EP1292385A1 - Procede et installation pour produire des microcapsules membranaires - Google Patents

Procede et installation pour produire des microcapsules membranaires

Info

Publication number
EP1292385A1
EP1292385A1 EP01947241A EP01947241A EP1292385A1 EP 1292385 A1 EP1292385 A1 EP 1292385A1 EP 01947241 A EP01947241 A EP 01947241A EP 01947241 A EP01947241 A EP 01947241A EP 1292385 A1 EP1292385 A1 EP 1292385A1
Authority
EP
European Patent Office
Prior art keywords
drops
beads
precipitated
coating
suspension
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01947241A
Other languages
German (de)
English (en)
Inventor
Rainer Pommersheim
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CAVIS MICROCAPS GmbH
Original Assignee
Pommersheim Rainer
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pommersheim Rainer filed Critical Pommersheim Rainer
Publication of EP1292385A1 publication Critical patent/EP1292385A1/fr
Withdrawn legal-status Critical Current

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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes

Definitions

  • the invention relates to a method and to a plant for the production of micro-membrane capsules on an industrial scale, for use in food technology, biotechnology, the chemical and / or pharmaceutical industry and medicine.
  • Such capsules consist of a preferably spherical core which contains the immobilized substance or living cells or microorganisms and which can be surrounded by a shell which completely surrounds this core.
  • yeast immobilized in alginate spheres for bottle fermentation in the production of sparkling wine This means that the time-consuming, manual shaking of the yeast deposit can be replaced by the rapid sinking of the beads in the champagne bottle.
  • a disadvantage of these immobilizates, however, is the fact that yeast growth from the beads cannot always be prevented.
  • the German laid-open specification DE 3836894 AI describes a method and an apparatus which can be used to produce such alginate beads.
  • a suspension is formed from the microorganisms to be immobilized and the alginate base material, which is then dripped into a precipitation bath. This is done via capillaries, which are set in vibration.
  • the process described here can also be used to produce larger amounts of capsules, the immobilisates obtained are not suitable for including chemical substances due to the lack of an additional capsule membrane. The cells cannot grow out of the capsules either.
  • the PCT application PCT / CH96 / 00097 describes a similar process for the production of microcapsules which, in contrast to the above-mentioned production process, enables the beads to be prepared under sterile conditions, that is to say mainly provides capsules for the medical field.
  • the immobilisates obtained with the device described here have the same shortcomings as those in the above method.
  • Cell growth cannot be guaranteed and chemical compounds such as proteins (enzymes) cannot be kept in the capsules.
  • Patent specification P 43 12 970.6 describes a membrane capsule which is suitable for immobilizing enzymes and proteins, but also living cells.
  • the core which contains the immobilizate, surrounded by a multilayer shell, each of these layers imparting a certain property to the entire shell.
  • the shell polymers Through the advantageous choice of the shell polymers, the permeability of the membrane can be reduced so that enzymes also remain in the capsule, while the much smaller substrates and products can pass through the membrane. So far, however, these capsules can only be produced on a laboratory scale, i.e. in small quantities.
  • the invention has for its object to provide a method and an associated system that or that makes it possible for the first time to manufacture micro-membrane capsules in large quantities, that is, on an industrial scale.
  • the solution of the disclosure of the invention is carried out with a method according to claim 1 and a system according to claim 26.
  • the manufacturing process according to the invention is therefore divided into two sections, namely the shaping and the coating.
  • the material to be encapsulated is suspended or dissolved in a basic solution, preferably sodium alginate.
  • a basic solution preferably sodium alginate.
  • This basic material suspension or solution is then conveyed into a coating reactor via a suitable device. This can either be done with compressed air, but pumps, screw conveyors etc. can also be used. This suspension or solution is then added dropwise to a precipitation bath.
  • Ball shaped This can be done either by complexing with a polyvalent salt solution as in the case of the alginate, or by changing physical parameters such as e.g. Temperature.
  • a polyvalent salt solution as in the case of the alginate, or by changing physical parameters such as e.g. Temperature.
  • Liquid drops thus form the gel and enclose the material to be encapsulated.
  • capillaries can be used in which the drop is torn off by an air stream, as in F. Lim and A. Sun in Science; Volume 210, pages 908-910, year 1980. This gives capsule sizes between approx. 200 ⁇ m and approx. 2 mm with a very narrow size distribution.
