WO1999048480A2 - Verfahren zur herstellung von mikrokapseln - Google Patents
Verfahren zur herstellung von mikrokapseln Download PDFInfo
- Publication number
- WO1999048480A2 WO1999048480A2 PCT/EP1999/001626 EP9901626W WO9948480A2 WO 1999048480 A2 WO1999048480 A2 WO 1999048480A2 EP 9901626 W EP9901626 W EP 9901626W WO 9948480 A2 WO9948480 A2 WO 9948480A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acid
- microcapsules
- solution
- group
- weight
- Prior art date
Links
Classifications
-
- 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
-
- 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
Definitions
- the present invention relates to an improved method for producing microcapsules.
- Microcapsules are produced by encapsulating finely dispersed liquid phases by coating them with film-forming polymers. Microcapsules are used primarily in the field of depot preparations, according to which the active ingredient contained in the microcapsules is protected by the shell of the microcapsule and is not released immediately but only with a delayed release.
- US Pat. No. 4,352,883 describes a two-stage process for producing microcapsules in which living cells, such as, for example, Langerhans islet cells, are encapsulated.
- living cells such as, for example, Langerhans islet cells
- the living cells are suspended in sodium alginate and this suspension is sprayed into a precipitation bath which contains polyvalent cations (for example Ca + ).
- polyvalent cations for example Ca +
- the capsules produced in this way are mixed with a cationic polymer, which brings about further physical crosslinking.
- poly-lenimine and polylysine are mentioned as polycations.
- US-A-5 389 379 discloses a method for producing microcapsules in which the liquid droplets produced by means of an ultrasound nozzle are first introduced into a liquid in which the liquid droplets are not soluble (for example in ethanol). Then this liquid is replaced by water replaced.
- This elaborate 2-stage process is chosen because it is not possible to introduce the liquid droplets directly, since otherwise a thin polymer film is formed on the water surface instead of the microcapsules.
- the size of the microcapsules formed in this way is given as 10 to 1000 ⁇ m.
- US Pat. No. 5,472,648 describes a process for the production of microcapsules, small droplets of liquid being produced from an alginate solution by means of ultrasound and injected into a vessel with a CaCl 2 solution. After the liquid droplets in this CaCl 2 solution (precipitation bath) have hardened, the microcapsules obtained in this way are brought out of the CaCl 2 solution using a conveyor device (belt sieve).
- a conveyor device belt sieve.
- the size of the microcapsules obtainable in this way is given as 100 to 4000 ⁇ m.
- US-A-5 484 721 describes a process for the preparation of microcapsules containing microorganisms.
- the aqueous solution containing the polyanion is atomized by means of air pressure and a spray nozzle, and the liquid droplets thus obtained are introduced into a liquid film which contains calcium or potassium ions as crosslinking agent.
- the size of the microcapsules produced according to this publication is between 10 ⁇ m and 4 mm.
- these microcapsules are not suitable for encapsulating active substances that are to be released after a delay.
- US-A-5 589 370 relates to the production of microparticles by salting out polymers.
- the microparticles produced in this way dissolve as soon as they are placed in water. In this respect, they are not suitable for the production of depot preparations.
- the object of the present invention is to provide a process for the production of microcapsules which are suitable for the production of sustained release preparations and which can be produced in such a size that they can also be used for the parenteral administration of sustained release preparations can be used.
- This object is achieved by a process for the production of microcapsules by atomizing an aqueous solution 1, which contains 0.1 to 5% by weight of at least one water-soluble polyanion, into liquid droplets, the liquid droplets thus obtained being applied to a flowing film of an aqueous one Impact solution 2 containing:
- chitosan with a number average molecular weight greater than 40,000 g / mol; and / or • 0.1 to 5% by weight of chitosan with a number average molecular weight between 500 and 40,000 g / mol.
- microcapsules produced in accordance with the method according to the invention have a particularly stable crosslinking of the outer shell, which is primarily due to the simultaneous use of calcium cations and polycations as crosslinking agents. Because of this property, these microcapsules are particularly suitable for the encapsulation of active substances for the manufacture of depot preparations.
