WO2003043729A1

WO2003043729A1 - Nanocapsules and microcapsules comprising reactive polymers and method for the production thereof

Info

Publication number: WO2003043729A1
Application number: PCT/EP2002/012913
Authority: WO
Inventors: Steffen Panzner; Silke Lutz; Steffen Burgold
Original assignee: Novosom Ag
Priority date: 2001-11-18
Filing date: 2002-11-18
Publication date: 2003-05-30
Also published as: AU2002358514A1; DE10157046A1

Abstract

The invention relates to nanocapsules and microcapsules comprising reactive polymers. The preferred polymers P1 are soluble in water and particularly comprise anhydride, imide, acid chloride and/or aldehyde functions. Polymers P1 together with other water-soluble polymers P2, which have a plurality of functional groups, form covalently bonded networks on the surface of colloidal carriers.

Description

Nano- and microcells include reactive polymers and processes for making them

The invention relates to microcapsules and / or nanocapsules made from crosslinked polymers, these capsules comprising at least one reactive polymer and at least one different water-soluble polymer. These micro and / or nanocapsules can be used for pharmaceutical or cosmetic applications; for example in the encapsulation of aromas, fragrances or therapeutically active substances.

It is known that colloidal carriers can be stabilized sterically and electrostatically by the application of polymer layers. Suitable structures and methods are described in the prior art for this purpose, which are briefly described below:

WO 00/28972 discloses the coating of liposomes with several layers of water-soluble polymers which are covalently crosslinked with one another. In addition to the use of low molecular weight crosslinkers, the use of reactive polymers such as oxidized or hydrazylated dextrans or starches has also been described. However, the presence of low molecular weight crosslinking agents, which are difficult to separate and make the production process more expensive and cause health problems, is disadvantageous. For example, the use of glutaraldehyde is only permitted to a limited extent in the manufacture of cosmetics. Similar problems also arise in the production of structures according to US 5,540,927.

US 5,837,747 and several documents of the patent family concerned disclose the manufacture and use of Biopolymers with ethylenically unsaturated groups. However, the compounds listed are comparatively complex to produce and are not readily available. The presence of unreacted ethylenically unsaturated groups in biological systems is also disadvantageous, since these groups can, for example, undergo further reactions with free thiols of the proteins or glutathione.

WO 00/03797 furthermore discloses covalently crosslinked cladding layers on colloidal templates or nanohollow bodies and methods for their production. According to this process, water-soluble polyelectrolytes are first deposited on the template in several layers and then crosslinked by adding bifunctional reagents. As with other prior art processes, the disadvantage here is the use of low molecular weight crosslinking agents such as glutaraldehyde, which entails ecological and health problems.

Microcapsules using polyaspartic acid are known, for example, from US5540927. They arise during the coacervation of gelatin and polyaspartate and can subsequently be stabilized by glutaraldehyde. The disadvantage is the use of the ecologically problematic aldehyde and the comparatively high consumption of gelatin and polyaspartate in the production of the microcapsules.

The object of the invention is therefore to provide structures and a simple and safe method for their production which do not have the disadvantages mentioned; especially those structures and processes that avoid the use of low molecular weight crosslinkers.

The invention solves this technical problem by providing microcapsules and / or nanocapsules made of crosslinked polymers, the capsules comprising at least one reactive polymer Pl comprising imide, aldehyde, anhydride and / or acid chloride functions and at least one different water-soluble polymer P2. The invention is therefore based on the surprising teaching that nano- or microparticles or nano- and / or microcapsules can be coated simply and effectively with different polymers, at least one of these polymers having a large number of imide, anhydride, aldehyde and / or comprises acid chloride functions and another second polymer with the. the first polymer can form covalent bonds, such as amide bonds or ester bonds, and crosslinked structures are formed as a result; the structures being networked in such a way that they can be used in particular in the field of pharmacy, clinic and / or cosmetics.