  • several nozzles are arranged on a nozzle plate incorporated in the reactor.
  • Another usable method for droplet generation is that described in patent application DE 3836894.
  • Several capillaries are vibrated here, which leads to the liquid jets being broken down into individual drops. Such nozzle plates can be introduced into the reactor.
  • the capsules obtained here also have a diameter between approximately 200 ⁇ m and approximately 2 mm, the productivity being significantly higher than in the case of the above-mentioned nozzles, but with a much broader size distribution.
  • Very small particles in the range from approx. 20 ⁇ m to approx. 200 ⁇ m, are obtained by spinning on a turntable.
  • the flight cone of the drops must be taken into account when designing the reactor, so that they get into the precipitation bath and do not get caught on the walls.
  • the resulting gel particles are coated by immersing them in the respective coating solutions.
  • These are dilute aqueous solutions of polymers with anionic or cationic groups such as chitosan, polyvinylpyrrolydone, polyethyleneimine, carbocymethyl cellulose, alginate, polyacrylic acid, etc., which form so-called polyelectrolyte complex layers on the capsule surface.
  • polymers with anionic or cationic groups such as chitosan, polyvinylpyrrolydone, polyethyleneimine, carbocymethyl cellulose, alginate, polyacrylic acid, etc.
  • the manufacturing process takes place at approx. 25 ° C and atmospheric pressure. Nevertheless, a temperature control option can be provided for the reactors to heat the liquids up to approx. 65 ° C or to cool them down to approx. 5 ° C if necessary.
  • Fig. La; 1b; 2a: 2b; 3a; and 3c show several exemplary embodiments of the method and the associated plants for the large-scale production of membrane capsules.
  • 3a and 3b show variants of a plant which only works with one reactor and in which, as shown in FIG. 3b, all the reagents used in the process can initially be present as concentrates.
  • a suspension of the material to be encapsulated and the basic material solution is first prepared and poured into the pressure vessel GS.
  • the vessel is pressurized (approx. 8-10 bar), whereby the suspension is pressed into the corresponding reactor via the open valve V.
  • This can be FR or R depending on the system.
  • the vessel GS can be additionally ventilated by means of an additional valve BV, which is shown in some embodiments according to the invention.
  • the liquid must be transported using compressed air so that the material to be encapsulated is not damaged. However, other gentle systems such as suitable pumps or screw conveyors can also be used.
  • the suspension is broken down into individual drops using a suitable device. Due to the precipitation reagent into which the drops fall, they gel into gel particles. The size of the resulting particles depends on the dropletisation process used.
  • the volume flow of the basic material suspension is regulated via RV.
  • the precipitation reagent can get from the storage vessel FB into the reactor FR or R in different ways. Since the liquid is introduced tangentially in all cases, the gel particles are swirled, so that additional stirring is not necessary.
  • the suction tube must be provided with a filter so that no capsules are sucked in.
  • the solutions can be tempered by means of the heat exchanger WT1 or WT.
  • the precipitation reagent is conveyed into the shaping reactor FR by opening the valve V17, V19, and V22 and by pumping via the pump P1.
  • V17 and VI9 are closed and V20 is opened, whereby the solution circulates in a circle.
  • the solution is pumped back to FB by closing V22 and opening V21 and V18.
  • the beads are then washed with DI water by closing V18 and V21 and by opening V15, V19 and V22, which, like the precipitation reagent, is first circulated by means of an analog valve position and then by closing V22 and opening V21 and V16 Part is pumped out again.
  • the gel particles formed are then conveyed as an aqueous suspension into the coating reactor BR by gravity by opening the ball valve KHL.
  • this method step takes place analogously to that in FIG. 1 a, but here the 2-way valves VI9 and V20 or V21 and V22 from FIG. 1 a have been replaced by correspondingly arranged 3-way valves V15 and V12 , V17 and V18 or V15 and V16 from la correspond to valves V13 and V14 or V8 and Vll.
  • this first method step proceeds according to the invention in the embodiment shown in FIG. 3a. V15 and VI6; V17 and V18; V19 and V20; V21 and V22 from the system shown in FIG.
  • FIGS. 1b and 2b. represented variants can thanks to the presence of two pumps (Pl and P2) the precipitation reagent with the appropriate position of the valves V13 and V14 in Fig. lb or V10 and Vll in Fig. 2b, ⁇ during the entire first step of the process from the reservoir FB to Reactor FR can be pumped back and forth to FB. Since the precipitation bath in FR is constantly renewed in this way, the active substance concentration in the precipitation bath remains almost constant during this entire first process step. After a few minutes of curing time, the beads are also washed with di-water in the variants shown here by switching the valves V13 and V14 (Fig. Lb) or V10 and Vll (Fig. 2b). Thanks to the two pumps Pl and P2, the reaction vessel can always be supplied with new water and does not have to be circulated as in the variants shown in FIGS. 1a, 2a and 3a.
