EP1063970A1 - Microcapsules a liberation retardee - Google Patents

Microcapsules a liberation retardee

Info

Publication number
EP1063970A1
EP1063970A1 EP99908958A EP99908958A EP1063970A1 EP 1063970 A1 EP1063970 A1 EP 1063970A1 EP 99908958 A EP99908958 A EP 99908958A EP 99908958 A EP99908958 A EP 99908958A EP 1063970 A1 EP1063970 A1 EP 1063970A1
Authority
EP
European Patent Office
Prior art keywords
acid
solution
microcapsules
chitosan
hcl
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Withdrawn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
EP99908958A
Other languages
German (de)
English (en)
Inventor
Uwe Bayer
Bernd Hahn
Anna Majeres
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.)
Aventis Research and Technologies GmbH and Co KG
Original Assignee
Aventis Research and Technologies GmbH and Co KG
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 Aventis Research and Technologies GmbH and Co KG filed Critical Aventis Research and Technologies GmbH and Co KG
Publication of EP1063970A1 publication Critical patent/EP1063970A1/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Withdrawn legal-status Critical Current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
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/11—Encapsulated compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/736—Chitin; Chitosan; Derivatives thereof
    • 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
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q13/00—Formulations or additives for perfume preparations
    • 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
    • B01J13/10—Complex coacervation, i.e. interaction of oppositely charged particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/41—Particular ingredients further characterized by their size
    • A61K2800/412—Microsized, i.e. having sizes between 0.1 and 100 microns

Definitions

  • the present invention relates to microcapsules with a greatly delayed release of the active ingredients.
  • microcapsules is understood to mean capsules with a size of 50 nm to 3 mm, which have an outer shell made of polymers and an inner, usually liquid phase. Microcapsules are usually produced by encapsulating finely dispersed liquid phases by coating with film-forming polymers. Such microcapsules are used above all in the field of depot preparations, according to which the active substance located in the inner phase of the microcapsules is protected by the shell of the microcapsule and is not released immediately but only with a delayed release (active substance release).
  • US-A-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 2+ ).
  • polyvalent cations for example Ca 2+
  • the capsules produced in this way are mixed with a cationic polymer, which brings about further physical crosslinking.
  • Polyethyleneimine and polylysine are mentioned as polycations in this publication.
  • capsules are for proteins with a molecular weight less than 100,000 g / mol completely permeable. There is therefore no delayed release of these substances.
  • 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). This liquid is then replaced by water in order to crosslink the microcapsules.
  • Chitossan is the general term for a polymer produced by deacetylating chitin, an unbranched ⁇ (1-4) -linked polysaccharide of 2-acetamido-2-deoxy-D-glucose (N-acetyl-D-glucosamine) , is available.
  • the ratio of deacetylated to acetylated segments is greater than 1 and the number average molecular weight is between 50,000 and several million g / mol.
  • This chitosan is insoluble in water and can be obtained, for example, from Fluka. This is how CA. McKnight et al. in Journal of Bioactive and Compatible Poly- 3 mers, Vol. 3, 1988, pp. 334 to 355 a three-stage process for the production of microcapsules based on alginate and chitosan. According to this method, the alginate solution containing the active ingredient is first introduced into a calcium chloride solution, where the outer capsule surface is first hardened.
  • the hardened capsules are then coated with a chitosan solution, which leads to a cross-linking of the outer shell. Finally, the microcapsules obtained in this way are washed with alginate.
  • the chitosan used in this publication has a number average molecular weight of 160,000 to 330,000. Permeability studies of these chitosan / alginate membranes have shown that the molecular weight of the chitosan used has no significant influence on the permeation behavior of various proteins. After only two hours, 20% of the active ingredient BSA has diffused into the microcapsules containing chitosan. The release of these microcapsules is already very high after a short time.
  • a disadvantage of the known processes for producing chitosan-containing microcapsules is that they are produced in two or more different working steps. Above all, the transportation of the microcapsules from one reaction container to the other requires complex devices, especially when small microcapsules are to be produced. 4
  • the object of the present invention is to provide microcapsules which have a delayed release of the active compounds compared to the known prior art.
  • these microcapsules are said to be easy to manufacture.
  • the weight ratio of HCl-containing solution to commercial chitosan is between 1 and 50 and the product of normality of the HCl solution and the hydrolysis time in hours is between 0.1 and 7; and b) after the addition of solution 1 has ended for a period of 15 to 360 minutes, in particular for a period of 60 to 180 minutes, the microcapsules thus obtained remain in solution 2.
  • microcapsules produced according to the invention show a significantly reduced permeability compared to the chitosan-containing microcapsules of the prior art. After 10 days of measurement, the release of the microcapsules produced according to the invention is still below 50% (active ingredient: bovine serum albumin).
  • active ingredient bovine serum albumin
  • the process according to the invention has the advantage that the microcapsules are produced in a single process step. The elaborate devices which were previously necessary in the multi-stage processes of the prior art for transporting the microcapsules are thus eliminated. 5
  • the aqueous solution 1 can be converted into liquid droplets by methods known per se. In particular, commercially available atomizers can be used for this.
  • 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 polysulfates of polysaccharides.
  • 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 consisting of polyiysin, 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 consisting of polyiysin, 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.
  • diacid chlorides such as succinic acid chloro- 6 rid, fumaric acid chloride, glutaric acid chloride, adipic acid chloride, or tricarboxylic acids, such as citric acid, 1,2,3-propane tricarboxylic acid, hemimellitic acid, trimellitic acid, trimesic acid.
  • the size of the microcapsules produced according to the invention is between 1 and 3,000 ⁇ m, in particular between 10 and 1,000 ⁇ m.
  • microcapsules according to the invention are preferably used as carriers for active substances, in particular for pharmaceuticals, food additives, flavors, fragrances, colorants, herbicides, fungicides, bactericides, pesticides and insecticides.
  • Solution 1 is dripped into solution 2 by means of a nozzle consisting of a cannula with an inner diameter of 0.2 mm and an outer diameter of 0.4 mm.
  • the nozzle is embedded concentrically in a hollow cylinder, so that a tangential air flow can be generated via the resulting annular gap, which entrains the drops emerging from the cannula. The drops thus created fall into solution 2.
  • microcapsules formed After 1 ml of solution 1 has been introduced into 15 ml of solution 2, the microcapsules formed are allowed to sediment and the solution is decanted off. The microcapsules obtained are then suspended three times with 0.9% NaCl solution. The most common size of the microcapsules produced in this way was determined by diffraction of women and was 90 ⁇ m.
  • the model protein BSA-FITC from Sigma (catalog number: A-9771) is used.
  • Other materials are: Nathum 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 number: 71230).
  • 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). First, the proportion of trapped BSA-FITC is 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 due to the intrinsic coloration of the chitosan is avoided by the absorption 8 tion of the chitosan is withdrawn. 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 release of the microcapsules obtained in this way is only 20% of the encapsulated active ingredient after 11 days.
  • Example 2 The procedure is analogous to Example 1. 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 glyoxal solution for 30 minutes and left to stand. Then they are washed with 0.9% NaCl solution. The release of the microcapsules obtained in this way is less than 10% of the encapsulated active ingredient after 45 days.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Birds (AREA)
  • Dispersion Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Preparation (AREA)
  • Manufacturing Of Micro-Capsules (AREA)

