CA2325420A1 - Method for the production of microcapsules - Google Patents
Method for the production of microcapsules Download PDFInfo
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- CA2325420A1 CA2325420A1 CA002325420A CA2325420A CA2325420A1 CA 2325420 A1 CA2325420 A1 CA 2325420A1 CA 002325420 A CA002325420 A CA 002325420A CA 2325420 A CA2325420 A CA 2325420A CA 2325420 A1 CA2325420 A1 CA 2325420A1
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/04—Making microcapsules or microballoons by physical processes, e.g. drying, spraying
- B01J13/043—Drying and spraying
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
- C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
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Abstract
A method for the production of micro capsules by atomizing an aqueous solution (1) containing 0.1-5 wt. % of at least one water-soluble polyanion to form liquid droplets. The liquid droplets thus obtained impinge upon a liquid film of an aqueous solution (2), containing: 0.1-5 wt. % calcium cations, 0.001-0.4 wt. % chitosane with a molecular weight of more than 40,000 g/mol, and/or 0.15 wt. % chitosane with a average molecular weight of 500-40,000 g/mol.
Description
Process for the production of microcapsules Description The present invention relates to an improved process for the production of microcapsules.
Microcapsules are produced by encapsulation of finely dispersed liquid phases by enveloping with film-forming polymers. Microcapsules are especially used in the area of depot preparations, accordingly the active compound contained in the microcapsules is protected by the shell of the microcapsule and is not released immediately, but only with a delayed release.
It is known to produce microcapsules by atomization of a polymer solution and active compound by means of ultrasound, the liquid droplets produced in this way being sprayed into a precipitation bath.
Thus US-A-4 352 883 describes a 2-stage process for the production of microcapsules, in which living cells, such as, for example, islet of Langerhans cells, are encapsulated. For this, the living cells are suspended in sodium alginate and this suspension is sprayed into a precipitation bath which contains polyvalent cations (for example Ca2+).
The physical crosslinking of the alginate on the surface occurs here due to the polyvalent cation. In the second step, the capsules produced in this way are mixed with a cationic polymer, which brings about further physical crosslinking. Polycations mentioned in this publication are polyethylene-imine and polylysine.
US-A-5 389 379 discloses a process for the production of microcapsules in which the liquid droplets produced by means of an ultrasonic nozzle are first introduced into a liquid in which the liquid droplets are not soluble (for example into ethanol). This liquid is then replaced by water. This complicated 2-stage process is chosen because direct introduction of the liquid droplets is not possible, since otherwise instead of the microcapsules a thin polymer film forms on the surface of the water. The size of the microcapsules formed in this way is specified as 10 to 1000 Vim.
Microcapsules are produced by encapsulation of finely dispersed liquid phases by enveloping with film-forming polymers. Microcapsules are especially used in the area of depot preparations, accordingly the active compound contained in the microcapsules is protected by the shell of the microcapsule and is not released immediately, but only with a delayed release.
It is known to produce microcapsules by atomization of a polymer solution and active compound by means of ultrasound, the liquid droplets produced in this way being sprayed into a precipitation bath.
Thus US-A-4 352 883 describes a 2-stage process for the production of microcapsules, in which living cells, such as, for example, islet of Langerhans cells, are encapsulated. For this, the living cells are suspended in sodium alginate and this suspension is sprayed into a precipitation bath which contains polyvalent cations (for example Ca2+).
The physical crosslinking of the alginate on the surface occurs here due to the polyvalent cation. In the second step, the capsules produced in this way are mixed with a cationic polymer, which brings about further physical crosslinking. Polycations mentioned in this publication are polyethylene-imine and polylysine.
US-A-5 389 379 discloses a process for the production of microcapsules in which the liquid droplets produced by means of an ultrasonic nozzle are first introduced into a liquid in which the liquid droplets are not soluble (for example into ethanol). This liquid is then replaced by water. This complicated 2-stage process is chosen because direct introduction of the liquid droplets is not possible, since otherwise instead of the microcapsules a thin polymer film forms on the surface of the water. The size of the microcapsules formed in this way is specified as 10 to 1000 Vim.