The e.g. Anhydrides present, in particular acid anhydride groups and / or acid chlorides, can in particular react with water, primary and secondary alcohols and primary and secondary amines. The first polymer can therefore form networks with further polymers P2 which comprise a large number of such groups. Another advantage is that the reactivity of the polymer decreases after the encapsulation reactions carried out here have ended and finally disappears completely.

The encapsulation of liposomes with water-soluble polymers is described in WO 00/28972 and leads to structures which are surrounded by very thin, often monomolecular, layers of polymers. By means of covalent bonds, a firm connection between the polymers and the particle surface is achieved; in further reaction steps, several layers of polymer can be applied, so that a stable network is created. After removing the internal liposome, hollow nanobodies can also be produced in this way. A first group of polymers is derived, for example, from polysuccinimide. This compound has long been produced on an industrial scale and can in particular be converted into functionalized derivatives or polyaspartic acid. Polysuccinimide is not water-soluble, polyaspartic acid is readily water-soluble, so that during the hydrolysis intermediate stages occur which are both water-soluble and have reactive imide functions.

One possibility for the targeted synthesis of a water-soluble copolymer of succinimide and aspartic acid units and of derivatives of this compound is described by Sikes et al. disclosed in US 5981681. An advantage over the synthesis from polysuccinimide is that the polymer can be prepared from naturally occurring L-aspartic acid, which leads to a very biocompatible product.

Advantageously, the use of reactive polymers makes it possible to dispense with the use of low-melocular crosslinking agents, since the reactive polymers already contain the covalent crosslinking agent due to their chemically reactive groups. When constructing the polymer shell, a polymer pair P1 and P2 is used according to the invention, which in particular has complementary reactivities. The polymer P1 with its chemical groups can form the active part, ie the reaction polymer, of which P2 is a reaction partner. For example, there can be active chemical groups on PI which react with amino functions. For example, it is possible to first deposit the polymer P1 on a template particle and then to add the polymer P2, which bears, for example, amino groups. This then forms the second layer. By adding the polymer Pl again, a third layer can be deposited; this process can of course be repeated. The condition of the complementary reactivity of polymer P1 and P2 means in particular that the reactive polymer P1 does not groups which react with one another, that is to say preferably comprise only like-minded reactivities. The use of reactive polymers comprising the imide functions and / or anhydride, in particular acid anhydride functions, is preferred. A major advantage over other known polymers is their reactivity with water, which leads to hydrolysis and thus advantageously to a disappearance of the reactivity within a short time. In the end product, no unwanted further reactions are possible, which can lead to health hazards when used in pharmaceutical or cosmetic areas.

Preferred polymers P2 are proteins, peptides, gelatin, albumins, globins, hemoglobins, casein, or protein mixtures such as whey, soy protein, wheat glue, serum or vegetable extracts, protamines, polylysine, polyserine, polyornithine, and also carbohydrates such as chitosan, amino-functionalized dextrans , Dextrans, starches, polyethyleneimine, polyallylamine or acrylates, comprising primary amino functions, polyvinyl alcohol or polythiols.

It can be advantageous if both polymers P1 and P2 or polymer P1 or P2 and the particles to be encapsulated form electrostatic interactions. These can be used for a non-covalent pre-fixation; the structures are then stabilized by the comparatively slow formation of the covalent bonds. WO 01/64330 describes the rapid and continuous encapsulation of colloids with polyelectrolytes, which is included in the disclosure content of the teaching according to the invention.

Advantageously, both Pl and P2 can initially be connected to the

Particle surface are bound; it is possible to attach this covalently or by means of hydrophobic molecular parts or mediated through ionic interactions. Regardless of the type of binding, Pl and P2 form a stable, covalently linked network that completely surrounds a single colloid particle. A decrease in the interaction between Pl and P2, for example due to a change in pH, is therefore advantageously little or not disadvantageous after the crosslinking reaction has ended, since the enclosed colloid cannot escape due to its size. For example, the electrostatic attraction of poly (maleic anhydride-co-acrylic acid) (PI) and albumin (P2), which exists at pH 4, is converted into an electrostatic repulsion by changing to pH 7.5. Albumin as a protein has an isoelectric point at pH 5, above it is negative, below it positively charged. However, if both polymers are covalently cross-linked, the layers cannot detach. In the case of the preferred liposomal templates, a complete or partial elimination of the interaction can be advantageous if, for example, an undesired permeabilization of the structure occurs due to clustering of lipids. An undesired permeabilization of liposomes, including phosphatidylethanolamine and other charged lipids, is observed when coating with complementarily charged polyelectrolytes.

In a preferred embodiment, the nano- and / or microcapsules comprise a polymer P1, comprising succinimide monomers and, particularly preferably, further functional groups. Polysuccinimide, for example, is sparingly or not soluble in water. Advantageously, the nano- and / or microparticles can comprise further hydrophilic functions such as, for example, sulfonic acids, ethoxy groups, amides or carboxylic acids, in order to ensure or increase the solubility of the polymer - such as polysuccinimide - in water. The presence of carboxylic acid functions can advantageously be achieved by partial hydrolysis of polysuccinimide. For this purpose, the product is heated in particular with water with the addition of alkali. The reaction can be stopped when most of the polysuccinimide has gone into solution. Such a preparation advantageously leads to the desired product. An even more elegant and controllable method is, for example, the thermal copolymerization of aspartic acid and its salts under suitable conditions, as described, inter alia, in US Pat. No. 5,981,691, which is included in the disclosure content of the teaching according to the application. Here you immediately get a water-soluble product that is well suited for further use. A variation in the chain length can preferably be achieved by using bifunctional comonomers, such as diamines.

The imido groups present in the polymer P1 can react with water, alcohols and primary amines under slightly alkaline conditions. The first polymer P1 can advantageously form networks with further polymers P2 which comprise a large number of such groups. Another advantage is that the reactivity of the polymer P1 decreases after the encapsulation reactions carried out here have ended and finally disappears completely. This creates products with very low toxicity. In a preferred embodiment of the invention, the micro- and / or nanocapsules comprise a copolymer comprising aspartic acid and succinimide. A copolymer of aspartic acid and succinimide hydrolyzes completely to polyaspartic acid, a hardly toxic and ecologically harmless polymer from amino acids (cf. Baypure ™ DS100, Bayer, product description).

In a further embodiment of the invention, polymers PI, comprising acid anhydride functions or acid chlorides, are used Encapsulation of particles used. Suitable polymers are obtainable from monomers such as, for example, acrylic anhydride, citraconic anhydride, methacrylic anhydride, methacryloyl trimellitic anhydride, acryloyl chloride, methacryloyl chloride, or maleic anhydride. They contain other functional groups to improve their solubility in water, such as sulfonic acid groups, carboxyl groups or ethoxy groups or tertiary or quaternary amino functions or acid amides.

Another group of polymers contains acid anhydride functions or acid chlorides in the side chain in the sense of a graft polymer. Polymers that are not water-soluble, such as polymaleic anhydride or copolymers of maleic anhydride and olefins or polyacryloyl chloride, can be partially hydrolyzed to improve water solubility. They are then interpreted as copolymers of anhydridischen and carboxylisehen monomers and covered by the ^{'above-described} compounds.

A preferred embodiment is the use of copolymers with hydrophilic substituents, such as sulfonyl, tertiary amino, ammonio, amide or carboxylic acid functions. Preferred comonomers are therefore, for example, acrylic acid, methacrylic acid, diethylaminoethyl acrylate, prosthesis, methylaminoethyl acrylamide, acryloxyethyltrimethylammonium chloride, dimethyldiallylammonium chloride, propenesulfonic acid, sulfethyl methacrylate, styrenesulfonic acid, acrylamide, methacrylamide, acryloyltris-hydroxymethylacrylate, methacryloyl methacrylate,

Vinyl pyrrolidone, vinyl alcohol and other such compounds.

Another preferred copolymer comprises acrylic acid and a

Maleic acid, e.g. B. a maleic anhydride and possibly other hydrophilic monomers such as acrylamide. A is preferred Copolymer comprising maleic acid and acrylic acid. Other preferred copolymers are poly (vinyl methyl ether-co-maleic anhydride), poly (butadiene-co-maleic anhydride), poly (ethylene-co-maleic anhydride).

In a further preferred embodiment, the copolymer comprises an aspartic acid and a succinimide, the aspartic acid preferably being an L-aspartic acid. In a further preferred embodiment, the reactive polymer is a copolymer comprising maleic anhydride monomers. It is particularly preferred that the copolymer comprises maleic acid and acrylamide.

In a further preferred embodiment, the water-soluble polymer P2 comprises at least one amino and / or hydroxyl function. The polymer P2 is preferably a protein, a carbohydrate and / or a peptide structure or a mixture of these. It is preferred that P2 comprises gelatin, albumins, globins, hemoglobins, casein, whey, soy protein, wheat gluten, serum and / or vegetable extracts. It is further preferred that P2 comprises protamines, polylysine, polyserine, polyornithine and other carbohydrates. The other carbohydrates are preferably chitosan, amino-functionalized dextrans, dextrans, starches, polyethyleneimine, polyallylamine, polyacrylates, polyvinyl alcohol and / or polythiols. It is preferred that the acrylates comprise primary amino functions.

In a further particularly preferred embodiment of the invention, the microcapsules and / or nanocapsules comprise colloidally dissolved particles in their interior. It is preferred that the colloidal particles are liposomes, cells, latex particles, crystals, oil-in-water emulsions, water-in-oil-in-water emulsions (w / o / w), protein aggregates and / or pigments. In a further embodiment of the invention, polymers P1, comprising aldehyde functions, are used to encapsulate particles. Suitable polymers are accessible, for example, by polymer-analogous reaction of poly sugars with oxidizing agents such as H202, potassium peroxodisulfate or sodium periodate. Two vicinal hydroxyl groups are oxidized to the aldehyde and at the same time the 6-ring of the sugar is split, but the main polysaccharide chain remains intact. Two aldehyde functions are formed per monomer, the total content of aldehyde groups can be controlled via the reaction time or oxidant concentration. The polymers contain further functional groups to improve their water solubility, such as sulfonic acid groups, carboxyl groups, which are often already present due to the natural origin of the material (cf. heparin, alginate) or tertiary or quaternary amino functions or acid amides.

The invention also relates to a method for producing microcapsules and / or nanocapsules, reactive polymers comprising imide, aldehyde, anhydride and / or acid chloride functions being used to produce a capsule wall.

A preferred embodiment is the layer-by-layer deposition of polymers on liposomal templates according to WO 00/28972. Surprisingly, it was found that other structures, such as cells, oil-in-water (o / w) emulsions, multiple emulsions - such as w / o / w double emulsions -, pigments, crystals, protein aggregates or latex particles can also be found in this way have it coated. A prerequisite for a coating of the type mentioned is, for example, the presence of functional groups such as amino, thiol, hydrazo, aldehyde, carboxyl, active ester, hydroxyl or azide hydrogen groups on the surface of the colloidally dissolved particles or an electrostatic attraction between the polymer and Colloid. The shell layer is built up in particular at a phase boundary, for example that between a lipid layer and the medium, but advantageously not beyond this boundary. All of the polymers P1 and P2 are preferably water-soluble and there is no separation of the polymers in two different phases, as is the case, for example, in known polycondensation reactions between a water-soluble and an oil-soluble polymer.

Advantageously, a reactive polymer or another polymer can first be brought into contact with the templates. A preferred embodiment is that a reactive polymer is first brought into contact with the template and another polymer is added before the imido- or anhydride or acid chloride functions are completely hydrolysed.

A particularly preferred embodiment of the method for producing the nano- and / or microparticles is based on the formation of electrostatic interactions between the template and the first polymer or between an already single or multiple coated particle and a next polymer. In the latter case, the single or multiple-coated particles themselves are to be understood as templates for the reaction. The number of layers applied is at least two, but can also be much larger.

An advantageous method and a device for producing electrostatically stabilized polymer layers on colloidal templates is disclosed in WO 01/64330, which is included in the disclosure content of the invention. Many of the reactive polymers described here are water-soluble in particular, but can only be stored to a limited extent or not as an aqueous solution, since reactive groups such as anhydrides, acid chlorides and imides react with water and cancel the activation. It is therefore an advantage if the Reactive polymers P1 are dissolved in water-free, polar, but water-miscible solvents, such as DMF, THF, dioxane, acetone or DMSO, before coating. DMSO is particularly preferred because of its low toxicity for pharmaceutical and cosmetic applications. With the method, template particles can also be coated using these reactive polymers if they are fed into the process in organic solution. If carboxyls, sulfonates or other charged groups are present to increase the hydrophilicity of the molecule, there is advantageously a rapid attachment of PI to the colloid particles due to electrostatic attraction and thus to a spatially close fixation on the reaction partner. This advantageously achieves a high local concentration of the chemically reactive groups on the reactant with respect to water. The device described in WO 01/64330 allows continuous and rapid process control with a mixture of the reactants, in particular within 1 second, which is not the case with conventional process control in a batch process with stirring, wherever the entire reaction volume has to be moved. The combination of the teaching according to the invention with the method according to WO 01/64330 advantageously makes it possible due to its special design that only a small part of the reactive groups escapes the crosslinking reaction by hydrolysis.

In one embodiment, it is preferred that the polymers are deposited in layers. All electrostatically charged colloidal particles, such as cells, liposomes, o / w emulsions, w / o / w double emulsions, crystals, protein aggregates, pigments, latex particles and others, are particularly suitable as templates for this method. If o / w emulsions or w / o / w emulsions or liposomes are to be encapsulated, a first polymer with amphipath properties can be used. exemplary

Compounds are polyelectrolytes based on acrylate or vinyl, in which a proportion of up to about 10% of the monomers is provided with long-chain hydrocarbon chains; e.g.

Poly (N-ethyl-4-vinyl-pyridinium-co- (N-palmityl- -vinyl-pyridinium) bromide). Also ionic complexes with surfactants

Polyelectrolytes are suitable compounds, such as poly (diallyldimethyl) ammonium poly (stearate) or poly

(methacrylate poly (dimethyldioetadecyl ammonium).

Further preferred processes for the production of nano- or microcapsules with reactive polymers are known to the person skilled in the art as coacervate formation (see R. Voigt: Pharmaceutical Technology, Ullstein Mosby, 1995, p. 289 ff.)

Reactive polymers such as those described here can be used in the complex coacervation of, for example, gelatin. However, they can also be used for the subsequent consolidation of simple coacervates.

The teaching of the invention is used e.g. in the encapsulation of colloids or in the production of nano and hollow micro spheres. Encapsulation of colloids can be used to increase the mechanical or physiological stability of such particles. For example, liposomes can be protected against mechanical and biochemical stressors by encapsulation. The mechanically sensitive droplets of a w / o / w double emulsion can also be stabilized in this way.

In another embodiment, the colloid stability, i.e. the avoidance of flocculation or aggregation, can be achieved.

For example, liposomes are unstable in the presence of an emulsion and fuse with the droplets of the emulsion. By This process can be avoided by individually encapsulating the liposomes or the emulsion droplets. Improved use of liposomes as stable active substance containers or as depot forms or as transporters in cosmetics or pharmaceuticals is then possible.

Other possible uses of the particles are in the encapsulation of fragrances, aromas or other volatile substances which are to be released only slowly.

If the colloids are encapsulated with reactive polyaspartates, slow release in biological systems can be achieved by hydrolysis or proteolytic cleavage. This is the case, for example, if the particles are injected subcutaneously or intramuscularly. This is also the case when the particles are applied to the skin and are dissolved by the action of ^■ bacteria. In this case, the capsules are suitable, for example, for the production of deodorants or for the prevention of bacterial infections.

The invention also relates to the use of the micro- and / or nanocapsules for the production of cosmetic products. The invention also relates to the use of the microcapsules and / or nanocapsules for the transport of active ingredients in pharmaceutical applications. The invention further relates to the use of the microcapsules and / or nanocapsules for the delayed release of active substances in pharmaceutical applications. Another preferred embodiment of the invention relates to the use of microcapsules and / or nanocapsules for encapsulating aromas and / or fragrances.

The invention is to be illustrated below with the aid of examples, without being restricted to these examples. example 1

Activation of alginate

A solution of 1 mg / ml (5.88 mM in monomer) alginate is used to generate reactive aldehyde groups in a poly sugar

(SIGMA, low viscosity) in 10 mM acetate buffer at pH 5 to a

Sodium periodate concentration adjusted to 20 mM and allowed to react for 2 hours. The excess NaI04 is then removed from the reaction mixture by dialysis against water. Buffering is restored by further dialysis against 10 mM HEPES / 100 mM NaCl pH 7.5. The degree of oxidation was measured by photometric aldehyde determination with Purbald® at 355 nm (G. Avigad, Analytical Biochemistry (1983), 134, 499-

504). 70% of the monomer units were oxidized (when using

10 mM NaJ04 is 63%).

Example 2 Coating liposomes with activated alginate

Production of liposomes

60 mol% distearoylphosphytidylglycerol and 40 mol% cholesterol are dissolved in a mixture of isopropanol and chloroform (2/1) and evaporated to dryness under vacuum. The lipid film is then rehydrated in so much buffer (10mM Na acetate, 100mM NaCl, pH 4) that a lipid concentration of 15 mg / ml is obtained. The suspensions are extruded several times through isopore polycarbonate membranes with a pore size of 200nm.

Coating the liposomes with activated alinate and polvallylamine

Activated alginate (according to Example 1) and polyallylamine (SIGMA) are in a concentration of 1 mg / ml in 10 mM HEPES / 100mM NaCl pH 7.5 buffer dissolved. The liposomes are diluted in the same buffer to a lipid concentration of 0.15 mg / ml. The amounts of polymer given below are successively added to the liposomes:

Cycle polymer μg polymer / mg lipid

1 polyallylamine 50

2 alginate 120

3 polyallylamine 90

4 alginate 165

Evidence of stabilization through covalent crosslinking:

The crosslinking reaction was carried out at room temperature and at 37 ° C.

In parallel to the nanocapsules with activated alginate, those with commercially available alginate were also prepared. The amounts of polymer for the coating did not differ from those mentioned above. Both types of nanocapsules were incubated for 3 days in 0.5 M NaCl and their particle size measured after certain time intervals. An instability is shown by an increase in size, i.e. Aggregate formation (- no agg. To +++ strong agg. Formation / flocculation).

aggregation

1 d in 0.5 M 3 d in 0.5 M NaCl NaCl

Unconnected +++ +++

Networks 3d RT - - / +

Networked 2h - - / +

37 ° C

Connected 17h RT + ++

Networked 17h - -

37 ° C As shown in the table, the higher temperature of 37 ° C leads to much more stable particles due to better cross-linking.

Example 3

Coating the liposomes with chitosan and

Polysuccinimide / aspartate

Chitosan (Pronova) and polyaspartate with 30% imide groups are dissolved in a concentration of 1 mg / ml in buffer (10 mM Na acetate, pH 4). The liposomes (as in Example 2) are diluted in the same buffer to a lipid concentration of 0.15 mg / ml. The amounts of polymer given below are successively added to the liposomes:

Cycle polymer μg polymer / mg lipid

1 Chitosan 87

2 polyaspartate 52

3 Chitosan 48

4 polyaspartate 117

Na borate buffer (100 mm pH 9.5) is then added and the suspension is kept at 50 ° C. for 4 h. After cooling, a pH of 7.5 is set with hydrochloric acid.

Evidence of the formation of envelope structures

Liposomes or part of the suspension are treated with Triton X-100 (0.2% in water) after the reaction has ended. This will dissolve the liposomes. Liposomes can no longer be detected by means of light scattering, the encapsulated structures still scatter the incident light even after the inner liposomes have dissolved. Example 4

Stabilization of liposomes in o / w emulsions

Preparation of the Liposomes Liposomes are prepared as in Example 2. The

Hydration takes place in a buffer containing 10MM HEPES,

50mM NaCl, 100mM carboxyfluoreseein, pH 7.5) so that one

Lipid concentration of 15 mg / ml is obtained. The suspension is extruded as above. Carboxyfluoreseein not included is by

Gel filtration separated. A buffer (10 mM Na acetate pH4) is used for this.

The liposomes are coated as in Example 3.

Analyzes the stability of the structures lml of the liposomes or 1ml of ^■ nanocapsules produced therefrom are mixed with each 5 ml of a o / w emulsion (Lipovenös) and incubated for 24h. The mixture of liposomes and the emulsion then fluoresces with more than 30% of the maximum intensity. The mixture of the nanocapsules and the emulsion fluoresces with less than 15% of the maximum intensity.

Example 5

Coating an emulsion

50 mg of poly (diallyldimethyl) ammonium poly (stearate) are dissolved in 5 g of Avocadool and emulsified with 45 mL of HEPES 10 mM pH 7.5 using an Ultraturrax. 2.75 ml of an mg / ml polyacrylic acid (corresponding to 55 μg polymer / mg emulsifier) are added to this emulsion in order to place a first polymer layer around the oil droplets which does not yet contain any reactive polymer. Then 10 mL of this emulsion were diluted with 90 mL HEPES 10 M. The Additional layers are applied to the emulsion droplets by adding the following amounts of the polymers polyallylamine (1 mg / ml in HEPES 10 mM pH 7.5) and poly (ethylene-co-maleic anhydride) (1 mg / ml in dioxane):

Cycle μg polymer / mg

Polymer emulsifier

1 polyallylamine 35

2 poly (E-co-

75 MSA)

3 polyallylamine 40

4 poly (E-co-

90 MSA)

5 polyallylamine 40

6 poly (E-co-

110 MSA)

The coated emulsion is then freed from the organic solvent in a tangential dialysis and concentrated to 10% based on the oil content. The resulting emulsion is stable for months.

Example 6

Production of nanocapsules with poly (ethylene-co-maleic anhydride) and polyallylamine

Liposomes DSPG / Chol according to Example 2 are diluted to 0.15 mg / ml with HEPES 10 mM pH 7.5. Polyallylamine hydrochloride (Aldrich) is provided as an mg / ml solution in HEPES 10 mM pH 7.5, poly (ethylene-co-maleic anhydride) as a 1 mg / ml solution in dioxane.

The amounts of polymer given below are successively added to the liposomes: Cycle polymer μg polymer / mg lipid

1 polyallylamine 48

2 poly (E-co-MSA) 79

3 polyallylamine 53

4 poly (E-co-MSA) 110

5 polyallylamine 125

6 poly (E-co-MSA) 185

The organic solvent is then removed from the nanocapsule suspension using tangential dialysis.

Example 7

Continuous production of nanocapsules with poly (ethylene-co-maleic anhydride) and albumin

Liposomes DSPG / Chol according to Example 2 are diluted to 0.15 mg / ml with water and adjusted to pH 4 with 1N HCl. Bovine serum albumin is provided as an mg / ml solution in water (buffer-free, pH 4), poly (ethylene-co-maleic anhydride) as a 1 mg / ml solution in dioxane. To coat the liposomes with the polymers, the liposome solution is passed through the device according to WO 01/64330 in a constant flow using a pump. The polymers used for the coating are introduced one after the other into the system of the main flow section. The reactants are mixed in the mixing chambers at the feed points. After passing through the device, the nanocapsule suspension is collected. In each case 1L portions are freed of the organic solvent on a tangential dialysis using a hollow fiber module and then concentrated to 20 ml.

