a ..

Such conditions easily lead to their damage when encapsulating sensitive substances.

In the case of very frequently used complex coaceration, the wall material is precipitated by two oppositely charged polymers (W. Sliwka: Angew. Chem. 87 (1975) pp. 556-567).

The use of non-water-miscible organic liquids as the core material and the mostly still necessary solidification of the capsule wall, for which sometimes quite drastic reaction conditions are required, are the main disadvantages for this process.

A relatively gentle inclusion process consists in producing mixtures of the material to be encapsulated with an aqueous polyelectrolyte solution and introducing this mixture into a precipitation bath containing low molecular weight ions. As a result of ion diffusion, dimensionally stable structures with a continuous gel network are formed (J. Klein, U. Hackel, P. Schara and H. Eng: Angew. Makromol. Chem. 76/77 (1977) pp. 329-350, DE-AS 1 917 738).

This process also leads to partial damage to sensitive substances due to necessary pH changes and / or the presence of polyvalent metal ions. In addition, such networks have no permeable or semipermeable capsule wall and no liquid core.

DE-OS 3 012 233 describes a further developed process for immobilizing sensitive biological systems, based on such gel particles, in which the bead-shaped particles are surrounded with a polyelectrolyte complex membrane by subsequent treatment with a suitable polyelectrolyte solution and the gel by ion exchange with corresponding buffer solutions is liquefied again. The microcapsules obtained in this way have the disadvantage that they are very sensitive to external influences during manufacture and handling659 591

are borrowed because the capsule walls have very little mechanical strength. The process does not exclude the potentially damaging influence of polyvalent metal ions.

In addition, the necessary reliquefaction of the gel core through ion exchange represents an additional intervention in the entire system.

The aim of the invention is to develop microcapsules with improved properties and a process for their production in order to open up new possibilities with regard to the microencapsulation of sensitive substances and new fields of application of the products obtained.

The invention is therefore based on the object of developing microcapsules and a suitable process for their production, the encapsulation of sensitive substances at the same time having to be ensured or sought. The capsule production should be as gentle as possible, e.g. B. physiological conditions are feasible and the capsule wall is an elastic, permeable or semipermeable membrane, which should be sufficiently stable against chemical influences and mechanical stresses. The interior of the capsule should be liquid and should not cause any damage to the substance to be encapsulated.

According to the invention, the object is achieved by entering the aqueous solution to be encapsulated in the form of preformed, preferably spherical particles of the polyelectrolyte 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 the core material. Due to the 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, which includes the substance to be encapsulated in the liquid core material, immediately forms on the contact surface of both solutions.

When the method according to the invention is used, this shell represents a very thin, but mechanically stable membrane which is impermeable to dissolved high-molecular compounds and which includes the polyelectrolyte solution used as the core material and the substance which may be encapsulated. The nature of the polyelectrolytes or the low molecular weight organic ions used, the precipitation conditions, the concentration ratios in the boundary layer and the viscosity of the solution used as core material are essential for the formation and the properties of the membrane shell formed. It was found that the capsule wall thickness in the radial direction to the interior of the capsule can be controlled by different residence times of the droplets of polyelectrolyte solution in the precipitation bath. The encapsulation conditions can be varied within wide limits with regard to the temperature and pH of the polyelectrolyte solutions, although temperatures of 273 to 323 K and pH values of 5 to 9 are preferred for the most gentle encapsulation of sensitive substances.

Pure water can be used as the solvent for the respective polyelectrolyte components or the low molecular weight organic ions.

The use of buffer mixtures, such as. B. 0.001 to 1 M phosphate buffer, or of solutions of low molecular weight electrolytes also enables the targeted 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, sulfate- or carbo-

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oxysate-containing polysaccharides or polysaccharide derivatives, such as. As cellulose sulfate, dextran sulfate, starch sulfate, cellulose acetate sulfate, carboxymethyl cellulose sulfate, carboxymethyl cellulose or alginate, in the form of their sodium salts, alone or in a mixture, has proven particularly useful. However, synthetic polymers containing carboxylate or sulfonate groups are also suitable. B. poly- or copolyacrylates, -maleinates or polystyrene sulfonate. The polyelectrolyte concentration in the aqueous core material solution can be varied between 0.5 to 20% by mass, depending on the nature of the polyelectrolyte used and the degree of polymerization.