In US-A-5 472 648, a process for the production of microcapsules is specified in which small liquid droplets are produced from an alginate solution by means of ultrasound and are sprayed into a vessel with a CaCl2 solution. After the liquid droplets have hardened in this CaCl2 solution (precipitation bath), the microcapsules obtained in this way are brought out of the CaCl2 solution with the aid of a conveyor device (belt sieve). In order to produce microcapsules which are as uniform as possible, it is proposed in this publication to additionally add a surface-active agent to the CaCl2 solution in order to lower the surface tension, or to foam the CaCl2 solution in order to lower the mechanical stress on the liquid droplets when impinging onto the CaCl2 solution. The size of the microcapsules obtainable in this way is specified as 100 to 4000 Vim.
US-A-5 484 721 describes a process for the production of capsules containing microorganisms. For this, the aqueous solution containing the polyanion is atomized by means of compressed air and a spray nozzle and the liquid droplets thus obtained are introduced into a liquid film which contains calcium or potassium ions as crosslinkers. The size of the microcapsules produced according to this publication is specified as between 10 ~m and 4 mm. However, these microcapsules are not suitable for the encapsulation of active compounds which are to be released in a delayed manner.
US-A-5 589 370 relates to the production of microcapsules by salting out polymers. The microparticles produced in this way, however, dissolve immediately, as soon as they are added to water. To this extent, they are not suitable for the production of depot preparations.
The object of the present invention consists in the provision of a process for the production of microcapsules which are suitable for the production of depot preparations having delayed release, and which can be produced in such a size that they can also be used for the parenteral administration of depot preparations.
This object is achieved by a process for the production of microcapsules by atomization of an aqueous solution 1, which contains 0.1 to 5% by weight of at least one water-soluble polyanion, to give liquid droplets, the liquid droplets thus obtained impinging onto a flowing film of an aqueous solution 2, containing:
~ 0.1 to 5% by weight of calcium cations; and ~ 0.001 to 0.4% by weight of chitosan having a number-average molecular weight of greater than 40,000 g/mol; andlor ~ 0.1 to 5% by weight of chitosan having a number-average molecular weight of between 500 and 40,000 g/mol.
The microcapsules produced according to the process according to the invention have a particularly stable crosslinkage of the outer shell, which is especially to be attributed to the simultaneous use of calcium cations and polycations as crosslinking agents. On account of this property, these microcapsules are particularly suitable for the encapsulation of active substances for the production of depot preparations.
The process according to the invention additionally has the advantage that no agglomeration or caking of the microcapsules occurs, as is the case, for example, when the solution 1 atomized by means of ultrasound is sprayed into a stirred precipitation bath of the solution 2.
The film can flows over a fixed substrate according to the process according to the invention, the substrate preferably not being arranged horizontally. According to a particularly preferred embodiment, the substrate forms an inclined or a vertical plane.
It has proven advantageous if the water-soluble polyanion is an alginate, in particular an alginate having a high guluronic acid content.
The water-soluble polyanion, however, can also be selected from the group consisting of carrageenan, sulfated polysaccharides, gelatin and agar-agar.
According to a particularly preferred embodiment of the present invention, the solution 1 additionally contains at least one polyacid or its alkali metal salt, selected from the group consisting of polyamino acids, poly-phosphates and polysulfates of polysaccharides.
Preferred examples of a polyphosphate are sodium polyphosphate and a polyphosphate of a polysaccharide.
WO 99/48480 PCTlEP99/01626 The polysaccharide can be selected from the group consisting of starch hydrolyzates, inulin, hydroxyethyl starch, xylan and dextrans.
As a polyamino acid, it is preferred to use polyaspartic acid or polyglutamic acid.
According to a further advantageous embodiment of the invention, the solution 2 additionally contains a polycation selected from the group consisting of polylysine, polyvinylamine, poly-a,~i-(2-2dimethylaminoethyl~
D,L-aspartamide, aminated polysaccharides, such as, for example, aminated dextrans, cyclodextrins, cellulose ethers, starches, pectins, and their hydrophobically substituted derivatives.
The release can moreover be produced by reacting the microcapsules, after preparation of the particles, in an additional process step with a crosslinker selected from the group consisting of glyoxal, glutaraldehyde, succinaldehyde, or dicarboxylic acids, such as, for example, oxalic acid, succinic acid, fumaric acid, malefic acid, malic acid, glutaric acid, adipic acid, 2,3-O-isopropylidenetartaric acid, diacid chlorides, such as, for example, succinyl chloride, fumaryl chloride, glutaryl chloride, adipoyl chloride, or tricarboxylic acids, such as, for example, citric acid, 1,2,3-propanetricarboxylic acids, hemimellitic acid, trimellitic acid, trimesic acid.