  • the embodiment shown in Fig. 3b does not work with ready-to-use solutions but with concentrates that have to be diluted first.
  • the filter F and the valve V10 by means of the pump P via the Mixing chamber MK and the heat exchanger WT di-water passed into the reaction vessel R.
  • V8 is closed and V9 is opened so that the water circulates in a circle.
  • the quantity of concentrate corresponding to the desired final concentration is then metered in from V4.
  • the suspension in reaction vessel R is then dripped from GS.
  • the beads remain in the reactor R after they have hardened.
  • the second process step, coating takes place.
  • this is done by rinsing the capsules alternately with a cationic and an anionic, dilute polymer solution. Wash steps are provided in between.
  • the 'particles are each exposed to the solutions for a few minutes, which can be pumped back into the Vorratsbereheat. It is important that the capsules are kept in a kind of fluidized bed during the entire process, so that the membrane can form all around. This can be done by means of special agitators, or, as shown in the present explanations, by tangentially introducing the solutions at a relatively high speed, which should be several meters per second at the pipe outlet opening.
  • the liquids can be tempered via the appropriate heat exchangers WT2 or WT.
  • the finished membrane capsules are washed and rinsed out of the reaction vessel.
  • a drying step can then be carried out, whereby the water is removed from the capsules.
  • the selected drying process is largely determined by the material enclosed in the capsules.
  • the first coating reagent, the polycation 1 is conveyed from the storage vessel PK1 into the coating reactor BR by opening the valve V3, V23, and V26 and by pumping via the pump P2. After reaching a corresponding level in BR, V3 and V23 are closed and V24 is opened, whereby the solution circulates in a circle.
  • the solution is pumped back to PKI by closing V26 and opening V25 and V4.
  • the beads are then washed with di-water by closing V4, V24 and V25 and by opening VI, V23 and V26, which, like the precipitation reagent, is first circulated through an analog valve position and then by closing VI, V23 and V26 and opening V2, V24 and V26 is pumped out again.
  • the reactor BR is then rinsed in an analog circuit with the detergent solution from the storage tank E, and then with the first polyanion from the container PA1, which is followed by 2-3 washing steps.
  • the reactor is then supplied from the PK2 vessel with the second polycationic solution, which is then pumped back there.
  • this method step takes place analogously to that in FIG. 1a, but here the coating is carried out in the same vessel R as the shaping. 3a corresponds to V17 and V18, V23 and V24 from la, or V19 and V20, V25 and v26 from FIG.
  • the finished capsules are rinsed out of the reactor by opening the KH ball valve.
  • the coating reagents can always be pumped back and forth from the storage containers to the reactor BR during the entire process step if the valves are in the appropriate position. Since the coating baths in BR are constantly renewed in this way, the active substance concentrations in the reactor remain almost constant during this entire process step.
  • the valves VI and V2 are opened and V15, 17 and V16 are switched accordingly.
  • the pump P4 pushes the liquid into the reactor P3 and returns it to the storage tank.
  • the liquid level in BR is set via the corresponding control of the two pumps.
  • FIGS. 2a and 2b do not work with ready-to-use solutions but with concentrates which first have to be diluted.
  • filter F and valve V10 FIG. 2a) or V9 (FIG. 2b) by means of pump P2 (FIG. 2a) or P3 (FIG. 2b) passed through the mixing chamber MK and the heat exchanger WT2 di-water into the reaction vessel R.
  • pump P2 FIG. 2a
  • P3 FIG. 2b
  • V7 is closed and V9 (Fig. 2a) or V8 (Fig. 2b) opened so that the water circulates in a circle.
  • the amount of polycation 1 concentrate corresponding to the desired final concentration is then metered in via VI from PKl and the solution is circulated.
  • V9 (FIG. 2a) or V8 (FIG. 2b) is opened and V10 (FIG. 2a) or V9 (FIG. 2b) is changed over and the solution is discarded.
  • the reactor BR is again filled with water via V7 and the detergent is removed from the vessel E and then discarded.
  • the beads are washed around with the other coating solutions, the concentrates of PA1 (polyanion 1), PK2 (polycation 2) etc. being metered in.
  • the capsules are rinsed out by opening KH2 after the coating has been completed.
  • the coating process takes place analogously to the explanations given in FIGS. 2a and 2b.
  • the difference is that coating is carried out in the same vessel R in which the dropletization (shaping) of the suspension has previously taken place.
  • V4, V5, V6, V7 from Fig. 2a. correspond to the valves V5, V6, V7, V8.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Manufacturing Of Micro-Capsules (AREA)

