EP0639048A1 - Microencapsulation - Google Patents

Microencapsulation

Info

Publication number
EP0639048A1
EP0639048A1 EP93911053A EP93911053A EP0639048A1 EP 0639048 A1 EP0639048 A1 EP 0639048A1 EP 93911053 A EP93911053 A EP 93911053A EP 93911053 A EP93911053 A EP 93911053A EP 0639048 A1 EP0639048 A1 EP 0639048A1
Authority
EP
European Patent Office
Prior art keywords
gel
active material
biologically active
droplets
polymer
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Withdrawn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
EP93911053A
Other languages
German (de)
English (en)
Inventor
Stanley Tocker
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.)
EIDP Inc
Original Assignee
EI Du Pont de Nemours and Co
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 EI Du Pont de Nemours and Co filed Critical EI Du Pont de Nemours and Co
Publication of EP0639048A1 publication Critical patent/EP0639048A1/fr
Withdrawn legal-status Critical Current

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
    • A61K9/5089—Processes
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/26—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests in coated particulate form
    • A01N25/28—Microcapsules or nanocapsules
    • 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
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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
    • 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
    • B01J13/06—Making microcapsules or microballoons by phase separation
    • B01J13/12—Making microcapsules or microballoons by phase separation removing solvent from the wall-forming material solution
    • 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
    • B01J13/06—Making microcapsules or microballoons by phase separation
    • B01J13/14—Polymerisation; cross-linking
    • B01J13/16—Interfacial polymerisation