The atomization can be carried out using all suitable devices; atomization by means of an ultrasonic nozzle or an aerosol generator is particularly preferred.
The size of the microcapsules produced according to the invention is between 50 nm and 500 Vim, in particular between 100 nm and 150 Vim.
The following examples serve to illustrate the invention Example 1:
Preparation of the solution 1:
9 mg of sodium alginate from Sigma (catalog No.: A-7128) together with 6 mg of BSA-FITC (from Sigma, catalog No.: A-9771 ) are dissolved in 3 ml of 0.9% NaCI solution.
Preparation of the solution 2:
1500 ml of 1.0 M hydrochloric acid are heated to 90°C in a 4 I two-necked flask, equipped with a condenser. 60 g of chitosan (obtainable under the name chitosan from Fluka, catalog No.: 22743) are then slowly added with 5 stirring. After addition has taken place, the reaction mixture is stirred at 90°C for 4 hours and then filtered through a G2 frit. The filtrate obtained is allowed to stand overnight in a refrigerator at 2-8°C. The precipitate obtained in this way is isolated by centrifugation (Lobofuge GL from Heraeus; at 4500 rpm, 25 min). The residue is dissolved in water and freeze-dried with the aid of a freeze-drying device (LDC-1 m from Christ).
600 mg of the chitosan prepared in this way is dissolved in 30m1 of water together with 900 mg of CaCl2 (from Riedel deHaen, catalog No.: 12018).
Production of the microcapsules:
3 ml of the solution 1 are atomized at a working frequency of 58 kHz using an ultrasonic atomizer US2 from Lechler GmbH & Co. KG. With the aid of carrier air, the spray jet obtained is stabilized to give a spray cone of about 30° in order to prevent it from being possible for the spray jet to be influenced by the surrounding atmosphere. In this way, it can effectively be guaranteed that the drops can bridge relatively large distances. The size of the liquid droplets obtained in this way is 30 Vim.
This spray cone is directed, at a distance of the nozzle of 3 cm, onto a glass plate with the dimensions of 5 cm x 10 cm, which is inclined at 30° to the horizontal. The solution 2 at a rate of 30 Ilh is added above this glass plate with the aid of a peristaltic pump (from Cole-Parmer Instrument Co., model: Masterflex L/STM, tubing LISTM16, speed stage 7). The solution 2 is continuously recirculated in the course of this.
The liquid film comprising the microcapsules is collected in a beaker. After completion of the atomization process, the microcapsules are separated from the solution 2 by decantation, washed with 0.9% strength NaCI
solution and stored in this solution. The most widespread microparticle size is 90 Vim.
Determination of the release of active compound:
For the determination of the release properties of the capsules produced, BSA-FITC from Sigma (catalog No.: A-9771 ) is used as a model protein.
Further materials are: sodium alginate from Sigma (A-7128), chitosan from Fluka (22743), CaCl2 from Riedel de Haen (12018), NaCI from Merck (6404).
The release measurements are carried out in PBS buffer (Sigma, P4417), additionally using 0.005% timerosol (from Fluka, catalog No.: 71230).
After production, the PEC capsules are transferred to 10 ml of PBS buffer solution, in 15 ml rolled-rim vials, and the microcapsules are incubated at 37°C.
The BSA-FITC concentration is measured by means of a UV/VIS
spectrophotometer from Beckmann (DU 70). First, the proportion of included BSA-FITC is determined by determining the BSA-FITC
concentration in the combined supernatants. The concentration is determined by measurement of the absorption at 494 nm using a calibration curve. Falsification of the measurement by the intrinsic coloration of the chitosan is circumvented by subtracting the absorption of the chitosan. From the amount of BSA-FITC employed, it can be calculated how much.
The release measurement is carried out by removing 3 ml from the incubation solution and determining the BSA-FITC concentration in this supernatant. After completion of the measurement, the sample solution is combined again with the release sample. The microcapsules obtained in this way showed that only 44% of the encapsulated active compound was released after 30 days.