- the process according to the invention has the further advantage that there is no agglomeration or clumping of the microcapsules, as is the case, for example, when spraying solution 1 atomized by means of ultrasound into a stirred precipitation bath from solution 2.
- the film can flow over a fixed substrate, the substrate preferably not being arranged horizontally. is not.
- the substrate forms an inclined or a vertical plane.
- the water-soluble polyanion is an alginate, in particular an alginate with a high guluronic acid content.
- the water-soluble polyanion can also be selected from the group of carrageenan, sulfated polysaccharides, gelatin and agar.
- solution 1 additionally contains at least one polyacid or its alkali salt, selected from the group of polyamino acids, polyphosphates and
- Preferred examples of a polyphosphate are sodium polyphosphate and a polyphosphate of a polysaccharide.
- the polysaccharide can be selected from the group of starch hydrolyzates,
- Polyaspartic acid or polyglutamic acid is preferably used as the polyamino acid.
- solution 2 additionally contains a polycation selected from the group of polylysine, polyvinylamine, poly-, ⁇ - (2-2dimethylaminoethyl) -D, L-aspartamide, aminated polysaccharides, such as e.g. aminated dextrans, cyclodextrins, cellulose ethers, starches, pectins, and their hydrophobically substituted derivatives.
- a polycation selected from the group of polylysine, polyvinylamine, poly-, ⁇ - (2-2dimethylaminoethyl) -D, L-aspartamide, aminated polysaccharides, such as e.g. aminated dextrans, cyclodextrins, cellulose ethers, starches, pectins, and their hydrophobically substituted derivatives.
- the release can also be reduced by reacting the microcapsules with a crosslinker in an additional process step, selected from the group of glyoxal, glutardialdehyde, succinic acid dialdehyde, or dicarboxylic acids, such as oxalic acid, succinic acid, fumaric acid, maleic acid, in an additional process step.
- a crosslinker selected from the group of glyoxal, glutardialdehyde, succinic acid dialdehyde, or dicarboxylic acids, such as oxalic acid, succinic acid, fumaric acid, maleic acid, in an additional process step.
- Malic acid, glutaric acid, adipic acid, 2,3-0-isopropylidene tartaric acid, diacid chlorides such as, for example, succinic acid chloride, fumaric acid chloride, glutaric acid chloride, adipic acid chloride, or tricarboxylic acid ren, such as citric acid, 1, 2,3-propane tricarboxylic acid, hemimellitic acid, trimellitic acid, trimesic acid.
- the atomization can take place with all suitable devices, atomization by means of an ultrasound nozzle or an aerosol generator is particularly preferred.
- the size of the microcapsules produced according to the invention is between 50 nm and 500 ⁇ m, in particular between 100 nm and 150 ⁇ m.
- 3 ml of solution 1 are atomized with an ultrasonic atomizer US2 from Lechler GmbH & Co. KG with a working frequency of 58 kHz.
- the spray jet obtained is stabilized to a spray cone of approximately 30 ° in order to prevent the spray jet from being influenced by the ambient atmosphere. In this way it can be effectively ensured that the drops can bridge larger distances.
- the size of the liquid droplets obtained in this way is 30 ⁇ m.
- This spray cone, with a distance of the nozzle of 3 cm, is directed onto a glass plate with the dimensions of 5 cm x 10 cm, which is inclined horizontally by 30 °.
- Solution 2 in an amount of 30 l / h is added to this glass plate using a peristaltic pump (from Cole-Parmer Instrument Co., model: Masterflex US TM, hose L / S TM 16, speed level 7). Solution 2 is constantly pumped around.
- the liquid film containing the microcapsules is collected in a beaker. After the atomization process has ended, the microcapsules are separated from solution 2 by decanting, washed with 0.9% NaCl solution and stored in this solution. The most common microparticle size is 90 ⁇ m.
- the model protein BSA-FITC from Sigma (catalog number: A-9771) is used.
- Other materials are: sodium alginate from Sigma (A-7128), chitosan from Fluka (22743), CaCI 2 from Riedel de Haen (12018), NaCI from Merck (6404).
