EP1237988A1

EP1237988A1 - Method for producing nanoparticulate chitosans or chitosan derivatives

Info

Publication number: EP1237988A1
Application number: EP00972819A
Authority: EP
Inventors: Christian Kropf; Stephan Reil
Original assignee: Cognis Deutschland GmbH and Co KG
Current assignee: BASF Personal Care and Nutrition GmbH
Priority date: 1999-10-29
Filing date: 2000-10-20
Publication date: 2002-09-11
Also published as: JP2003514046A; DE19952073A1; WO2001032751A1

Abstract

The invention relates to a method for producing nanoparticulate chitosans or chitosan derivatives with particle diameters in the range of from 10 to 1000 nm. According to the inventive method, (a) the chitosan or chitosan derivative is dissolved in an acidic aqueous medium and (b) the pH of the solution is raised in the presence of a surface modifier to such an extent that the chitosan is precipitated. The invention allows for the production of non-agglomerating nanoparticles in dispersed or dry form in a simple manner and independent of organic solvents.

Description

Process for the production of nanoparticulate chitosans or chitosan derivatives

The invention is in the field of nanoparticles and relates to the production of chitosans or chitosan derivatives in nanoparticulate form.

In contrast to most hydrocolloids, which are negatively charged in the range of biological pH values, chitosan is a cationic biopolymer under these conditions. The positively charged chitosan can interact with oppositely charged surfaces and is therefore used, for example, in cosmetic hair and body care products as well as pharmaceutical preparations (cf. Ullmann ^'s Encyclopedia of Industrial Chemistry, 5th Ed., Vol. A6, Weinheim, Verlag Chemie, 1986, pp. 231-332), where it is used as a moisturizer and film former. The same applies to derivatives of chitosan in which the basic character of the molecule is retained. These include, for example, chitosan alkoxylation products such as ethoxylates and propoxylates.

The properties and possible uses of chitosans and chitosan derivatives depend considerably on the form in which these substances are present, in particular the particle size and consistency. A typical characteristic of chitosan is its poor solubility in the neutral and alkaline pH range as well as in general in non-aqueous media. Another characteristic is its pronounced tendency to gel even at low concentrations, which makes the handling of chitosan and its use, in particular in cosmetics, problematic in many cases. Furthermore, chitosan is only compatible to a limited extent with other components, for example in cosmetic formulations. There is thus a need for chitosans which are easy to handle and dose, are stable in storage and can be processed and used in formulations better than conventional product qualities.

Various attempts are known from the literature to influence the properties of chitosan via its particle size and to use small chitosan particles for specific purposes. The chitosan microspheres loaded with an oil body and described in DE 19712978 are suitable as active substance depots which release the active substance in a time-delayed and controlled manner. The microspheres described there represent beads with a diameter of 0.01 to 6 mm. WO 0047177 discloses that the absorption of chitosans or chitosan derivatives can be significantly increased both by the stratum corneum of the skin and by the keratin fibrils of the hair, if these are in the form of nanoparticles, ie particles with an average diameter in the range from 10 to 300 and preferably 50 to 150 nm. JP-A 09221502 discloses chitosan nanospheres which are produced by emulsifying aqueous chitosan solutions in organic solvents in the presence of quaternary ammonium salts. WO-A 9801162 and WO-A 9801160 describe chitosan nanospheres which consist of complexes of chitosan with nucleic acids and are produced by coacervation techniques.

A disadvantage of the production processes known from the prior art, which use an organic solvent, is the often difficult isolability of the nanoparticles. In addition, it is often not possible to completely free the nanoparticles from the organic solvent, which severely limits cosmetic and pharmaceutical applications in particular.

Another disadvantage of prior art manufacturing processes is that salts produced as by-products are often difficult to remove.

For a broader application, for example in cosmetics and pharmacy, there is a need for chitosan particles whose size is in the nanometer range, which can be produced without organic solvents and which are not necessarily associated with a specific active ingredient, such as nucleic acids in the case of the two aforementioned WOs -Scripts or Ölkörpem in the case of DE 19712978, or a certain surfactant are preloaded. Furthermore, a manufacturing process for such particles should be technically simple and inexpensive and be feasible in conventional and widespread technical plants.

Surprisingly, it was found that the object described above can be achieved by a production process in which an aqueous solution of chitosans or chitosan derivatives is precipitated in the presence of surface modification agents.

The invention thus relates to processes for the preparation of nanoparticulate chitosans or chitosan derivatives with an average particle diameter in the range from 10 to 1000 nm, preferably from 50 to 200 nm, in which

(a) dissolving the chitosan or chitosan derivative in an acidic aqueous medium

(b) raises the pH of the solution in the presence of a surface modifier to such an extent that the chitosan precipitates.

The process is preferably carried out in the absence of organic solvents. The term organic solvents does not explicitly include the O- Surface modification agent and, if appropriate, organic acids used in step (a) of the process for dissolving the chitosan or chitosan derivative.

Chitosans are biopolymers and belong to the group of hydrocolloids. From a chemical point of view, these are partially deacetylated chitins of different molecular weights. The production of chitosans is based on chitin, preferably the shell remains of crustaceans, which are available in large quantities as cheap raw materials. The chitin is usually first deproteinized by adding bases, demineralized by adding mineral acids and finally deacetylated by adding strong bases, it being possible for the molecular weights to be distributed over a broad spectrum. Appropriate methods are, for example, made from Makromol. Chem. 177, 3589 (1976) or French patent application FR 2701266 A1. Those types are preferably used as are disclosed in German patent applications DE 4442987 A1 and DE 19537001 A1 (Henkel), which have an average molecular weight of 800,000 to 1,200,000 Daltons, a Brookfield viscosity (1% by weight ig in glycolic acid) below 5000 mPas, have a degree of deacetylation in the range from 80 to 88% and an ash content of less than 0.3% by weight. Chitosan derivatives in the sense of the present invention are to be understood as those derivatives which are water-soluble at acidic pH values, but are sparingly soluble in water in the neutral range and at alkaline pH values, i.e. H. which have a similar solubility behavior as the chitosans themselves. Such chitosan derivatives are, for example, alkoxylation products of chitosans with ethylene oxide, propylene oxide or mixtures of the two, and also derivatives which contain basic amino groups.

In the first step of the process according to the invention, a chitosan or chitosan derivative is dissolved in water as a solvent with the addition of an acid. The chitosan or chitosan derivative is dissolved by salt formation with a mineral acid or an organic acid, for example with hydrochloric acid, sulfuric acid, methanesulfonic acid, glycolic acid, lactic acid, salicylic acid, adipic acid or ascorbic acid. Hydrochloric acid, glycolic acid and lactic acid are preferred according to the invention. The order in which the individual components are put together is not critical in the preparation of the solution. The chitosan or chitosan derivative is preferably placed in water and mixed with the amount of acid required to form a solution while stirring. The chitosan or chitosan derivative is preferably dissolved at pH values between 1 and 5. In a further preferred embodiment, the chitosan or chitosan derivative is introduced into an aqueous acid. In the second step of the process, the pH of the aqueous solution of the chitosan or chitosan derivative is raised to such an extent by means of an alkalizing agent in the presence of a surface modifying agent that the nanoparticulate chitosan or chitosan derivative is precipitated. Aqueous solutions of hydroxides of alkali or alkaline earth metals or ammonia are preferably used as the alkalizing agent. The precipitation is preferably carried out with mechanical mixing, for example by means of a stirrer. During the precipitation, either the acidic solution of the chitosan or chitosan derivative is introduced and the alkalizing agent is added, or the procedure is reversed. It is essential to the invention that the acidic solution of the chitosan or chitosan derivative is precipitated in the presence of a surface modifier. The surface modifier can be either in the acidic solution or in the alkalizing agent. In a further variant of the production process according to the invention, the acidic solution of the chitosan or chitosan derivative, the alkalizing agent and the surface modifying agent, preferably in the form of aqueous solutions, can also be combined with one another at the same time.

Surface modification agents are understood to mean substances which physically adhere to the surface of the finely divided particles, but which do not, or only chemically, react with them to a small extent. The individual molecules of the surface modification agents adsorbed on the surface are essentially free of intermolecular bonds with one another. Surface modifiers are to be understood in particular as dispersants. Dispersants are also known to the person skilled in the art, for example, under the terms emulsifiers, protective colloids, wetting agents, detergents, etc.

Suitable surface modifiers are, for example, emulsifiers of the nonionic surfactant type from at least one of the following groups:

- Adducts of 2 to 60 moles of ethylene oxide and / or 0 to 5 moles of propylene oxide with linear fatty alcohols with 8 to 22 carbon atoms, with fatty acids with 12 to 22 carbon atoms and with alkylphenols with 8 to 15 carbon atoms in the alkyl group;

- Cι ₂ / i8 fatty acid monoesters and diesters of adducts of 1 to 30 moles of ethylene oxide with glycerol;

- Glycerol mono- and diesters and sorbitan mono- and diesters of saturated and unsaturated fatty acids with 6 to 22 carbon atoms and their ethylene oxide addition products;

- Alkyl mono- and oligoglycosides with 8 to 22 carbon atoms in the alkyl radical and their ethoxylated and / or propoxylated analogs;

- Adducts of 15 to 60 moles of ethylene oxide with castor oil and / or hardened castor oil;

- polyol and especially polyglycerol esters, e.g. Polyglycerol polyricinoleate, polyglycerol poly-12-hydroxystearate or polyglycerol dimerate. Mixtures of compounds from several of these classes of substances are also suitable;

- Adducts of 2 to 15 moles of ethylene oxide with castor oil and / or hydrogenated castor oil;

- Partial esters based on linear, branched, unsaturated or saturated C6 / 22 fatty acids, ricinoleic acid as well as 12-hydroxystearic acid and glycerol, polyglycerol, pentaerythritol, dipentaerythritol, sugar alcohols (eg sorbitol), alkyl glucosides (eg methyl glucoside, butyl glucoside, ) and polyglucosides (eg cellulose);

- Mono-, di- and trialkyl phosphates as well as mono-, di- and / or tri-PEG-alkyl phosphates and their salts;

- wool wax alcohols;

- Polysiloxane-polyalkyl-polyether copolymers or corresponding derivatives;

- Mixed esters of pentaerythritol, fatty acids, citric acid and fatty alcohol and / or mixed esters of fatty acids with 6 to 22 carbon atoms, methyl glucose and polyols, preferably glycerol or polyglycerol and

- polyalkylene glycols. The adducts of ethylene oxide and / or of propylene oxide with fatty alcohols, fatty acids, alkylphenols, glycerol mono- and diesters as well as sorbitan mono- and diesters of fatty acids or with castor oil are known, commercially available products. These are homolog mixtures, the middle of which Degree of alkoxylation corresponds to the ratio of the amounts of ethylene oxide and / or propylene oxide and substrate with which the addition reaction is carried out.

Cβ-alkyl mono- and oligoglycosides, their preparation and their use are known from the prior art. They are produced in particular by reacting glucose or oligosaccharides with primary alcohols with 8 to 18 carbon atoms. Regarding the glycoside residue, both monoglycosides in which a cyclic sugar residue is glycosidically bonded to the fatty alcohol and oiigomeric glycosides with a degree of oligomerization of up to preferably about 8 are suitable. The degree of oligomerization is a statistical mean value which is based on a homolog distribution customary for such technical products.

Typical examples of anionic emulsifiers are soaps, alkyl benzene sulfonates, alkane sulfonates, olefin sulfonates, alkyl ether sulfonates, glycerol ether sulfonates, α-methyl ester sulfonates, sulfo fatty acids, alkyl sulfates, alkyl ether sulfates such as, for example, fatty alcohol ether sulfates, glyceryl ether ether sulfate, sulfate (sulfate ether) sulfate ethersulfate, fatty acid (sulfate ether) sulfate, sulfate ether (sulfate) ether sulfate, sulfate ether (sulfate), sulfate ether (sulfate), sulfate ether (sulfate), sulfate ether (sulfate), sulfate ether (sulfate), sulfate ether (sulfate), sulfate ether (sulfate), sulfate ether (sulfate), sulfate ether (sulfate), sulfate ether (sulfate), sulfate ether (sulfate), sulfate ether (sulfate), sulfate ether (sulfate), sulfate ether (sulfate), sulfate ether (sulfate), sulfate ether (sulfate), sulfate ether (sulfate ether, sulfate), , Mono- and dialkyl-sulfosuccinates, mono- and dialkyl-sulfosuccinamates, sulfotriglycerides, amide soaps, ether carboxylic acids and their salts, fatty acid isethionates, fatty acid sarcosinates, fatty acid retaurides, N-acylamino acids such as, for example, acylglutamates and acylsulfate co-fatty acids, especially sylol acyl aspartate fats (alkylsulfate acylatespartate, alkylsulfate acylatespartate fats, alkylsulfate acylates, such as alkylsulfates, such as alkylsulfates, such as alkylsulfates, such as alkylsulfates, such as alkylsulfates, especially alkylsulfates, such as alkylsulfates, such as alkylsulfates, such as alkylsulfates, such as alkylsulfates, such as alkylsulfates, such as alkylsulfates, such as alkylsulfates, such as alkylsulfates, such as alkylsulfates, such as alkylsulfates that vegetable products based on wheat), and alkyl (ether) phosphates. If the anionic surfactants contain polyglycol ether chains, they can have a conventional, but preferably a narrow, homolog distribution.

Zwitterionic surfactants can also be used as emulsifiers. Zwitterionic surfactants are surface-active compounds that contain at least one quaternary ammonium group and at least one carboxylate and one sulfonate group in the molecule. Particularly suitable zwitterionic surfactants are the so-called betaines such as the N-alkyl-N, N-dimethylammonium glycinate, for example coconut alkyldimethylammonium glycinate, N-acylamino propyl-N, N-dimethylammonium glycinate, for example coconut acylaminopropyl dimethylammonium glycinate, and 2 -Alkyl-3-carboxylmethyl-3-hydroxyethylimidazolines each having 8 to 18 carbon atoms in the alkyl or acyl group and the cocoacylaminoethylhydroxyethylcarboxymethylglycinate. The fatty acid amide derivative known under the CTFA name of Cocamidopropyl Betaine is particularly preferred. Suitable emulsifiers are ampholytic surfactants. Such surface-active compounds are used under ampholytic surfactants. stood, which in addition to a Cβ / iβ-alkyl or acyl group in the molecule contain at least one free amino group and at least one -COOH or -S0 ₃ H group and are capable of forming internal salts. Examples of suitable ampholytic surfactants are N-alkylglycines, N-alkylpropionic acids, N-alkylaminobutyric acids, N-alkyliminodipropionic acids, N-hydroxyethyl-N-alkylamidopropylglycines, N-alkyltaurines, N-alkyl sarcosines, 2-alkylaminopropionic acids and alkylami- noacetic acids each with about 8 to 18 carbon atoms in the alkyl group. Particularly preferred ampholytic surfactants are N-cocoalkylaminopropionate, cocoacylaminoethylaminopropionate and Ci2 / i8-acylsarcosine. In addition to the ampholytic emulsifiers, quaternary emulsifiers are also suitable, those of the esterquat type, preferably methyl-quaternized difatty acid triethanolamine ester salts, being particularly preferred.