Example 2 (high-molecular weight chitosan):
The procedure is carried out analogously to Example 1, but the solution 2 is prepared as follows: 90 mg of high-molecular weight chitosan (from Fluka, catalog No.: 22743) is dissolved in 30 ml of water together with 900 mg of CaCl2 (from Riedel deHaen, catalog No.: 12018) and approximately 100 ~I of acetic acid (Riedel deHaen). The most widespread size of the microcapsules obtained in this way is 90 Vim; the release of active compound after 30 days is only 38% of the active compound encapsulated.
Example 3 (crosslinking using glyoxal):
The procedure is carried out analogously to Example 1. After the production of the microparticles, the particles are crosslinked using glyoxal.
For this, the microparticles are introduced into 10 ml of a 2% strength by weight solution for 30 minutes and allowed to stand. They are then washed with 0.9% NaCI solution.
The most widespread size of the microcapsules contained in this way is 90 Vim.
Example 4 (aftertreatment with pentosan polysulfate) The procedure is carried out analogously to Example 1. After the production of the microparticles, the particles are treated with a polyanion solution. The particles are introduced into 20 ml of a 2% by weight pentosan polysulfate solution (pentosan polysulfate from Sigma, catalog No.: P8275) and allowed to stand for 30 minutes. They are then washed with 0.9% NaCI solution.
The most widespread size of the microcapsules obtained in this way is 90 Vim; the release of active compound after 30 days is only 20% of the encapsulated active compound.
Example 5 (nanoparticles):
The procedure is carried out analogously to Example 1, but the solution 1 is atomized by a "Pari Inhalierboy" aerosol generator from Pari GmbH. The size of the liquid droplets obtained in this way is less than 5 Vim. The most widespread microparticle size of the microcapsules produced is 300 nm.
Example 6 (comparative examplej:
The procedure is carried out analogously to Example 1, but 30 ml of the solution 2 are introduced into a 250 ml beaker. 3 ml of the solution 1 are atomized using a US2 ultrasonic atomizer from Lechler GmbH & Co. KG
having a working frequency of 58 kHz. With the aid of carrier air, the spray jet obtained is stabilized to a spray cone of about 30° and directed into the beaker. In this case, caking was observed on the surface of solution 2, which is to be attributed to uncontrolled crosslinking between alginate and chitosan. No microcapsules were obtained.
Description of the figures The following figures show a determination of the particle size distribution of the microcapsules, produced according to Example 1 (ultrasonic generator) - Figure 1 - and Example 5 (aerosol generator) - Figure 2 -. In the case of Example 1, the particle size was determined by Frauenhofer diffraction (Cilas granulometer, Cilas 920); in the case of Example 5 by dynamic light scattering (Malvern Instruments, Mastersizer Microplus).
US-A-5 484 721 describes a process for the production of capsules containing microorganisms. For this, the aqueous solution containing the polyanion is atomized by means of compressed air and a spray nozzle and the liquid droplets thus obtained are introduced into a liquid film which contains calcium or potassium ions as crosslinkers. The size of the microcapsules produced according to this publication is specified as between 10 ~m and 4 mm. However, these microcapsules are not suitable for the encapsulation of active compounds which are to be released in a delayed manner.
US-A-5 589 370 relates to the production of microcapsules by salting out polymers. The microparticles produced in this way, however, dissolve immediately, as soon as they are added to water. To this extent, they are not suitable for the production of depot preparations.
The object of the present invention consists in the provision of a process for the production of microcapsules which are suitable for the production of depot preparations having delayed release, and which can be produced in such a size that they can also be used for the parenteral administration of depot preparations.
This object is achieved by a process for the production of microcapsules by atomization of an aqueous solution 1, which contains 0.1 to 5% by weight of at least one water-soluble polyanion, to give liquid droplets, the liquid droplets thus obtained impinging onto a flowing film of an aqueous solution 2, containing:
~ 0.1 to 5% by weight of calcium cations; and ~ 0.001 to 0.4% by weight of chitosan having a number-average molecular weight of greater than 40,000 g/mol; andlor ~ 0.1 to 5% by weight of chitosan having a number-average molecular weight of between 500 and 40,000 g/mol.
The microcapsules produced according to the process according to the invention have a particularly stable crosslinkage of the outer shell, which is especially to be attributed to the simultaneous use of calcium cations and polycations as crosslinking agents. On account of this property, these microcapsules are particularly suitable for the encapsulation of active substances for the production of depot preparations.