Abstract

L'invention concerne un procédé et une installation pour produire des microcapsules membranaires servant à immobiliser des principes actifs chimiques, des protéines, des cellules et/ou des micro-organismes vivants, à l'échelle industrielle. Selon l'invention, la matière à encapsuler est acheminée à un réacteur à partir d'un réservoir de stockage, sous forme de suspension ou de solution dans une substance de base. Dans le réacteur, des gouttes sont produites et précipitées pour former des billes qui enferment la matière puis sont revêtues par rinçage répété dans la même cuve et/ou dans une autre cuve.
EP01947241A 2000-04-28 2001-04-25 Procede et installation pour produire des microcapsules membranaires Withdrawn EP1292385A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10020889 2000-04-28
DE10020889 2000-04-28
PCT/EP2001/004684 WO2001083099A1 (fr) 2000-04-28 2001-04-25 Procede et installation pour produire des microcapsules membranaires

Publications (1)

Publication Number Publication Date
EP1292385A1 true EP1292385A1 (fr) 2003-03-19

Family

ID=7640238

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01947241A Withdrawn EP1292385A1 (fr) 2000-04-28 2001-04-25 Procede et installation pour produire des microcapsules membranaires

Country Status (5)

Country Link
US (1) US20040017018A1 (fr)
EP (1) EP1292385A1 (fr)
AU (1) AU6898001A (fr)
CA (1) CA2408025A1 (fr)
WO (1) WO2001083099A1 (fr)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080026068A1 (en) * 2001-08-16 2008-01-31 Baxter Healthcare S.A. Pulmonary delivery of spherical insulin microparticles
DE102004013977A1 (de) * 2004-03-19 2005-10-06 Cavis Microcaps Gmbh Technischer Prozess sowie Anlage zur Herstellung von Koazervatkapseln
US8728525B2 (en) * 2004-05-12 2014-05-20 Baxter International Inc. Protein microspheres retaining pharmacokinetic and pharmacodynamic properties
JP2008539259A (ja) * 2005-04-27 2008-11-13 バクスター・インターナショナル・インコーポレイテッド 表面を修飾した微粒子およびその形成方法および使用
US20070281031A1 (en) * 2006-06-01 2007-12-06 Guohan Yang Microparticles and methods for production thereof
JP5118139B2 (ja) 2006-08-04 2013-01-16 バクスター・インターナショナル・インコーポレイテッド 新規発症自己免疫性糖尿病を予防および／または逆転させるためのマイクロスフィアに基づく組成物
WO2008060786A2 (fr) * 2006-10-06 2008-05-22 Baxter International Inc. Microcapsules contenant des microparticules modifiées en surface et leurs procédés de formation et d'utilisation
GB0707612D0 (en) * 2007-04-19 2007-05-30 Stratosphere Pharma Ab Cores and microcapsules suitable for parenteral administration as well as process for their manufacture
KR101680181B1 (ko) 2008-07-16 2016-11-28 케이셉 시스템즈, 엘엘씨 유동층을 이용하여 입자들을 처리하는 방법 및 이를 위한 시스템
US8367427B2 (en) * 2008-08-20 2013-02-05 Baxter International Inc. Methods of processing compositions containing microparticles
US8323615B2 (en) * 2008-08-20 2012-12-04 Baxter International Inc. Methods of processing multi-phasic dispersions
US8323685B2 (en) * 2008-08-20 2012-12-04 Baxter International Inc. Methods of processing compositions containing microparticles
US20100047292A1 (en) * 2008-08-20 2010-02-25 Baxter International Inc. Methods of processing microparticles and compositions produced thereby
WO2019226618A1 (fr) 2018-05-22 2019-11-28 Nantkwest, Inc. Procédés et systèmes de formation de lit de cellules pendant un biotraitement

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US4743545A (en) * 1984-08-09 1988-05-10 Torobin Leonard B Hollow porous microspheres containing biocatalyst
JPS637784A (ja) * 1986-06-27 1988-01-13 Hitachi Plant Eng & Constr Co Ltd 微生物包括ペレツトの製造装置
DE3836894A1 (de) * 1988-10-29 1990-05-03 Krc Umwelttechnik Gmbh Verfahren und vorrichtung zum herstellen von perlen aus perlen bildenden loesungen
DE4312970A1 (de) * 1993-04-21 1994-10-27 Juergen Dr Schrezenmeir Mikrokapsel sowie Verfahren und Vorrichtung zu ihrer Herstellung
US5589370A (en) * 1995-08-01 1996-12-31 Lever Brothers Company, Division Of Conopco, Inc. Process for encapsulating sensitive materials

Non-Patent Citations (1)

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Title
See references of WO0183099A1 *

Also Published As

Publication number Publication date
US20040017018A1 (en) 2004-01-29
CA2408025A1 (fr) 2001-11-08
AU6898001A (en) 2001-11-12
WO2001083099A1 (fr) 2001-11-08

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