Definitions

  • TITLE MICROENCAPSULATION This invention relates to the microencapsulation of biologically active material within polymer particles,- which is useful for slow release of the biologically active material.
  • Handjani et al. U.S. 5,139,783 discloses alginate capsules which may contain a cosmetic active agent such as a biological compound, and which may be contained in an external gel phase.
  • the present compositions differ from those of Handjani et al. in that the biologically active material is introduced during the formation of the microcapsules, not afterwards.
  • the present invention provides a process for encapsulating biologically active material in which equipment costs and power needs are low, effective encapsulation of insoluble biological active material is accomplished, microcapsule dispersions of long-term stability are obtained, and such dispersions can be advantageously used.
  • One embodiment of the present invention is-the process for microencapsulating biologically active material, comprising forming a thixotropic gel which is essentially nonflowable but is stirrable without fracturing, forming a substantially homogeneous carrier composition of said biologically active material and hardenable immiscible organic liquid, combining said gel and said homogeneous carrier composition one with the other in a proportion in which said gel is the continuous phase and said homogeneous carrier composition is the dispersed phase in the resultant combination in the presence of stirring of said gel to finely disperse said homogeneous carrier composition as droplets in said gel without causing appreciable fracture of said gel, and hardening said droplets to obtain as a result thereof a stable dispersion of microencapsulated biologically active material.
  • compositions comprising a continuous phase of essentially non-flowable aqueous thixotropic gel and fine microcapsules of polymer stably dispersed therein, said microcapsules containing a pesticide.
  • the aqueous gel is formed by mixing sufficient water-soluble gelation agent with water to form the gel in the viscous, essentially non-flowable form desired by the present invention.
  • Insufficient amounts of gelation agent merely thicken the resultant solution, such as by forming a colloid, so that the solution is still readily pourable.
  • thickened solution r unlike gels, suspended droplets or suspended solids eventually settle upon standing over time, e.g., one day or one month.
  • the essentially non-flowable state of the gel desired for the present invention can be defined with reference to the pouring characteristics of the gel when housed in a cylindrical glass container having an inner diameter of about 5 cm.
  • the essentially non- flowable gel will not pour for a period of at least 3 seconds, preferably at least 5 seconds.
  • the gel contents of the container have been disturbed, such as by stirring of the gel, the gel may be pourable as a slow-moving mass resembling partially crystallized honey.
  • the gel remains nonpourable, i.e., essentially rigid for at least 5 seconds, upon inversion of the container holding the gel.
  • the gel While essentially non-flowable, the gel is also stirrable without causing fracture of the gel, i.e., the gel can be stirred without causing it to break into pieces. Fracture detracts from the ability of the gel to disperse the hardenable organic liquid as will be described later herein.
  • the non-flowable and stirrable natures of the present gels preferably exist at room temperature, e.g, 15° to 25°C.
  • the gels of the present invention are thixotropic in that they are rigid and non-pourable, thin appreciably upon stirring, but then become rigid and non-flowable again upon standing.
  • gelation agents examples include clays, cellulose derivatives, polyacrylic acids, poly- saccharides, gelatins, gums, starches, alginates, ___: polyvinyl alcohols, sodium stearate polyethylene glycol and ethylene maleic anhydride copolymer.
  • Preferred gelation agents include carboxymethyl cellulose and ethylene maleic anhydride copolymer after having been treated (hydrolyzed) with aqueous base such as NaOH to form the salt of the copolymer. Without the aqueous base treatment, the copolymer may thicken water, but tends not to gel it unless used in very large amounts, e.g., 25% by weight based on the weight of the water in the gel.
  • the amount of gelation agent required to make the essentially non-flowable, stirrable gel will depend on the gel-effectiveness of the particular agent. Generally the effective amount to provide these characteristics will fall within 1 to 15% based on the weight of the water plus gelation agent. When the agent is carboxy ethyl cellulose salt, the preferred amount is from 8 to 12% by weight, and when the copolymer salt is the agent, the preferred amount is from 1 to 5% by weight.
  • the preferred aqueous gels are 10% by weight aqueous metal salts of carboxymethyl cellulose and gels derived from hydrolysis of crosslinked ethylene-maleic anhydride copolymers (EMA ® -91 and EMA ® -61, Monsanto Chemical Co.) .
  • the dispersion or solution of biologically active material in the hardenable organic liquid is formed by mixing powdered or liquid active material with the hardenable liquid.
  • the carrier composition is a solution
  • the carrier composition is a dispersion.
  • a dispersing agent may be used.
  • the proportions of material and hardenable liquid can vary widely to obtain the ultimate result of forming microcapsules encapsulating the biologically active material.
  • the selection of organic liquid depends on which embodiment of hardening is employed.
  • the organic liquid includes a dissolved polymer or a polymer precursor.
  • the hardening of the liquid involves either (1) precipitating the polymer out of its solution, e.g., by removing the solvent, and having the active ingredient dissolved or dispersed within the polymer, or (2) polymerizing the polymer precursor, to form polymer microcapsules which contain the biologically active material in the gel as is hereinafter described.
  • the carrier composition is a liquid by virtue of the presence of the hardenable organic liquid and is mixed with the gel to form a fine dispersion of droplets of the carrier composition within the gel.
  • the fine dispersion can be achieved by stirring the gel as the liquid composition is added. Preferably, slow speed stirring is all that is necessary.