Abstract

L'invention concerne un procédé de production de microcapsules. Ce procédé consiste a) à ajouter, en une opération, des gouttelettes d'une solution aqueuse (1) contenant au moins un polyanion soluble dans l'eau, dans une solution aqueuse (2) qui contient 0,1 à 5 % en poids de cations de calcium; et 0,1 à 5 % en poids de chitosane hydrolysé ayant un poids moléculaire moyen compris entre 2.200 et 40.000 g/mol, cette substance pouvant être obtenue par hydrolyse partielle d'un chitosane ayant un poids moléculaire moyen de plus de 50.000 g/mol dans une solution aqueuse contenant 0,1 à 4 N HCl à une température comprise entre 50 et 95 DEG C pendant un temps compris entre 0,5 et 8 heures, le rapport du poids de la solution contenant le HCl par rapport au poids de chitosane courant dans le commerce est compris entre 1 et 50 et le produit de normalité de la solution HCl et la durée d'hydrolyse est compris entre 0,1 et 7 heure. Une fois la solution (1) ajoutée, ce procédé consiste b) à laisser les microcapsules ainsi obtenues dans la solution (2) pendant 15 à 360 minutes, notamment pendant 60 à 180 minutes.
EP99908958A 1998-03-25 1999-03-12 Microcapsules a liberation retardee Withdrawn EP1063970A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE1998113010 DE19813010A1 (de) 1998-03-25 1998-03-25 Mikrokapseln mit verzögertem Release
DE19813010 1998-03-25
PCT/EP1999/001625 WO1999048479A1 (fr) 1998-03-25 1999-03-12 Microcapsules a liberation retardee

Publications (1)

Publication Number Publication Date
EP1063970A1 true EP1063970A1 (fr) 2001-01-03

Family

ID=7862189

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99908958A Withdrawn EP1063970A1 (fr) 1998-03-25 1999-03-12 Microcapsules a liberation retardee

Country Status (6)

Country Link
EP (1) EP1063970A1 (fr)
JP (1) JP2002507472A (fr)
AU (1) AU736941B2 (fr)
CA (1) CA2325554A1 (fr)
DE (1) DE19813010A1 (fr)
WO (1) WO1999048479A1 (fr)