- the release measurements are carried out in PBS buffer (Sigma, P4417) with an additional 0.005% timerosol (from Fluka, catalog no .: 71230). After production, the PEC capsules are transferred to 10 ml PBS buffer solution, in 15 ml crimp-top vials, and the microcapsules are incubated at 37 ° C.
- the BSA-FITC concentration was measured using a UV / VIS spectrophotomer from Beckmann (DU 70).
- the proportion of trapped BSA-FITC is first determined by determining the BSA-FITC concentration in the combined supernatants. The concentration is determined by measuring the absorption at 494 nm using a calibration curve. A falsification of the measurement by the intrinsic coloration of the chitosan is avoided by subtracting the absorption of the chitosan.
- the amount of BSA-FITC used can be used to calculate how much of the BSA-FITC was included.
- the release measurement is carried out by taking 3 ml from the incubation solution and determining the BSA-FITC concentration on this supernatant. After the measurement is completed, the sample solution is combined with the release sample. The microcapsules obtained in this way showed that after 30 days only 44% of the encapsulated active ingredient were released.
- solution 2 is prepared as follows: 90 mg of high molecular weight chitosan (from Fluka, catalog no .: 22743) is mixed with 900 mg of CaCI 2 (from Riedel deHaen, catalog no .: 12018) and about 100 ⁇ l acetic acid (Riedel deHaen,) dissolved in 30 ml water.
- the most common size of the microcapsules obtained in this way is 90 ⁇ m; the drug release after 30 days is only 38% of the encapsulated drug.
- Example 4 After the microparticle production, the particles are crosslinked with glyoxal. For this purpose, the microparticles are placed in 10 ml of a 2% by weight solution for 30 minutes and left to stand. Then they are washed with 0.9% NaCl solution. The most common size of the microcapsules obtained in this way is 90 ⁇ m.
- Example 4 aftertreatment with pentosan polysulfate)
- Example 2 The procedure is analogous to Example 1. After the microparticle production, the particles are mixed with a polyanion solution. The particles are placed in 20 ml of a 2% by weight pentosan polysulfate solution (pentosan polysulfate from Sigma, catalog number: P8275) for 30 minutes and left to stand. Then they are washed with 0.9% NaCl solution.
- pentosan polysulfate solution pentosan polysulfate from Sigma, catalog number: P8275
- the most common size of the microcapsules obtained in this way is 90 ⁇ m; the active ingredient release after 30 days is only 20% of the encapsulated active ingredient.
- Example 2 The procedure is analogous to Example 1, but 30 ml of solution 2 are placed in a 250 ml beaker. 3 ml of solution 1 are atomized with a US2 ultrasonic atomizer from Lechler GmbH & Co. KG with a working frequency of 58 kHz. With the help of carrier air, the spray jet obtained is stabilized to a spray cone of approximately 30 ° and directed into the beaker. A clumping was observed on the surface of solution 2, which is due to an uncontrolled crosslinking between alginate and chitosan. No microcapsules could be obtained.