The process according to the invention additionally has the advantage that no agglomeration or caking of the microcapsules occurs, as is the case, for example, when the solution 1 atomized by means of ultrasound is sprayed into a stirred precipitation bath of the solution 2.
The film can flows over a fixed substrate according to the process according to the invention, the substrate preferably not being arranged horizontally. According to a particularly preferred embodiment, the substrate forms an inclined or a vertical plane.
It has proven advantageous if the water-soluble polyanion is an alginate, in particular an alginate having a high guluronic acid content.
The water-soluble polyanion, however, can also be selected from the group consisting of carrageenan, sulfated polysaccharides, gelatin and agar-agar.
According to a particularly preferred embodiment of the present invention, the solution 1 additionally contains at least one polyacid or its alkali metal salt, selected from the group consisting of polyamino acids, poly-phosphates and polysulfates of polysaccharides.
Preferred examples of a polyphosphate are sodium polyphosphate and a polyphosphate of a polysaccharide.
WO 99/48480 PCTlEP99/01626 The polysaccharide can be selected from the group consisting of starch hydrolyzates, inulin, hydroxyethyl starch, xylan and dextrans.
As a polyamino acid, it is preferred to use polyaspartic acid or polyglutamic acid.
According to a further advantageous embodiment of the invention, the solution 2 additionally contains a polycation selected from the group consisting of polylysine, polyvinylamine, poly-a,~i-(2-2dimethylaminoethyl~
D,L-aspartamide, aminated polysaccharides, such as, for example, aminated dextrans, cyclodextrins, cellulose ethers, starches, pectins, and their hydrophobically substituted derivatives.
The release can moreover be produced by reacting the microcapsules, after preparation of the particles, in an additional process step with a crosslinker selected from the group consisting of glyoxal, glutaraldehyde, succinaldehyde, or dicarboxylic acids, such as, for example, oxalic acid, succinic acid, fumaric acid, malefic acid, malic acid, glutaric acid, adipic acid, 2,3-O-isopropylidenetartaric acid, diacid chlorides, such as, for example, succinyl chloride, fumaryl chloride, glutaryl chloride, adipoyl chloride, or tricarboxylic acids, such as, for example, citric acid, 1,2,3-propanetricarboxylic acids, hemimellitic acid, trimellitic acid, trimesic acid.
The atomization can be carried out using all suitable devices; atomization by means of an ultrasonic nozzle or an aerosol generator is particularly preferred.
The size of the microcapsules produced according to the invention is between 50 nm and 500 Vim, in particular between 100 nm and 150 Vim.
The following examples serve to illustrate the invention Example 1:
Preparation of the solution 1:
9 mg of sodium alginate from Sigma (catalog No.: A-7128) together with 6 mg of BSA-FITC (from Sigma, catalog No.: A-9771 ) are dissolved in 3 ml of 0.9% NaCI solution.
Preparation of the solution 2:
1500 ml of 1.0 M hydrochloric acid are heated to 90°C in a 4 I two-necked flask, equipped with a condenser. 60 g of chitosan (obtainable under the name chitosan from Fluka, catalog No.: 22743) are then slowly added with 5 stirring. After addition has taken place, the reaction mixture is stirred at 90°C for 4 hours and then filtered through a G2 frit. The filtrate obtained is allowed to stand overnight in a refrigerator at 2-8°C. The precipitate obtained in this way is isolated by centrifugation (Lobofuge GL from Heraeus; at 4500 rpm, 25 min). The residue is dissolved in water and freeze-dried with the aid of a freeze-drying device (LDC-1 m from Christ).
600 mg of the chitosan prepared in this way is dissolved in 30m1 of water together with 900 mg of CaCl2 (from Riedel deHaen, catalog No.: 12018).
Production of the microcapsules:
3 ml of the solution 1 are atomized at a working frequency of 58 kHz using an ultrasonic atomizer US2 from Lechler GmbH & Co. KG. With the aid of carrier air, the spray jet obtained is stabilized to give a spray cone of about 30° in order to prevent it from being possible for the spray jet to be influenced by the surrounding atmosphere. In this way, it can effectively be guaranteed that the drops can bridge relatively large distances. The size of the liquid droplets obtained in this way is 30 Vim.