While the degree of substitution of the polysaccharide sulfates or carboxylates can be varied within wide limits, e.g. B. between 0.3 and 2.5, the degree of polymerization should not be too low, since a certain minimum viscosity is required for the stability of the microcapsules at the stage of formation. The viscosity of the finished core material mixture should preferably be kept within the limits of 0.1 to 10 Pa.s and be 10 to 100 times the viscosity of the precipitation bath. The viscosity of the core material mixture can be controlled both via the concentration and the degree of polymerization of the polyelectrolyte used, but also by adding other suitable water-soluble polymers.

For the precipitation bath, aqueous solutions of polycations with quaternary ammonium groups, such as, for. B. polydimethyldiallylammonium chloride and polyvinylbenzyltrimethylammonium chloride, or of low molecular weight organic cations, in particular cationic surfactants and / or cationic dyes with a quaternary nitrogen grouping.

Quaternary ammonium salts such as e.g. B. Lauryldimethylbenzylammoniumchlo-rid, pyridinium salts, such as. B. Stearamidomethylenpyridi-nium chloride and imidazolium salts, such as. B. heptadecylimi-dazolium chloride, as suitable. The hydrophilic long-chain alkyl or arylalkyl radical of the surfactant can be interrupted by hetero atoms or hetero atom groups, e.g. B. diisobutylphenoxyethoxyethyldimethylbenzylammonium chloride, dodecylcarbamylmethylbenzyldimethylammonium chloride.

Cationic dyes that can be used are, for example, amino-triarylmethane dyes, acridine dyes, methine dyes, thiazine dyes, oxazine dyes or azo dyes. The concentration of polycation, cationic surfactant and / or cationic dye in the precipitation bath should be 0.1 to 20% by mass, preferably 0.2 to 10% by mass.

The implementation of the method according to the invention is extremely simple. First, the aqueous polyelectrolyte solution provided for the core material is mixed with the substance to be encapsulated at the optimum pH value for the substance to be encapsulated and with the substance to be encapsulated, which can already be present as an aqueous solution, dispersion or in solid form. 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, for. B. using a concentric nozzle, deformed into spherical particles and introduced into the stirred or otherwise moved, optionally tempered and buffered precipitation bath. The capsule shell is formed immediately when the core droplets and the precipitation bath come into contact with one another. For this reason, the microcapsules formed can also be separated off immediately after the entry. However, the microcapsules are advantageously left in the coagulation bath for a further 10 s to 120 min or even longer. In this way, the thickness of the wall layer and its properties can also be easily reproduced with the same material and constant encapsulation conditions.

The wall thickness here is in the order of magnitude of s 0.1 to 50 (in. However, when using low molecular counterions, it can be considerably larger. The size of the microcapsules can be within the limits of, due to an appropriate technical design of the deformation process and the viscosity of the core material solution 50 to 5000 microns 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 precipitation bath surface.

The actual microencapsulation is generally followed by the separation of the microcapsules formed from the precipitation bath by filtration or decanting and rinsing off the excess adhering precipitation bath with water or buffer solution.

In order to solidify and reduce the permeability of the capsule wall, treatment of the microcapsules with a diluted, for. B., 0.01 to 1% aqueous solution of the polyelectrolyte used as the core material, which is conveniently followed by another precipitation bath treatment. 25 The microcapsules produced according to the invention are very stable against deformation and increased osmotic pressure. If the mechanical stress is too great, however, they burst open and release the liquid capsule content.

30 They can be frozen without the capsule wall being damaged after thawing. Against chemical influences, such as. B. 0.1 N NaOH, 0.1 N HCl, ethanol, acetone, the capsule wall is also stable. For low molecular weight inorganic and organic sub-35, such as. B. protons, hydroxyl ions, water, dissolved salts, dyes and sugar, the membrane is not an essential diffusion barrier.

The method according to the invention is to be explained in more detail with reference to the examples given below.