- Example 1 ultrasonic generator
- Example 5 aerosol generator
- the particle size was determined by means of Oberhof diffraction (Cilas Granulometer, Cilas 920), in the case of game 5 determined by dynamic light scattering (Maivern Instruments, Mastersizer Microplus).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Dispersion Chemistry (AREA)
- Manufacturing Of Micro-Capsules (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000537530A JP2002507473A (ja) | 1998-03-25 | 1999-03-12 | マイクロカプセルの製造法 |
CA002325420A CA2325420A1 (en) | 1998-03-25 | 1999-03-12 | Method for the production of microcapsules |
AU33306/99A AU733233B2 (en) | 1998-03-25 | 1999-03-12 | Process for the production of microcapsules |
EP99914516A EP1066031A2 (de) | 1998-03-25 | 1999-03-12 | Verfahren zur herstellung von mikrokapseln |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE1998113011 DE19813011A1 (de) | 1998-03-25 | 1998-03-25 | Verfahren zur Herstellung von Mikrokapseln |
DE19813011.2 | 1998-03-25 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1999048480A2 true WO1999048480A2 (de) | 1999-09-30 |
WO1999048480A3 WO1999048480A3 (de) | 1999-11-25 |
Family
ID=7862190
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1999/001626 WO1999048480A2 (de) | 1998-03-25 | 1999-03-12 | Verfahren zur herstellung von mikrokapseln |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP1066031A2 (de) |
JP (1) | JP2002507473A (de) |
AU (1) | AU733233B2 (de) |
CA (1) | CA2325420A1 (de) |
DE (1) | DE19813011A1 (de) |
WO (1) | WO1999048480A2 (de) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10008305A1 (de) * | 2000-02-23 | 2001-09-06 | Henkel Kgaa | Mittel zur Reinigung und Pflege von Haut und/oder Haaren |
FR2843965A1 (fr) * | 2002-08-28 | 2004-03-05 | Rhodia Chimie Sa | Particules sous forme de poudre et dispersions a base d'alginate modifie, et leurs procedes de preparation |
CN100391540C (zh) * | 2006-02-16 | 2008-06-04 | 武汉理工大学 | 一种药物载体羧甲基壳聚糖纳米粒的制备方法 |
CN100400580C (zh) * | 2005-12-20 | 2008-07-09 | 武汉大学 | 一种聚电解质多糖纳米粒子及其制备方法 |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7578951B2 (en) | 2004-01-27 | 2009-08-25 | Hewlett-Packard Development Company, L.P. | Method of making microcapsules utilizing a fluid ejector |
JP2005220068A (ja) * | 2004-02-05 | 2005-08-18 | Toppan Printing Co Ltd | 経口物用コーティング剤 |
JP5691273B2 (ja) * | 2009-07-23 | 2015-04-01 | Jnc株式会社 | 液晶配向剤、液晶配向膜及び液晶表示素子 |
US10413515B2 (en) | 2014-12-30 | 2019-09-17 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Liquid-core capsules comprising non-crosslinked alginate |
KR101970470B1 (ko) * | 2017-10-27 | 2019-04-19 | 충남대학교산학협력단 | 분무건조 방식을 이용한 에어로졸 입자 생성장치 |
CN113981555A (zh) * | 2021-12-07 | 2022-01-28 | 罗莱生活科技股份有限公司 | 一种芳香型再生纤维素纤维、面料及制备方法 |
Citations (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 |
US5484721A (en) * | 1990-10-19 | 1996-01-16 | Lvmh Recherche | Process and apparatus for forming solid particles by cross-linking drops of a cross-linkable material with a free-falling stream of cross-linking agent |
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/de not_active Withdrawn
-
1999
- 1999-03-12 JP JP2000537530A patent/JP2002507473A/ja active Pending
- 1999-03-12 CA CA002325420A patent/CA2325420A1/en not_active Abandoned
- 1999-03-12 AU AU33306/99A patent/AU733233B2/en not_active Ceased
- 1999-03-12 WO PCT/EP1999/001626 patent/WO1999048480A2/de not_active Application Discontinuation
- 1999-03-12 EP EP99914516A patent/EP1066031A2/de not_active Withdrawn
Patent Citations (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 |
US5484721A (en) * | 1990-10-19 | 1996-01-16 | Lvmh Recherche | Process and apparatus for forming solid particles by cross-linking drops of a cross-linkable material with a free-falling stream of cross-linking agent |
US5589370A (en) * | 1995-08-01 | 1996-12-31 | Lever Brothers Company, Division Of Conopco, Inc. | Process for encapsulating sensitive materials |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10008305A1 (de) * | 2000-02-23 | 2001-09-06 | Henkel Kgaa | Mittel zur Reinigung und Pflege von Haut und/oder Haaren |