This spray cone is directed, at a distance of the nozzle of 3 cm, onto a glass plate with the dimensions of 5 cm x 10 cm, which is inclined at 30° to the horizontal. The solution 2 at a rate of 30 Ilh is added above this glass plate with the aid of a peristaltic pump (from Cole-Parmer Instrument Co., model: Masterflex L/STM, tubing LISTM16, speed stage 7). The solution 2 is continuously recirculated in the course of this.
The liquid film comprising the microcapsules is collected in a beaker. After completion of the atomization process, the microcapsules are separated from the solution 2 by decantation, washed with 0.9% strength NaCI
solution and stored in this solution. The most widespread microparticle size is 90 Vim.
Determination of the release of active compound:
For the determination of the release properties of the capsules produced, BSA-FITC from Sigma (catalog No.: A-9771 ) is used as a model protein.
Further materials are: sodium alginate from Sigma (A-7128), chitosan from Fluka (22743), CaCl2 from Riedel de Haen (12018), NaCI from Merck (6404).
The release measurements are carried out in PBS buffer (Sigma, P4417), additionally using 0.005% timerosol (from Fluka, catalog No.: 71230).
After production, the PEC capsules are transferred to 10 ml of PBS buffer solution, in 15 ml rolled-rim vials, and the microcapsules are incubated at 37°C.
The BSA-FITC concentration is measured by means of a UV/VIS
spectrophotometer from Beckmann (DU 70). First, the proportion of included BSA-FITC is determined by determining the BSA-FITC
concentration in the combined supernatants. The concentration is determined by measurement of the absorption at 494 nm using a calibration curve. Falsification of the measurement by the intrinsic coloration of the chitosan is circumvented by subtracting the absorption of the chitosan. From the amount of BSA-FITC employed, it can be calculated how much.
The release measurement is carried out by removing 3 ml from the incubation solution and determining the BSA-FITC concentration in this supernatant. After completion of the measurement, the sample solution is combined again with the release sample. The microcapsules obtained in this way showed that only 44% of the encapsulated active compound was released after 30 days.
Example 2 (high-molecular weight chitosan):
The procedure is carried out analogously to Example 1, but the solution 2 is prepared as follows: 90 mg of high-molecular weight chitosan (from Fluka, catalog No.: 22743) is dissolved in 30 ml of water together with 900 mg of CaCl2 (from Riedel deHaen, catalog No.: 12018) and approximately 100 ~I of acetic acid (Riedel deHaen). The most widespread size of the microcapsules obtained in this way is 90 Vim; the release of active compound after 30 days is only 38% of the active compound encapsulated.
Example 3 (crosslinking using glyoxal):
The procedure is carried out analogously to Example 1. After the production of the microparticles, the particles are crosslinked using glyoxal.
For this, the microparticles are introduced into 10 ml of a 2% strength by weight solution for 30 minutes and allowed to stand. They are then washed with 0.9% NaCI solution.
The most widespread size of the microcapsules contained in this way is 90 Vim.
Example 4 (aftertreatment with pentosan polysulfate) The procedure is carried out analogously to Example 1. After the production of the microparticles, the particles are treated with a polyanion solution. The particles are introduced into 20 ml of a 2% by weight pentosan polysulfate solution (pentosan polysulfate from Sigma, catalog No.: P8275) and allowed to stand for 30 minutes. They are then washed with 0.9% NaCI solution.
The most widespread size of the microcapsules obtained in this way is 90 Vim; the release of active compound after 30 days is only 20% of the encapsulated active compound.
Example 5 (nanoparticles):
The procedure is carried out analogously to Example 1, but the solution 1 is atomized by a "Pari Inhalierboy" aerosol generator from Pari GmbH. The size of the liquid droplets obtained in this way is less than 5 Vim. The most widespread microparticle size of the microcapsules produced is 300 nm.
Example 6 (comparative examplej:
The procedure is carried out analogously to Example 1, but 30 ml of the solution 2 are introduced into a 250 ml beaker. 3 ml of the solution 1 are atomized using a US2 ultrasonic atomizer from Lechler GmbH & Co. KG
having a working frequency of 58 kHz. With the aid of carrier air, the spray jet obtained is stabilized to a spray cone of about 30° and directed into the beaker. In this case, caking was observed on the surface of solution 2, which is to be attributed to uncontrolled crosslinking between alginate and chitosan. No microcapsules were obtained.