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Embodiments

1.0.5 g of Na cellulose sulfate with a degree of substitution of 2.0 are dissolved in 10 ml of 0.01 N phosphate buffer (pH 7.0). The solution obtained is pressed at room temperature through a capillary with an inner diameter of 0.2 mm and after a falling distance of 30 cm into a stirred precipitation bath made of 2 g of polydimethyldiyllylammonium chloride (molecular weight 40,000) and 100 ml of 0.01 M phosphate buffer 50 fer (pH 7.0). Immediately after entering the precipitation bath, the drops are covered with a skin made up of the complex of the two oppositely charged polyelectrolytes. After 30 min, the microcapsules obtained are separated from the precipitation bath by decanting and washed with 0.01 N 55 phosphate buffer (pH 7.0). The spherical microcapsules have a diameter of 2 to 3 mm, are transparent and contain the cellulose sulfate solution used as the core material.

The capsule wall formed is defect-free and represents a membrane which is permeable to 60 low molecular weight substances. If the microcapsules are suspended in 0.01 N NaOH stained with phenolphthalein and the suspension medium is decolorized after approx. 3 min with 0.1 N HCl, the capsules still retain a few minutes their red color and then slowly fade away. When salt is added to the suspension medium, the particles initially shrink with deformation. When they are subsequently washed with water, they take on their spherical shape again.

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2. 0.2 g of Na cellulose sulfate with a degree of substitution of 0.3 are dissolved in 10 ml of water. The solution obtained is pressed through a capillary with an inner diameter of 0.2 mm and blown off via 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 500 μm are formed.

After a falling distance of 15 cm, the spherical droplets enter a stirred precipitation bath composed of 2 g of polydimethyldiallylammonium chloride and 100 ml of water. Immediately after contact with the precipitation bath, the droplets are covered with a skin from the complex formed of the two oppositely charged polyelectrolytes. After 30 minutes, the microcapsules obtained are separated from the precipitation bath by decanting and washed with water. Clear spherical particles with a diameter of 100 to 500 µm are obtained, the capsule wall thickness of which is 1 to 5 µm.

3. 1.5 g of sodium dextran sulfate with a degree of substitution of 0.8 are dissolved in 10 ml of water. The solution obtained is tempered to 277 K and, as in Example 1, introduced into a precipitation bath tempered to 277 K from 10 g of polydimethyldiallylammonium chloride and 100 ml of water. To

The microcapsules formed are separated from the precipitation bath by decanting for 60 min, 100 ml of a 0.1% dextran sulfate solution are added, the dextran sulfate solution is separated off after 10 minutes and the treatment is then continued for 30 minutes with the precipitation bath. Microcapsules with a diameter of 3 to 4 mm are obtained, the wall thickness of which is approximately 20 | xm.

4.0.3 g of Na carboxymethyl 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 Example 1, introduced into a precipitation bath tempered to 313 K from 3 g of polyvinylbenzyltrimethylammonium chloride and 100 ml of water. After 60 minutes, the capsules are separated from the precipitation bath by decanting and washed with water. Transparent microcapsules with a diameter of approx. 3 mm are obtained.

5. 0.3 g of Na cellulose acetate sulfate are dissolved in 100 ml of water. The solution obtained is dripped into a precipitation bath as in Example 1, which was obtained by dissolving 3 g of polydimethyldiallylammonium chloride in 100 ml of dilute HCl with a pH of 4. After 60 minutes, the capsules are separated from the precipitation bath by decanting and washed with water. Transparent microcapsules with a diameter of approx. 3 mm are obtained.

6.0.3 g of Na polystyrene sulfonate are dissolved in 100 ml of water. As in Example 1, the solution obtained is dropped into a precipitation bath composed of 3 g of polydimethyldiyallylammonium chloride and 100 ml of water. After 30 minutes, the capsules are separated from the precipitation bath by decanting and washed with water. White-cloudy microcapsules with a diameter of approximately 2 mm and a liquid core are obtained.

7. 0.2 g of Na cellulose sulfate with a degree of substitution of 0.4 are dissolved in 9.8 ml of water. The solution obtained is pressed through a capillary with an inner diameter of 0.2 mm at room temperature and, after a falling distance of 30 cm, dripped into a stirred precipitation bath composed of 1 g of methylene blue and 99 ml of water. Immediately after entering the precipitation bath, the drops are covered with a skin. After 30 minutes, the capsules formed are separated from the precipitation bath by decanting and washed with water. Deep blue colored spherical capsules with a diameter of 3 to 5 mm are obtained.