Claims

claims

1. Micro- and / or nanocapsule made of crosslinked polymers, characterized in that the capsule comprises at least one reactive polymer P1 comprising imide, aldehyde, anhydride and / or acid chloride functions and at least one different water-soluble polymer P2.

2. Micro- and / or nanocapsule according to claim 1, characterized in that the reactive polymer is a copolymer comprising succinimide monomers.

3. Micro- and / or nanocapsule according to claim 2, characterized in that the copolymer comprises aspartic acid and succinimide.

4. Micro- and / or nanocapsule according to claim 3, characterized in that the aspartic acid is an L-aspartic acid.

5. Micro- and / or nanocapsule according to claim 1, characterized in that the reactive polymer is a copolymer comprising maleic anhydride.

6. micro- and / or nanocapsule according to claim 5, characterized in that the copolymer comprises maleic acid, acrylic acid and / or acrylamide.

7. Micro- and / or nanocapsules according to one of claims 1 to 6, characterized in that the water-soluble polymers P2 comprise at least one amino and / or hydroxyl function.

8. Micro and / or nanocapsules according to claim 7, characterized in that the polymers P2 comprise proteins, carbohydrates, peptides and / or mixtures of these.

9. micro- and / or nanocapsules according to claim 8, characterized in that the polymers P2 include gelatin, albumins, globins, hemoglobins, casein and / or mixtures thereof.

10. Micro- and / or nanocapsules according to claim 8, characterized in that the polymers include P2 whey, soy protein, wheat gluten, serum, vegetable extracts, protamines, polylysine, polyornithine and / or polyserine.

11. Micro- and / or nanocapsules according to claim 8, characterized in that the polymers P2 comprise chitosan, dextrans, starches, polyethyleneimine, polyallylamine and / or acrylates.

12. Micro- and / or nanocapsules according to claim 11, characterized in that the acrylates comprise primary amino functions, polyvinyl alcohol and / or polythiols.

13. Micro- and / or nanocapsules according to claim 1, characterized in that the capsules comprise colloidally dissolved particles inside.

14. micro- and / or nanocapsule according to claim 13, characterized in that the colloidal particles are multiple emulsions.

15. Micro- and / or nanocapsule according to claim 13 or 14, characterized in that the colloidal particles liposomes, cells, latex particles, crystals, oil-in-water emulsions, water-in-oil-in-water emulsions, protein aggregates and / or pigments.

16. A method for producing microcapsules and / or nanocapsules, characterized in that

Reactive polymers comprising imide, aldehyde, anhydride and / or acid chloride functions can be used to produce a capsule wall.

17. A method for producing micro- and / or nanocapsules according to claim 16, characterized in that carboxylic acid chloride functions are used as the acid chloride functions.

18. A method for producing micro- and / or nanocapsules according to claim 16 or 17, characterized in that the polymers are deposited in layers.

19. A method for producing micro- and / or nanocapsules according to claim 16, characterized in that the deposition of the polymers takes place by complex coacervation.

20. A method for producing micro- and / or nanocapsules according to one of claims 16 to 19, characterized in that the reactive polymers are used for the subsequent curing of preformed capsules.

21. Use of the micro- and / or nanocapsules according to one of claims 1 to 15 for the production of cosmetic products.

22. Use of the micro- and / or nanocapsules according to one of claims 1 to 15 for the transport of active ingredients in pharmaceutical applications.

23. Use of the micro- and / or nanocapsules according to one of claims 1 to 15 for the delayed release of active ingredients in pharmaceutical applications.

24. Use of the micro- and / or nanocapsules according to one of claims 1 to 15 for encapsulating flavors and / or

Fragrances.

25. Use of imide, aldehyde, anhydride and / or acid chloride functions for producing a capsule wall of micro and / or nanocapsules.