Description of the figures The following figures show a determination of the particle size distribution of the microcapsules, produced according to Example 1 (ultrasonic generator) - Figure 1 - and Example 5 (aerosol generator) - Figure 2 -. In the case of Example 1, the particle size was determined by Frauenhofer diffraction (Cilas granulometer, Cilas 920); in the case of Example 5 by dynamic light scattering (Malvern Instruments, Mastersizer Microplus).
Claims (15)
1. A process for the production of microcapsules by atomization of an aqueous solution 1 which contains 0.1 to 5% by weight of at least one water-soluble polyanion to give liquid droplets, the liquid droplets thus obtained impinging onto a fine film of an aqueous solution 2, comprising:
~ 0.1 to 5% by weight of calcium cations; and ~ 0.001 to 0.4% by weight of chitosan having a number-average molecular weight of greater than 40,000 g/mol;
and/or ~ 0.1 to 5% by weight of chitosan having a number-average molecular weight of between 500 and 40,000 g/mol.
~ 0.1 to 5% by weight of calcium cations; and ~ 0.001 to 0.4% by weight of chitosan having a number-average molecular weight of greater than 40,000 g/mol;
and/or ~ 0.1 to 5% by weight of chitosan having a number-average molecular weight of between 500 and 40,000 g/mol.
2. The process as claimed in claim 1, wherein the film flows over a fixed substrate.
3. The process as claimed in claim 2, wherein the substrate is not arranged horizontally.
4. The process as claimed in claim 3, wherein the substrate forms an inclined plane.
5. The process as claimed in claim 3, wherein the substrate forms a vertical plane.
6. The process as claimed in one of the preceding claims, wherein the water-soluble polyanion [lacuna] an alginate, in particular an alginate having a high guluronic acid content.
7. The process as claimed in one of the preceding claims, wherein the water-soluble polyanion is selected from the group consisting of carrageenan, sulfated polysaccharides, gelatin and agar-agar.
8. The process as claimed in one of the preceding claims, wherein the solution 1 additionally contains at least one polyacid or its alkali metal salts, selected from the group consisting of polyamino acids, polyphosphates and polysulfates of polysaccharides.
9. The process as claimed in claim 8, wherein the polyphosphate is sodium polyphosphate or a polyphosphate of a polysaccharide.
10. The process as claimed in claim 8 or 9, wherein the polysaccharide is selected from the group consisting of starch hydrolyzates, inulin, hydroxyethyl starch, xylan and dextrans.
11. The process as claimed in claim 8, wherein the polyamino acid is polyaspartic acid or polyglutamic acid.
12. The process as claimed in one of the preceding claims, wherein the solution 2 additionally contains a polycation selected from the group consisting of polylysine, polyvinylamine, poly-.alpha.,.beta.-(2-2dimethyl-aminoethyl)-D,L-aspartamide, aminated polysaccharides, such as, for example, aminated dextrans, cyclodextrins, cellulose ethers, starches, pectins, and their hydrophobically substituted derivatives.
13. The process according to one of the preceding claims, wherein the microcapsules are reacted in an additional process step with a crosslinker selected from the group consisting of glyoxal, glutaraldehyde, succinaldehyde, or dicarboxylic acids, such as, for example, oxalic acid, succinic acid, fumaric acid, maleic acid, malic acid, glutaric acid, adipic acid, 2,3-O-isopropylidenetartaric acid, diacid chlorides, such as, for example, succinyl chloride, fumaryl chloride, glutaryl chloride, adipoyl chloride or tricarboxylic acids, such as, for example, citric acid, 1,2,3-propanetricarboxylic acids, hemimellitic acid, trimellitic acid, trimesic acid.
14. The process as claimed in one of the preceding claims, wherein the atomization is carried out by means of an ultrasonic nozzle or an aerosol generator.