FR2843965A1 (fr) * | 2002-08-28 | 2004-03-05 | Rhodia Chimie Sa | Particules sous forme de poudre et dispersions a base d'alginate modifie, et leurs procedes de preparation |
CN100400580C (zh) * | 2005-12-20 | 2008-07-09 | 武汉大学 | 一种聚电解质多糖纳米粒子及其制备方法 |
CN100391540C (zh) * | 2006-02-16 | 2008-06-04 | 武汉理工大学 | 一种药物载体羧甲基壳聚糖纳米粒的制备方法 |
Also Published As
Publication number | Publication date |
---|---|
JP2002507473A (ja) | 2002-03-12 |
AU3330699A (en) | 1999-10-18 |
WO1999048480A3 (de) | 1999-11-25 |
EP1066031A2 (de) | 2001-01-10 |
AU733233B2 (en) | 2001-05-10 |
CA2325420A1 (en) | 1999-09-30 |
DE19813011A1 (de) | 1999-10-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO1999048479A1 (de) | Mikrokapseln mit verzögertem release | |
Desai et al. | Encapsulation of vitamin C in tripolyphosphate cross-linked chitosan microspheres by spray drying | |
EP0867177B1 (de) | Fliessfähige getrocknete Partikel | |
EP1066031A2 (de) | Verfahren zur herstellung von mikrokapseln | |
DE3615514A1 (de) | Mikrokapseln enthaltendes waessriges mittel und verfahren zu seiner herstellung | |
DE60011117T2 (de) | Hydrogel-mikrokügelchen mit einer sekundären schicht | |
Rosyada et al. | Characterization of chitosan nanoparticles as an edible coating material | |
DE69104576T2 (de) | Polysaccharid-enthaltendes Erzeugnis und dessen Verwendung. | |
Lascol et al. | Development of pectin microparticles by using ionotropic gelation with chlorhexidine as cross-linking agent | |
CN115282337B (zh) | 一种聚己内酯微球预分散组合物及由其制备的聚己内酯注射用凝胶 | |
Romita et al. | Microencapsulation of ferrous fumarate for the production of salt double fortified with iron and iodine | |
CN105055372A (zh) | 一种羧甲基魔芋葡甘聚糖纳米载药微球的制备方法 | |
EP1963000B1 (de) | Verfahren zur herstellung von teilchen aus einer emulsion in überkritischem oder flüssigem co2 | |
US20090117195A1 (en) | Hydrophilic Particles Based on Cationic Chitosan Derivatives | |
Mi et al. | Sustained-release of oxytetracycline from chitosan micro spheresprepared by interfacial acylation and spray hardening methods | |
CA2814184C (fr) | Poudre de polysaccharide et de polyol, comprimable et de haute viscosite | |
US4480089A (en) | Modified cellulose products by bleaching | |
WO2002017868A1 (de) | Mund- und zahnpflegemittel | |
DE60225560T2 (de) | Zusammensetzung enthaltend epigallocatechin-gallat | |
EP1562559B1 (de) | Bioabbaubare kolloidale partikel, insbesondere für pulmonale applikationen | |
DE102011055861B4 (de) | Verfahren zur Herstellung monodisperser Pektin-Mikrogele unter Verwendung eines mikrofluidischen Systems | |
JPS63210101A (ja) | キトサン又はキチン多孔質超微小粒状体の製造方法 | |
CA1062581A (en) | Method of making gels based on biologically produced saccharides | |
Morris et al. | An investigation into the effects of pH and material concentrations on the morphology of Chitosan-Alginate microspheres prepared using an Ionic Gelation technique. | |
Jain et al. | PREPARATION AND CHARACTERIZATION TECHNIQUES OF CHITOSAN MICROSPHERES. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AU CA JP US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
AK | Designated states |
Kind code of ref document: A3 Designated state(s): AU CA JP US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 1999914516 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 09646634 Country of ref document: US |
|
ENP | Entry into the national phase |
Ref document number: 2325420 Country of ref document: CA Ref country code: CA Ref document number: 2325420 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 33306/99 Country of ref document: AU |
|
WWP | Wipo information: published in national office |
Ref document number: 1999914516 Country of ref document: EP |
|
WWG | Wipo information: grant in national office |
Ref document number: 33306/99 Country of ref document: AU |
|
NENP | Non-entry into the national phase |
Ref country code: CA |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1999914516 Country of ref document: EP |