Families Citing this family (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6458387B1 (en) 1999-10-18 2002-10-01 Epic Therapeutics, Inc. Sustained release microspheres
DE19962350A1 (de) * 1999-12-23 2001-06-28 Henkel Kgaa Gefärbte Chitosan-Kapseln
DE19962348A1 (de) * 1999-12-23 2001-07-05 Henkel Kgaa Pigmentierte Chitosan-Kapseln
EP1167618A1 (fr) * 2000-06-20 2002-01-02 Primacare S.A. Agent auxiliaire pour textiles
EP1243319A1 (fr) * 2001-03-22 2002-09-25 Primacare S.L., c/o Cognis Iberica S.L. Microcapsules (XI)
EP1243324B1 (fr) * 2001-03-22 2005-03-02 Primacare S.L., c/o Cognis Iberica S.L. Microcapsules (XII)
JP4460892B2 (ja) 2001-06-21 2010-05-12 ジェネンテック インコーポレイテッド 徐放性組成物
US6723359B2 (en) * 2001-10-18 2004-04-20 Firmenich Sa Spray-dried compositions and method for their preparation
DE10164137B4 (de) * 2001-12-30 2016-04-28 Henkel Ag & Co. Kgaa Wasch-, Reinigungs- und/oder Pflegemittel-Formulierung enthaltender Formkörper mit erhöhter Lagerstabilität sowie Verfahren zu seiner Herstellung
AU2003230320A1 (en) * 2002-05-09 2003-11-11 Peptron Co., Ltd Sustained release formulation of protein and preparation method thereof
EP1837074A1 (fr) * 2006-03-20 2007-09-26 Cognis IP Management GmbH Procédé de préparation de microcapsules à dureté contrôlée
WO2008037576A1 (fr) * 2006-09-29 2008-04-03 Unilever Plc Procédé de production de composés constitués de particules contenant de l'amidon, enrobées, intégrées ou encapsulées dans au moins un biopolymère
WO2008037578A1 (fr) * 2006-09-29 2008-04-03 Unilever Plc Composés, qui sont des particules contenant de l'amidon revêtues, intégrées ou encapsulées dans au moins un biopolymère dans un arrangement multicouche
WO2008157514A2 (fr) * 2007-06-14 2008-12-24 Genesegues, Inc. Polymères biocompatibles traités par ion métallique utiles pour des nanoparticules
CN102960599A (zh) * 2012-11-19 2013-03-13 陕西科技大学 一种含益生元的双歧杆菌微胶囊的制备方法
CN111700877A (zh) 2014-09-03 2020-09-25 吉倪塞思公司 治疗性纳米粒子和相关的组合物、方法和系统
WO2016108234A1 (fr) * 2014-12-30 2016-07-07 Yissum Research Develoment Company Of The Hebrew University Of Jerusalem Ltd. Capsules à cœur liquide comprenant un alginate non réticulé
US10385296B2 (en) 2017-03-16 2019-08-20 The Procter & Gamble Company Methods for making encapsulate-containing product compositions
US10611988B2 (en) 2017-03-16 2020-04-07 The Procter & Gamble Company Methods for making encapsulate-containing product compositions
US10385297B2 (en) 2017-03-16 2019-08-20 The Procter & Gamble Company Methods for making encapsulate-containing product compositions
CN107712543B (zh) * 2017-09-20 2021-04-16 徐宝军 一种抗絮凝姜黄素微胶囊、制备方法及其应用
JP2023543578A (ja) 2020-10-16 2023-10-17 ザ プロクター アンド ギャンブル カンパニー 少なくとも２つの封入体集団を有する消費者製品組成物
US12398348B2 (en) 2020-10-16 2025-08-26 The Procter & Gamble Company Consumer product compositions comprising a population of encapsulates
US12486478B2 (en) 2020-10-16 2025-12-02 The Procter & Gamble Company Consumer products comprising delivery particles with high core:wall ratios
CN119280103B (zh) * 2024-10-16 2025-09-02 北京青颜博识健康管理有限公司 一种含有胶原蛋白的微胶囊乳液及其制备方法
CN121136213B (zh) * 2025-11-19 2026-02-10 武汉理工大学 一种氯盐控释型沥青自愈合胶囊及其制备方法

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JPS5974984A (ja) * 1982-10-21 1984-04-27 Sumitomo Chem Co Ltd 固定化酵素もしくは固定化微生物の製造方法
JP2511612B2 (ja) * 1992-02-28 1996-07-03 株式会社紀文フードケミファ 徐放性組成物

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Also Published As

Publication number Publication date
AU2836599A (en) 1999-10-18
WO1999048479A1 (fr) 1999-09-30
DE19813010A1 (de) 1999-10-14
JP2002507472A (ja) 2002-03-12
CA2325554A1 (fr) 1999-09-30
AU736941B2 (en) 2001-08-09

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