15. The process as claimed in one of the preceding claims, wherein the size of the microcapsules is between 50 nm and 500 µm, in particular between 100 nm and 150 µm.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19813011.2 | 1998-03-25 | ||
| DE1998113011 DE19813011A1 (en) | 1998-03-25 | 1998-03-25 | Process for the production of microcapsules |
| PCT/EP1999/001626 WO1999048480A2 (en) | 1998-03-25 | 1999-03-12 | Method for the production of micro capsules |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2325420A1 true CA2325420A1 (en) | 1999-09-30 |
Family
ID=7862190
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002325420A Abandoned CA2325420A1 (en) | 1998-03-25 | 1999-03-12 | Method for the production of microcapsules |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1066031A2 (en) |
| JP (1) | JP2002507473A (en) |
| AU (1) | AU733233B2 (en) |
| CA (1) | CA2325420A1 (en) |
| DE (1) | DE19813011A1 (en) |
| WO (1) | WO1999048480A2 (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10008305A1 (en) * | 2000-02-23 | 2001-09-06 | Henkel Kgaa | Micro- and nano-capsules with cationic charges on surface are used in laundry and other detergents, skin cleansers, shampoos and skin and hair cosmetics |
| FR2843965A1 (en) * | 2002-08-28 | 2004-03-05 | Rhodia Chimie Sa | New powder particles based on associative, amphiphilic polysaccharide, preferably alginate, useful for encapsulation of peptides, polypeptides or proteins, e.g. enzymes for use in detergents |
| US7578951B2 (en) * | 2004-01-27 | 2009-08-25 | Hewlett-Packard Development Company, L.P. | Method of making microcapsules utilizing a fluid ejector |
| JP2005220068A (en) * | 2004-02-05 | 2005-08-18 | Toppan Printing Co Ltd | Coating agent for oral material |
| CN100400580C (en) * | 2005-12-20 | 2008-07-09 | 武汉大学 | Polyelectrolyte polysaccharose nano paticle and preparation process thereof |
| CN100391540C (en) * | 2006-02-16 | 2008-06-04 | 武汉理工大学 | Prepn process of nanometer carboxymethyl chitosan particle as medicine carrier |
| JP5691273B2 (en) * | 2009-07-23 | 2015-04-01 | Jnc株式会社 | Liquid crystal alignment agent, liquid crystal alignment film, and liquid crystal display element |
| WO2016108234A1 (en) * | 2014-12-30 | 2016-07-07 | Yissum Research Develoment Company Of The Hebrew University Of Jerusalem Ltd. | Liquid-core capsules comprising non-crosslinked alginate |
| KR101970470B1 (en) * | 2017-10-27 | 2019-04-19 | 충남대학교산학협력단 | Core shell particle generator using spraying and drying method |
| CN113981555A (en) * | 2021-12-07 | 2022-01-28 | 罗莱生活科技股份有限公司 | Aromatic regenerated cellulose fiber, fabric and preparation method |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4352883A (en) * | 1979-03-28 | 1982-10-05 | Damon Corporation | Encapsulation of biological material |
| US4390484A (en) * | 1981-04-29 | 1983-06-28 | Ortho Diagnostics, Inc. | Methods for promoting the formation of microparticles |
| FR2668081B1 (en) * | 1990-10-19 | 1994-11-18 | Lvmh Rech | METHOD AND APPARATUS FOR MANUFACTURING SOLID PARTICLES FROM A SOLIDIFIABLE MATERIAL IN THE PRESENCE OF A SOLIDIFYING AGENT IN GOOD YIELDS. |
| US5589370A (en) * | 1995-08-01 | 1996-12-31 | Lever Brothers Company, Division Of Conopco, Inc. | Process for encapsulating sensitive materials |
-
1998
- 1998-03-25 DE DE1998113011 patent/DE19813011A1/en not_active Withdrawn
-
1999
- 1999-03-12 CA CA002325420A patent/CA2325420A1/en not_active Abandoned
- 1999-03-12 EP EP99914516A patent/EP1066031A2/en not_active Withdrawn
- 1999-03-12 JP JP2000537530A patent/JP2002507473A/en active Pending
- 1999-03-12 AU AU33306/99A patent/AU733233B2/en not_active Ceased
- 1999-03-12 WO PCT/EP1999/001626 patent/WO1999048480A2/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO1999048480A3 (en) | 1999-11-25 |
| DE19813011A1 (en) | 1999-10-14 |
| JP2002507473A (en) | 2002-03-12 |
| EP1066031A2 (en) | 2001-01-10 |
| AU3330699A (en) | 1999-10-18 |
| WO1999048480A2 (en) | 1999-09-30 |
| AU733233B2 (en) | 2001-05-10 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |