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WO1989001034A1 - Encapsulation de materiaux biologiques dans des membranes semi-permeables - Google Patents

Encapsulation de materiaux biologiques dans des membranes semi-permeables Download PDF

Info

Publication number
WO1989001034A1
WO1989001034A1 PCT/US1988/002413 US8802413W WO8901034A1 WO 1989001034 A1 WO1989001034 A1 WO 1989001034A1 US 8802413 W US8802413 W US 8802413W WO 8901034 A1 WO8901034 A1 WO 8901034A1
Authority
WO
WIPO (PCT)
Prior art keywords
gel forming
forming polymer
gelling
polymer
membrane
Prior art date
Application number
PCT/US1988/002413
Other languages
English (en)
Inventor
Somesh C. Nigam
Henry Y. Wang
Original Assignee
The Regents Of The University Of Michigan
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 The Regents Of The University Of Michigan filed Critical The Regents Of The University Of Michigan
Publication of WO1989001034A1 publication Critical patent/WO1989001034A1/fr

Links

Classifications

    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N11/00—Carrier-bound or immobilised enzymes; Carrier-bound or immobilised microbial cells; Preparation thereof
    • C12N11/02—Enzymes or microbial cells immobilised on or in an organic carrier
    • C12N11/04—Enzymes or microbial cells immobilised on or in an organic carrier entrapped within the carrier, e.g. gel or hollow fibres

Definitions

  • the present invention relates to encapsulated products. More particularly, the present invention relates to a process for the encapsulation of bioactive materials in semi-permeable membranes of gel forming polymers.
  • Encapsulation processes are finding increasing use in a variety of areas of biotechnology. Such processes are used to encapsulate various materials such as enzymes, hormones, drugs, adsorbents and cells which can then be used in bioreactors, artificial organs, bioseparation systems, controlled drug-release systems, and so forth. Prior art processes often require harsh conditions such as the use of non-aqueous solvents, extremes of pH, or high temperature. Such techniques are inherently unsuitable for encapsulating delicate biological materials such as live cells and labile proteins. Ideally, encapsulation techniques for biological materials should use mild conditions and a membrane material which is inert and non-toxic to the material being encapsulated.
  • the encapsulation technique should provide a semi-permeable membrane and allow for adjustment of membrane thickness and membrane pore size.
  • the charge on the membrane should be adjustable to suit different applications.
  • the membrane should also be strong enough to withstand liquid-shear or the friction effects arising out of agitation.
  • a well known membrane encapsulation method is the poly
  • (L-lysine) - alginate membrane method which involves formation of a polyelectrolyte membrane complex.
  • the mixture of bioactive material and sodium alginate is extruded through a droplet
  • the membrane has relatively poor mechanical strength and poor chemical stability in the presence of electrolytes such as heparin, polysulfonic acid and polyphosphoric acids which interact more strongly with alginate or poly (L-lysine) .
  • electrolytes such as heparin, polysulfonic acid and polyphosphoric acids which interact more strongly with alginate or poly (L-lysine) .
  • alginate remains within the capsule. Alginate can interfere with the functioning of bicmaterial by complexing with multivalent ions or other charged acromolecules. Alginate can also adsorb on positively charged surfaces and cause fouling.
  • the desired material is encapsulated within a semi-permeable membrane by a process comprising the steps of:
  • +2 + inducer such as Ca , K , polyphosphate, etc.
  • the medium may also contain a viscosity enhancer
  • the outer surface layer of the capsule can be coated with a second polymer to form a composite membrane.
  • the gelling solution comprises an effective amount of a second gel forming polymer in addition to the first gel forming polymer.
  • the capsules formed after the gelation of the first polymer can be removed from the polymer solution. The physico-chemical conditions can be altered to induce the gelling of the second polymer entrapped within the capsule membrane.
  • a gel forming polymer system is used to form a semi-permeable*membrane encapsulating various materials.
  • the process of this invention is particularly well suited for use in encapsulating biological materials. Unlike most of the known processes for encapsulating biological materials the present process ensures that most of the biological material never comes in contact with the gel forming polymer. The biological material stays within its original environment in the suspension.
  • the description of the preferred embodiments of this invention is in the context of encapsulating biological materials.
  • the process of this invention can also be used to encapsulate other materials and such other uses are contemplated to be within the broad scope of this invention.
  • the biological material to be encapsulated can be tissue, organelle, plant or animal cells, delta cells, whole islet of Langerhans, hepatocytes, bacteria, algae, fungi, viruses, proteins, pharmaceutical compounds and so forth.
  • the material must be of a size small enough to be suitable for encapsulation by the droplet method of this invention but can vary widely in diameter from less than a micron to several millimeters.
  • the present process allows viable cells to be encapsulated in a semi-permeable membrane allowing cells access to nutrients and other substances necessary for viability but protecting cells from substances having a molecular weight above a selected size such as an ibodies, toxins and bacteria. Thus the biological can be maintained in a viable state for an extended period of time.
  • the biological material is first suspended in an aqueous medium which is physiologically compatible with the material.
  • the medium should comprise required nutrients, be without toxic substances and have a suitable pH as, for example, a typical buffered solution.
  • the medium also comprises an effective amount of a gelling inducer.
  • the gelling inducer is of a type and in an amount effective to diffuse outwardly and cause the gel forming polymer to gel when coming into contact therewith as described in more detail hereinafter.
  • the aqueous medium also comprises a viscosity enhancer such as dextran, hyaluronic acid, polyethylene glycol, starch etc.
  • the suspension of material being encapsulated is formed into droplets of a size sufficient to envelop the material by, for example, dropping the suspension through a fine nozzle, capillary tube or hypodermic needle.
  • This method is amenable for delicate biological materials.
  • the material being encapsulated can be pelletized using a punch-press type apparatus or using a pellet mill for large scale applications.
  • the outer surface layer of the droplet or pellet is almost instantly provided with a gelled semi-permeable membrane by contacting the outer surface layer with the gel forming polymer as by, for example, dropping the droplet into a vessel containing a rapidly stirred solution of the gel forming polymer(s) .
  • the gel forming polymer is contacted by the gelling inducer to almost instantaneously form a semi-permeable membrane encapsulating the droplet.
  • the gel forming polymer can be any non-toxic water soluble gel forming polymer which forms a gel upon contact with a gelling inducer.
  • the gel forming polymer is an ionotropic gel forming polymer such as a water soluble pol saccharide.
  • Suitable polysaccharides include those typically extracted from vegetable matter and include sodium alginate, guar gum, gum arable, charagunan, pectin, tragacanth gum, xanthan gum, and deacylated chitin (chitosan) .
  • the polysaccharide molecules form a water-insoluble shape-retaining gel capsule.
  • the capsules can be recovered from the gelling solution and equilibriated with the desired media.
  • the mechanical and chemical properties of the capsule membrane can be further altered to suit different bioprocessing and biomedical applications.
  • a second gel forming polymer can be used to impart altered properties to the membrane such as mechanical strength, chemical stability, pore size and/or surface charge.
  • the second polymer can be another polyelectrolyte having opposite charge to that of the first poiymer.
  • the second polymer can be coated on the outer surface of the capsule to complex with the initial gel membrane. The resulting polyelectrolyte complex imparts greater chemical stability to the capsule.
  • sodium alginate capsules can be coated with polycations such as poly (L-lysine) , polyethylene-imine, chitosan or acrylate/methacrylate copolymers (Eudragit RL 100 from Rohm GmbH, Darmstadt, FRG) to form capsules having composite membranes. It is possible to obtain capsules with desired charge characteristics on either side of the membrane.
  • polycations such as poly (L-lysine) , polyethylene-imine, chitosan or acrylate/methacrylate copolymers (Eudragit RL 100 from Rohm GmbH, Darmstadt, FRG)
  • the gel forming solution comprises a solubilized second gel forming polymer in addition to the first polymer.
  • the almost instantaneous gelling of the first gel forming polymer to form the initial membrane entraps the second gel forming polymer in the membrane.
  • some polymer solution may adhere to the exterior of the capsule surface when it is removed from the gelling solution.
  • the capsules can be placed in an oil medium or in a buffer solution conta ing gelling inducer for the first and/or polymer. Both of these approaches curtail any loss of the thin liquid polymer solution film covering the capsule. It will be apparent to those skilled in the art that the physico-chemical conditions of the capsule can be altered in various ways to induce gelling of the second polymer.
  • the second gel forming polymer can be a thermal gel forming polymer.
  • Thermal gel forming polymers undergo gelation when their temperature is lowered below their gelation temperatures and generally have chemical and mechanical properties which are superior to ionotropic gels. Though widely used in gel entrapment, currently no method exists for membrane encapsulation using thermal gels. • A wide variety of thermal gel forming polymers can be used in the present invention, including, for example, agarose and kappa- ⁇ arrageenan.
  • the first polymer component of the composite membrane can be removed by means well known in the art.
  • the first polymer is an ionotropic gel forming polymer
  • its dissolution can be achieved by contacting the capsule with a chelating agent after the gelling of the second polymer is complete.
  • the membrane can be formed using a wide variety of available gel forming polymers. Membranes of different characteristics can be obtained by manipulating the type and the concentration of the polymers.
  • Aqueous thermal gels such as agarose, ⁇ -carrageenan, or gelatin may be employed to encapsulate delicate materials such as live cells and labile proteins. If the material being encapsulated is relatively stable in the presence of organic solvents, reactive cross-linking agents and extremes of pH for short durations of time, the list of polymers useful herein can be further expanded to include precipitation gels (eg. cellulose acetate) , polycondensation gels (eg.
  • This example illustrates formation of calcium alginate capsules containing material to be encapsulated.
  • a solution containing 0.8% sodium alginate (Sigma A 7128, type IV) is prepared and kept stirred using a magnetic stirrer at room temperature.
  • An aqueous suspension containing the material to be encapsulated is prepared in 0.1M HEPES buffer (pH 7) with 0.1M CaCl- and 20% dextran
  • the polymer solution Prior to the removal of the capsules the polymer solution is diluted five-fold by adding required amount of 0.1M HEPES buffer (pH 7) . This step dilutes the alginate solution outside the capsules and reduces the possibility of capsules joining each other when they are in close contact, due to the gelation of the alginate solution on their exterior surface. Capsules are removed from the solution and excess solution is drained using an appropriate size mesh. The capsules are transferred to 0.1M HEPES buffer (pH 7) containing 0.1M CaCl « and incubated for one minute to stabilize the exterior surface. Finally capsules are equilibriated with the desired media.
  • EXAMPLE 2 This example illustrates formation of agarose capsules containing the desired material.
  • a solution containing 0.5% agarose A solution containing 0.5% agarose
  • An aqueous buffered suspension containing the biological material is prepared with 0.1M CaCl-.
  • the viscosity of this suspension is increased by adding 20% dextran (Sigma D 4100) .
  • the suspension is dropped through a hypodermic needle to form droplets which fall into the alginate/agarose solution.
  • a capsular membrane forms almost instantaneously around the suspension drop due to the
  • the capsules thus formed were found to be reasonably strong due to the presence of agarose in the membrane matrix.
  • the capsules were also found to be stable in solutions containing high concentrations of NaCl, EDTA, Phosphate etc.
  • EXAMPLE 3 This example illustrates the formation of chitosan capsules containing the desired material.
  • 0.5% chitosan (Sigma C 3646) is dissolved in water containing 0.5% (v/v) acetic acid.
  • Material to be encapsulated is mixed with 1.5% sodium-tri-poly- phosphate solution (pH 5.5) contai ing 40% dextran (Sigma D 4133) .
  • This suspension is extruded through a hypodermic needle connected to an air-jet for generating small droplets (0.5 - 1.0 mm diameter) of the viscous suspension. Droplets instantly form a chitosan polyphosphate membrane enclosing the droplet.
  • Capsules are removed from the solution and further treated in 1.5% sodium-tri-poly- phosphate solution (pH 8.5) for a half hour. Finally the capsules are equilibriated in the desired buffer.
  • EXAMPLE 4 This example illustrates encapsulation of mammallian cells in alginate/poly-(L-lysine) capsules. KB cells are suspended in a solution consisting of 10% dextran, 1.3% CaCl- buffered with 13mM
  • Encapsulation processes are finding increasing use in a variety of areas, particularly in biotechnology. Such process are used to encapsulate various materials such as enzymes, hormones, drugs, adsorbents and cells which can then be used in bioreactors, artificial organs, bioseparation systems, controlled drug-release systems, and so forth.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Wood Science & Technology (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Dispersion Chemistry (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Medicinal Preparation (AREA)
  • Immobilizing And Processing Of Enzymes And Microorganisms (AREA)
  • Manufacturing Of Micro-Capsules (AREA)

Abstract

Un matériau biologique est encapsulé dans une membrane semi-perméable en suspendant le matériau dans un milieu qui comprend une quantité effective d'un agent d'induction de gélification, en donnant à la suspension une forme de gouttelette d'une taille suffisante pour envelopper le matériau, et en formant ensuite une capsule discrète en mettant en contact la partie de surface externe de la gouttelette avec une solution de gélification comprenant une quantité efficace d'un polymère de formation de gel qui se gélifie au contact de l'agent d'induction de gélification.
PCT/US1988/002413 1987-07-24 1988-07-21 Encapsulation de materiaux biologiques dans des membranes semi-permeables WO1989001034A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7723087A 1987-07-24 1987-07-24
US077,230 1987-07-24

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WO1989001034A1 true WO1989001034A1 (fr) 1989-02-09

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989010786A3 (fr) * 1988-04-22 1990-03-08 Microdrop Inc Procede de formation et d'utilisation de microgouttelettes
EP0454383A1 (fr) * 1990-04-23 1991-10-30 Aicello Chemical Co., Ltd. Formulation orale contenant des polypeptides dissociables dans le gros intestin
EP0460921A3 (en) * 1990-06-04 1992-08-12 Aicello Chemical Company Limited Large intestinal dissociative hard capsules
US5248500A (en) * 1990-12-21 1993-09-28 Del Monte Corporation Slow-release biodegradable granules of pasteuria penetrans
FR2699545A1 (fr) * 1992-12-18 1994-06-24 Oreal Agent gélifiant résultant de l'association d'un chitosane et d'un alginate d'alkyle ou d'hydroxyalkyle et son utilisation dans la préparation de compositions cosmétiques et pharmaceutiques.
WO1998021985A1 (fr) * 1996-11-22 1998-05-28 Lipotec, S.A. Produit permettant d'incorporer des ingredients dietetiques et alimentaires dans les boissons, les aliments et les produits dietetiques
US6297033B1 (en) * 1996-04-02 2001-10-02 Yissum Research Development Company Of The Hebrew University Of Jerusalem Means and process for nitrate removal
ES2164567A1 (es) * 1999-10-21 2002-02-16 Lipotec Sa Preparacion cosmetica o dermofarmaceutica compuesta de milicapsulas formadas por combinacion de alginato y agar-agar y su procedimiento de produccion.
ES2164566A1 (es) * 1999-10-21 2002-02-16 Lipotec Sa Preparacion cosmetica o dermofarmaceutica compuesta de milicapsulas conrecubrimiento de polisacaridos cationicos.
EP1306128A1 (fr) * 2001-10-29 2003-05-02 Tenaxis Gmbh Materiaux composites adsorbants
US7544855B2 (en) 2004-04-23 2009-06-09 Buck Institute Transgenic mouse whose genome comprises an APP having a mutation at amino acid 664
US7766637B2 (en) 2006-03-03 2010-08-03 Fmc Corporation Method and apparatus for the preparation of capsules
US7972620B2 (en) 2002-04-04 2011-07-05 Fmc Biopolymer As Polysaccharide capsules and methods of preparation
US20130316004A1 (en) * 2011-02-07 2013-11-28 Life Technologies Corporation Compositions and methods for stabilizing susceptible compounds
WO2024115801A1 (fr) * 2022-12-01 2024-06-06 Universitat D' Alacant / Universidad De Alicante (80%) Obtention de coacervats et utilisation de ces derniers en tant qu'instrument de lutte biologique en agriculture

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE377449T1 (de) * 1998-07-15 2007-11-15 Max Planck Gesellschaft Polyelektrolythüllen auf biologischen templaten
DE59908471D1 (de) * 1999-07-02 2004-03-11 Cognis Iberia Sl Mikrokapseln - II
DE59912558D1 (de) * 1999-07-02 2005-10-20 Cognis Ip Man Gmbh Mikrokapseln - IV
ES2247749T3 (es) * 1999-07-02 2006-03-01 Cognis Ip Management Gmbh Microcapsulas iii.
US20090035855A1 (en) * 2005-12-01 2009-02-05 Agency For Science, Technology And Research Three-dimensional reconstituted extracellular matrices as scaffolds for tissue engineering

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4409331A (en) * 1979-03-28 1983-10-11 Damon Corporation Preparation of substances with encapsulated cells

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4409331A (en) * 1979-03-28 1983-10-11 Damon Corporation Preparation of substances with encapsulated cells

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Biotechnology and Bioengineering, vol. 27, no. 2, February 1985 John Wiley & Sons, Inc. (New York, US) M.F.A Goosen et al.: "Optimization of microencapsulation parameters: semipermeable microcapsules as a bioartificial pancreas", pages 146-150 *
Chemical Abstracts, vol. 79, no. 25, 24 December 1973 (Columbus, Ohio, US) see page 218 *

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989010786A3 (fr) * 1988-04-22 1990-03-08 Microdrop Inc Procede de formation et d'utilisation de microgouttelettes
EP0454383A1 (fr) * 1990-04-23 1991-10-30 Aicello Chemical Co., Ltd. Formulation orale contenant des polypeptides dissociables dans le gros intestin
EP0460921A3 (en) * 1990-06-04 1992-08-12 Aicello Chemical Company Limited Large intestinal dissociative hard capsules
US5283064A (en) * 1990-06-04 1994-02-01 Aicello Chemical Co., Ltd. Large intestinal dissociative hard capsules
US5248500A (en) * 1990-12-21 1993-09-28 Del Monte Corporation Slow-release biodegradable granules of pasteuria penetrans
FR2699545A1 (fr) * 1992-12-18 1994-06-24 Oreal Agent gélifiant résultant de l'association d'un chitosane et d'un alginate d'alkyle ou d'hydroxyalkyle et son utilisation dans la préparation de compositions cosmétiques et pharmaceutiques.
US6297033B1 (en) * 1996-04-02 2001-10-02 Yissum Research Development Company Of The Hebrew University Of Jerusalem Means and process for nitrate removal
WO1998021985A1 (fr) * 1996-11-22 1998-05-28 Lipotec, S.A. Produit permettant d'incorporer des ingredients dietetiques et alimentaires dans les boissons, les aliments et les produits dietetiques
ES2129334A1 (es) * 1996-11-22 1999-06-01 Lipotec Sa Un producto para incorporar ingredientes dieteticos y alimentarios en bebidas, en productos para alimentacion y en productos para la dietetica.
ES2164567A1 (es) * 1999-10-21 2002-02-16 Lipotec Sa Preparacion cosmetica o dermofarmaceutica compuesta de milicapsulas formadas por combinacion de alginato y agar-agar y su procedimiento de produccion.
ES2164566A1 (es) * 1999-10-21 2002-02-16 Lipotec Sa Preparacion cosmetica o dermofarmaceutica compuesta de milicapsulas conrecubrimiento de polisacaridos cationicos.
WO2003037505A1 (fr) * 2001-10-29 2003-05-08 Preentec Ag Materiaux composites sorbants
EP1306128A1 (fr) * 2001-10-29 2003-05-02 Tenaxis Gmbh Materiaux composites adsorbants
US7972620B2 (en) 2002-04-04 2011-07-05 Fmc Biopolymer As Polysaccharide capsules and methods of preparation
US9017720B2 (en) 2002-04-04 2015-04-28 FMC Bioploymer AS Polysaccharide capsules and method of preparation
US7544855B2 (en) 2004-04-23 2009-06-09 Buck Institute Transgenic mouse whose genome comprises an APP having a mutation at amino acid 664
US7766637B2 (en) 2006-03-03 2010-08-03 Fmc Corporation Method and apparatus for the preparation of capsules
US8153037B2 (en) 2006-03-03 2012-04-10 Fmc Corporation Method and apparatus for the preparation of capsules
US8916192B2 (en) 2006-03-03 2014-12-23 Fmc Corporation Method and apparatus for the preparation of capsules
US20130316004A1 (en) * 2011-02-07 2013-11-28 Life Technologies Corporation Compositions and methods for stabilizing susceptible compounds
US10669522B2 (en) * 2011-02-07 2020-06-02 Life Technologies Corporation Compositions and methods for stabilizing susceptible compounds
US11028361B2 (en) 2011-02-07 2021-06-08 Life Technologies Corporation Compositions and methods for stabilizing susceptible compounds
WO2024115801A1 (fr) * 2022-12-01 2024-06-06 Universitat D' Alacant / Universidad De Alicante (80%) Obtention de coacervats et utilisation de ces derniers en tant qu'instrument de lutte biologique en agriculture
ES2976063A1 (es) * 2022-12-01 2024-07-22 Univ Alicante Obtencion de coacervados y su uso como herramienta de control biologico en agricultura

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