  • the liquid carrier composition rapidly disperses into fine droplets containing the biologically active material within the gel.
  • the stirring does not force the active material out of the hardenable liquid when the hardenable liquid is a dispersion rather than a solution of the biologically active material.
  • the gel is much more viscous than the liquid carrier composition, the latter of which preferably has a viscosity ranging from that of about 1 to 600 centepoises (cps) at 25°C.
  • the viscosity of the gel used in the present invention is about at least two times the viscosity of the liquid composition (i.e., about 2-1200 cps at 25°C) .
  • the viscosities described herein are measured using the Brookfield viscometer.
  • the stirring to form the gel composition is accomplished by a simple paddle mixing blade operating at a low rotational speed, e.g., as low as 60 rpm, and generally not higher than 150 rpm.
  • the dispersion of droplets can be usually obtained by hand mixing by using a spatula.
  • the proportions of the homogeneous carrier composition and aqueous gel are such that the gel is present in an amount sufficient to form the continuous phase and the carrier composition forms the dispersed phase. Generally, this requires that the dispersed phase not be more than at least 50% by weight of the total composition (continuous phase plus dispersed phase) .
  • the proportion of homogeneous carrier composition present as droplets depends on the concentration of bio ' logically active material desired. Generally, at least 0.5%, and preferably at least 1% of biologically active material based on the weight of the total composition is desired.
  • the high viscosity of the gel on the order of at least 1000 centapoises, keeps the droplets separated, unaggregated, and well dispersed in the gel. The dispersion facilitates the conversion of the droplets to microcapsules by the hardening of the organic liquid in the droplets.
  • the average particle size of the microcapsules obtained by the process of the present invention and present in the product of the present invention is from about 1 to 1000 microns and desirably is in the range of 1 to 200 microns in average diameter.
  • the smaller capsule sizes are desirable when the preferred application technique is to dilute the gel/microcapsule composition; followed by spraying.
  • the biologically active material can be present as a core within the microcapsules, i.e., surrounded by polymer shell, as would occur if the active material is present as a dispersion within the original hardenable organic liquid.
  • the hardening of the liquid by polymer precipitation often creates microcapsules within which the active material is homogeneously dispersed in a polymer matrix.
  • the method by which the organic liquid hardens e.g., interfacial polymerization, solvent evaporation, can also influence the physical structure of the microcapsules.
  • Microcapsules formed by interfacial polymerization usually have a polymer shell encapsulating the active ingredient.
  • microcapsules formed by evaporation of a solvent tend to be uniform dispersions of polymer and active ingredient.
  • the hardening is achieved by interfacial polymerization.
  • the organic liquid comprises at least one water-insoluble polyfunctional, polycondensation monomer, which contains at least two isocyanate or acid chloride groups or mixtures of such polyfunctional compounds and, optionally, a water-insoluble organic solvent.
  • the organic liquid/active material composition is then mixed with the aqueous gel as described above to give droplets of microencapsulated active material suspended in the gel matrix.
  • a water-soluble complementary monomer or mixture of monomers is added, by stirring into the gel, each containing at least two primary or secondary amino or hydroxyl groups, capable of undergoing interfacial polymerization with the monomer system in the droplets.
  • the preferred water-soluble complementary amine is diethylene triamine.
  • polyfunctional monomers include toluene diiso ⁇ cyanates, sebacoyl chloride, hexamethylene diiso- cyanate, * and terephthaloyl chloride.
  • the preferred polyisocyanate is polymethylene polyphenyl isocyanate available as PAPI ® (Dow Chemical Co.).
  • an interfacial polymerization process is carried out using at least one polyfunctional isocyanate without subsequent addition of a complementary water-soluble monomer system.
  • some of the isocyanate groups hydrolyze in the aqueous gel to give amino groups which produce polyurea by self-condensation.
  • the organic liquid is a solution of polymer in water-insoluble solvent and active material is dissolved or dispersed therein.
  • the liquid upon dispersion of this organic liquid in the gel, the liquid takes the form of discrete droplets containing solvent, polymer, and active material suspended in the gel.
  • the droplets are hardened by evaporating the solvent by heating of the gel composition, producing hard microcapsules.
  • the preferred polymers or this process are poly ethyl ethacrylate, polylactic acid, or lactic acid/glycolic acid copolymers.
  • the preferred polymer solvent is methylene chloride.
  • the organic solvent for the polymer is selected to be slowly water soluble, whereby the solvent slowly migrates into the gel matrix, spontaneously liberating microcapsules containing active material without heating.
  • water-soluble solvents include ethyl acetate, tetrahydrofuran, and cyclohexanone. While these solvents may be miscible in water and thereby in the aqueous gel, when present in solution with the water- insoluble polymer, the droplets are immiscible with the aqueous gel, which enables the active/organic liquid carrier composition to form as dispersed droplets in the aqueous gel.
  • agglomeration of the droplets tends to occur during stirring.
  • the stability of the droplet dispersion in the aqueous gel is maintained when the droplets harden to microcapsules.
  • the resultant product of the present invention i.e., the dispersion of microcapsules containing the biologically active material in the aqueous gel, is very stable as indicated by the lack of settling during three months in storage at room temperature as determined by visual inspection. With conventional aqueous suspensions, settling generally occurs overnight shortly after preparation, unless a thickener is employed, and even then settling often occurs on prolonged storage.