8. 0.3 g of Na carboxymethyl 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 nitrogen stream in such a way that individual liquid droplets with a diameter of 100 to 300 μm are formed. The droplets are discharged into a stirred precipitation bath 2 g of dodecylcarbamylmethylbenzyldimethylammonium chloride and 98 ml of water are blown in. After 120 minutes, the microcapsules formed are separated from the precipitation bath using a fine polyamide sieve and washed thoroughly with water, giving white opaque spherical particles with a diameter of 100 to 300 μm.

15 9. 0.2 g of Na-carboxymethyl cellulose sulfate with a degree of substitution of carboxyl groups of 0.6 and of sulfate ester groups of 0.3 are dissolved in 9.8 g of water. The solution obtained is shaped into spherical droplets as in Example 7 and introduced into a precipitation bath composed of 1 g of crystal vio-20 lett (C.I. Basic Violet 3) and 99 ml of water.

After 10 minutes, the capsules formed are separated from the precipitation bath by decanting and washed thoroughly with water until the water remains colorless. The capsules are dark purple in color and have a diameter of 3 25 to 5 mm.

10. 0.2 g of Na cellulose sulfate with a degree of substitution of 0.4 are dissolved in 9.8 ml of water. The solution obtained is shaped into spherical particles as in Example 8 and introduced into a precipitation bath made from 2 g of safranine (C.I. Basic Red 2) 30 and 98 ml of water. After 30 minutes, the microcapsules are sieved off from the precipitation bath and washed thoroughly with water. Dark red spherical particles with a diameter of 100 to 300 (im are obtained.

35 11. 0.2 g of Na alginate are dissolved in 9.8 ml of water and the solution is shaped into spherical particles as in Example 7. These are introduced into a stirred precipitation bath from 1 g of safranin (C.I. Basic Red 2), 1 g of polydimethyldiallylammonium chloride and 98 ml of water. After 60 minutes, the capsules are sieved and washed with water. Dark red spherical particles with a diameter of 3 to 5 mm are obtained.

12.0.2 g of Na cellulose sulfate with a degree of substitution of 0.4 are dissolved in 9.8 ml of water, the solution 45 obtained is pressed through a capillary as in Example 7 and into a precipitation bath made of 1 g of acridine orange (CI Basic Orange 14) and added dropwise 99 ml of water. After 60 min the capsules are sieved and washed with water until the wash water runs colorless. Strong orange colored spherical-50 capsules with a diameter of 3 to 5 mm are obtained.

13. 0.2 g of Na polystyrene sulfonate are dissolved in 9.8 ml of water, the solution obtained is pressed through a capillary as in Example 7 and added dropwise to a precipitation bath of 2 g of benzethonium 55 chloride and 98 ml of water. After 2 hours, the capsules formed are sieved off and washed thoroughly with water. White, opaque spherical particles with a diameter of 3 to 5 mm are obtained.

60 14. 0.2 g of Na cellulose sulfate are dissolved in 9.8 ml of water, the solution is pressed through a capillary as in Example 7 and added dropwise to a precipitation bath composed of 2 g of lauryldimethylbenzylammonium chloride and 98 ml of water. After 2 hours, the capsules formed are sieved off and washed thoroughly with water 65. White, opaque spherical particles with a diameter of 3 to 5 mm are obtained.

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Claims (22)

659591 PATENT CLAIMS 1. Microcapsules with semipermeable or permeable capsule wall and liquid core, characterized in that the capsule wall consists of a polyelectrolyte complex composed of at least one anionic and at least one cationic organic compound, at least one of the ionic compounds being a polymer and the liquid core being an aqueous polyelectrolyte solution contains. 2. Microcapsules according to claim 1, characterized in that the cationic compounds of the polyelectrolyte-complex polymer with quaternary ammonium groups and the anionic compounds are sulfate group-containing polysaccharides, sulfate group-substituted polysaccharides or sulfonate group-containing synthetic polymers and the liquid core contains one or more of these anionic compounds. 3. Microcapsules according to claim 1, characterized in that the cationic compounds of the polyelectrolyte complex cationic surfactants and / or cationic dyes alone or in a mixture with other polycations and the anionic compounds sulfate- or carboxylate group-containing polysaccharides, sulfate- or carboxylate group-substituted ge-substituted Polysaccharides or synthetic polymers containing sulfonate groups are and the liquid core contains one or more of these anionic compounds. 4. Microcapsules according to claim 2 or 3, characterized in that the sulfate-containing polysaccharides or sulfate-containing substituted polysaccharides are cellulose sulfate, cellulose acetate sulfate, carboxymethylcellulose sulfate, dextran sulfate or starch sulfate in the form of their sodium salts. 5. Microcapsules according to one of claims 2 to 4, characterized in that the degree of substitution of the sulfate group-containing polysaccharides or sulfate group-substituted polysaccharides on sulfate ester groups is 0.3 to 2.5. 6. Microcapsules according to claim 2 or 3, characterized in that the synthetic polymer containing sulfonate groups is sodium polystyrene sulfonate. 7. Microcapsules according to claim 3, characterized in that the carboxylate group-containing polysaccharides or carboxylate group-containing substituted polysaccharides are carboxymethyl cellulose, carboxymethyl cellulose sulfate or alginate in the form of their sodium salts. 8. Microcapsules according to claim 2, characterized in that the polymers with quaternary ammonium groups are polydimethyldiallylammonium chloride or polyvinylbenzyltrimethylammonium chloride. 9. Microcapsules according to claim 3, characterized in that the cationic surfactants are quaternary ammonium, pyridium or imidazolium salts and the cationic dyes are aminotriarylmethane dyes, acridine dyes, methine dyes, phenazine dyes, thiazine dyes, oxa-zine dyes or azo dyes. 10. Microcapsules according to one of claims 1 to 9, characterized in that the capsules have an outside diameter of 50 to 5000 (in. 11. Microcapsules according to one of claims 1 to 10, characterized in that the capsule wall thickness is 0.1 to 50 µm, in particular 1 to 20 µm. 12. Microcapsules according to one of claims 1 to 11, characterized in that the liquid core of the capsules contains further substances in dissolved, emulsified or suspended form. 13. The method for producing microcapsules according to claim 1 with a semipermeable or permeable capsule wall and liquid core by precipitation of polyelectrolytes, characterized in that the aqueous solution of a polyelectrolyte or a mixture of polyelectrolytes charged in the same direction is entered in the form of drops in an aqueous precipitation bath solution which contains organic ionic compounds charged opposite to the polyelectrolyte. 14. The method according to claim 13, characterized in that further substances to be encapsulated are added to the polyelectrolyte solution used for drop formation. 15. The method according to claim 13 or 14, characterized in that the drop formation is carried out by dripping from a capillary. 16. The method according to claim 13 or 14, characterized in that the drop formation is carried out by atomizing. 17. The method according to any one of claims 13 to 16, characterized in that the drops cover a distance of 5 to 200 cm, preferably 10 to 100 cm, to the precipitation bath surface after their formation. 18. The method according to any one of claims 13 to 17, characterized in that the concentrations of the polyelectrolyte solution to be used as the core material are 0.5 to 20% by mass, preferably 1 to 10% by mass. 19. The method according to any one of claims 13 to 16, characterized in that the concentration of polyelectrolyte or low molecular weight organic counterion in the precipitation bath is 0.1 to 20% by mass, preferably 0.5 to 10% by mass. 20. The method according to any one of claims 13 to 19, characterized in that water or 0.001 to 1 molar aqueous solutions of low molecular weight electrolytes, preferably buffer solutions, are used as solvents for the polyelectrolytes or for polyelectrolyte and low molecular weight organic counterion. 21. The method according to any one of claims 13 to 20, characterized in that the encapsulation takes place at pH values from 5 to 9. 22. The method according to any one of claims 13 to 21, characterized in that the microcapsules formed are left for 10 s to 24 h, preferably 5 to 120 min, at temperatures of 273 to 323 K in the precipitation bath.