  • the biologically active material and the organic liquid, whether monomer, polymer, solvent or any of these present in the substantially homogeneous carrier composition added to the gel should be inert to one another.
  • the active material is sufficiently inert (non-reactive) to water that even if active material is present at the surface of the dispersed droplets and microcapsules form therefrom, there is no appreciable reaction between the active material and the surrounding gel.
  • a wide variety of biologically active materials can be used in the present invention to provide therapeutic benefit to the subject to be contacted with the microcapsules.
  • biologically active materials include agrichemicals such as herbicides, fungicides, insecticides, nematicides, acaricides, miticides, virusides, algicides, bactericides, plant growth regulants, and mixtures thereof and pharmaceuticals.
  • the gel composition product of the present invention is especially useful as a way of handling agrichemicals in that leakage from exterior packaging is minimized.
  • the gel composition can be packaged in cartridges, toothpaste-type tubes, and bags, and can be directly applied from these containers.
  • the gel composition when applied as such have several advantages over conventional agricultural formulations. They may be directly applied to trees or foliage or crevices where insects may enter and because of the thixotropy of gels, be expected to remain in place longer than conventional agricultural sprays. These gels could be applied by direct injection into furrows. Also, these formulations can be mechanically injected into or mixed into water for dilution prior to application by spraying.
  • the polymer component controls the release of the active material present in the microcapsules.
  • the rate of release can be adjusted over a wide range by the amount of polymeric barrier used for a given weight of active, the size of the micro ⁇ capsules, the type of polymer used and use of optional adjuvants to control the porosity of the polymer.
  • the advantages cited in the literature for conventional controlled release systems, such as reduced mammalian toxicity, reduced worker exposure, and prolonged activity, are also true for the gel compositions of the present invention.
  • This invention provides low cost controlled release compositions comprising controlled release microcapsules suspended in gels.
  • compositions are unusually simple and uses conventional, low-intensity mixing equipment such as paddle stirrers, kneaders, and the like.
  • low shear mixing permits the use of not only solutions of active ingredients, but also dispersions of active ingredients, without production of unencapsulated active.
  • aqueous gel which was non-flowable but stirrable, was added with hand stirring for about 30 seconds, a mixture of 6 g of PAPI ® 901 and 0.3 g powdered bensulfuron methyl herbicide to produce a fine dispersion of droplets of PAPI ® and herbicide mixture in the gel. Then with constant hand stirring (using a spatula) was added 0.2 g diethylene triamine, generating crosslinked 2-50 micron diameter polyurea microcapsules. The PAPI ® and herbicide mixture was allowed to stand overnight in the gel.
  • HPLC High Pressure Liquid Chromatography
  • EXAMPLE 2 To 50 g of the 10% by weight CMC, as defined in Example 1, aqueous gel was added with hand stirring for about 15 seconds, a mixture of 6 g polymethylene polyphenylisocyanate (PAPI ® 901, Dow Chemical Co.) containing 0.1% dibutyltin dilaurate catalyst and 0.3 g of powdered N-( ( (4,6-dimethoxypyrimidin-2-yl)amino- carbonyl)-l-methyl-4-(2-methyl-2H-tetrazol-5-yl)-IH- pyrazole-5-sulfonamide herbicide to form a fine dispersion of droplets of the mixture in the gel.
  • PAPI ® 901 polymethylene polyphenylisocyanate
  • the mixture was allowed to stand overnight in the gel, whereby the droplets converted to polyurea shells around each of the droplets of PAPI ® mixture.
  • the capsules containing 5% by weight N-( ( (4,6-dimethoxy- pyrimidin-2-yl)aminocarbonyl)-l-methyl-4-(2-methyl-2H- tetrazol—5-yl)-lH-pyrazole-5-sulfonamide, released 41% of the active in water in 24 hours, compared to 100% for the powdered, unencapsulated compound control. Release rates were obtained as in Example 1.
  • the control sample was prepared as described in Example 2 without the addition of PAPI ® and dibutyltin dilaurate.
  • EXAMPLE 3 To 40 g of the 10% by weight CMC, as defined ⁇ " above, aqueous gel was added with hand stirring for about 10 seconds a mixture of 6 g PAPI ® 901, 1.0 g of liquid organophosphorous insecticide, 0,0-diethyl O- (l,2,2,2-tetrachloroethyl)phosphorothioate, and 0.01 g dibutyltin dilaurate to form a fine dispersion of droplets of the mixture in the gel. The mixture was allowed to stand overnight in the gel, whereupon the fine droplets polymerized by reaction with water in the gel to crosslinked polyurea microcapsules with an average particle size (diameter) of about 25 microns.
  • EXAMPLE 4 A non-flowable but stirrable ethylene/maleic anhydride copolymer gel was prepared by mixing 5.0 g EMA ® -91 polymer with 500 g water and treating with 2.3 g (50% by weight) sodium hydroxide.
  • Another gel mixture was prepared comprising 0.2 g diethylene triamine dispersed in 8.6 g of EMA ® gel prepared as described above.
  • aqueous gel was added a solution of 15 g 10% Elvacite ® 2008 poly(methylmethacrylate) (Du Pont Company) in methylene chloride and 0.3 g of powdered N-( ( (4, 6-dimethoxy-pyrimidin-2-yl)aminocarbonyl)-1- methyl-4-(2-methyl-2H-tetrazol-5-yl)-lH-pyrazole-5- sulfonamide herbicide, with mild mechanical stirring for 15 seconds. After a good dispersion of the methylene chloride solution was obtained, the mixture was stirred an additional 3.0 hours at 30-35°C to remove the solvent, giving hard 5-60 micron microcapsules.
  • EXAMPLE 6 To 60 g of a gel consisting of 10% by weight CMC, as defined in Example 1, in water was added by hand stirring a mixture of 15 g 10% Elvacite ® 2008 poly(methylmethacrylate) (Du Pont Co.) in ethyl acetate and 0.3 g of powdered N-(( (4,6-dimethoxypyrimidin-2- yl) minocarbonyl)-l-methyl-4-(2-methyl-2H-tetrazol-5- yl)-lH-pyrazole-5-sulfonamide herbicide.
  • Elvacite ® 2008 poly(methylmethacrylate) Du Pont Co.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dispersion Chemistry (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pest Control & Pesticides (AREA)
  • Agronomy & Crop Science (AREA)
  • Plant Pathology (AREA)
  • Toxicology (AREA)
  • Dentistry (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

On encapsule une substance biologiquement active en mélangeant d'abord une telle substance avec un liquide durcissable, par polymérisation par exemple, et en dispersant ensuite la composition produite dans un gel non coulant mais pouvant être remué, après quoi on fait durcir les gouttelettes dispersées contenant la substance biologiquement active pour former une dispersion stable de microcapsules contenant cette substance dans le gel.
EP93911053A 1992-05-05 1993-05-05 Microencapsulation Withdrawn EP0639048A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US87848292A 1992-05-05 1992-05-05
US878482 1992-05-05
PCT/US1993/004215 WO1993021764A1 (fr) 1992-05-05 1993-05-05 Microencapsulation

Publications (1)

Publication Number Publication Date
EP0639048A1 true EP0639048A1 (fr) 1995-02-22

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EP93911053A Withdrawn EP0639048A1 (fr) 1992-05-05 1993-05-05 Microencapsulation

Country Status (4)

Country Link
EP (1) EP0639048A1 (fr)
JP (1) JPH07506376A (fr)
CA (1) CA2134464A1 (fr)
WO (1) WO1993021764A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2418428A (en) * 2004-08-27 2006-03-29 Univ Cranfield Design and use of imprinted polymers, with specific affinity affecting controlled release of chemicals
WO2017029665A1 (fr) 2015-08-20 2017-02-23 Sol-Gel Technologies Ltd. Compositions pour application topique comprenant du peroxyde de benzoyle et de l'adapalène
JP2020527143A (ja) 2017-07-12 2020-09-03 ソル − ゲル テクノロジーズ リミテッド ざ瘡の治療のための方法および組成物
CA3069359C (fr) 2017-07-12 2023-01-10 Sol-Gel Technologies Ltd. Compositions comprenant de la tretinoine encapsulee

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4285720A (en) * 1972-03-15 1981-08-25 Stauffer Chemical Company Encapsulation process and capsules produced thereby
DE2532147B2 (de) * 1975-07-18 1981-06-25 Renker GmbH, 5160 Düren Verfahren zur Herstellung von Öl enthaltenden Mikrokapseln
FR2645439B1 (fr) * 1989-04-07 1991-06-21 Oreal Procede de preparation de capsules d'alginate(s) particulierement adaptees a un usage cosmetique, appareil pour sa mise en oeuvre et composition cosmetique contenant lesdites capsules
GB2246514B (en) * 1990-08-01 1993-12-15 Scras Sustained release pharmaceutical compositions and the preparation of particles for use therein

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9321764A1 *

Also Published As

Publication number Publication date
WO1993021764A1 (fr) 1993-11-11
CA2134464A1 (fr) 1993-11-11
JPH07506376A (ja) 1995-07-13

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