Protective colloids suitable as surface modifiers are e.g. natural water-soluble polymers such as B. gum arabic, starch, water-soluble derivatives of water-insoluble polymeric natural substances such. B. cellulose ethers such as methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose or modified carboxymethyl cellulose, hydroxyethyl starch or hydroxypropyl guar, and synthetic water-soluble polymers, such as. B. polyvinyl alcohol, polyvinyl pyrrolidone, polyalkylene glycols, polyaspartic acid and polyacrylates.

The nonionic surfactants are particularly preferred as surface modification agents. The nonionic surfactants of the type of alkyl glycosides, ethoxylated alkyl glycosides and addition products of 10 to 60 moles of ethylene oxide and / or 0 to 5 moles of propylene oxide with linear fatty alcohols with 8 to 22 carbon atoms have proven to be particularly effective.

As a rule, the surface modification agents are used in a concentration of 10 to 500, but preferably 50 to 250% by weight, based on the chitosans or chitosan derivatives.

When the acidic chitosan or chitosan derivative solution is precipitated according to the invention by raising the pH, a suspension is formed which contains a salt as the neutralization product. Desalination of the product and concentration can be carried out by methods familiar to the person skilled in the art, for example by dialysis and / or centrifugation, dialysis preferably followed by centrifugation. The major part of the water is preferably removed by centrifugation, the supernatant simultaneously being the largest part of the salts formed in the course of the process and the excess surface modification agent not required for covering the surface of the nanoparticles Will get removed. The final removal of the residual moisture, if desired, is carried out using standard drying processes, particularly preferably freeze-drying.

Powders of nanoparticulate chitosans or chitosan derivatives produced in this way typically still contain water contents in the range from 1 to 10% by weight, salt contents in the range from 0 to 3% by weight, and contents of surface modification agents in the range from 1 to 5% by weight. %, each based on the total weight of the nanoparticles. Depending on the method for removing the excess surface modification agent, contents of surface modification agent of up to 30% by weight can also result. According to the teaching of the invention, it is thus possible to produce nanoparticles which consist of more than 90% by weight of a chitosan or chitosan derivative. According to the invention, chitosans or chitosan derivatives can be obtained in the form of dry powders which are easy to handle and are stable even after prolonged storage, in particular do not tend to agglomerate or stick. They can be redispersed in water or other solvents using mechanical energy to form nanoparticulate dispersions.

WO 9100298 describes a process for the continuous production of microcrystalline chitosan in which, according to the description, chitosan is obtained as a dispersion of particles in a size range between 0.1 and 50 μm. From this dispersion, a powdery product with particle sizes between 1 and 100 μm should be obtained by drying. Embodiments that could support this information in the description are not provided. In the exemplary embodiments, only gels with a chitosan content of at most approx. 10% are described as process products. The revision of this WO document has shown that the teaching disclosed there only leads to flaky to gel-like products with chitosan particle sizes significantly above 1 μm, which after agglomeration produce clumped, agglomerated products with a further increased chitosan particle size, which are difficult to handle and in the sense of the task of the present invention are not useful.

The present invention furthermore relates to nanoparticulate chitosans or chitosan derivatives which are produced by the processes according to the invention described above.

The nanoparticulate chitosans or chitosan derivatives produced by the process described in the present invention can be used, for example, for the production of cosmetic and / or pharmaceutical preparations. Such preparations include, for example, hair shampoos, hair lotions, hair sprays, foam baths, creams, lotions or ointments. Additional ingredients in the formulation can be found in cosmetic and / or pharmaceutical Preparations contain adjuvants, as are usually used in such preparations, such as. B. preservatives, bactericides, antioxidants, perfumes, foam retardants, dyes, pigments, thickeners, moisturizing and / or moisturizing substances, surfactants, emulsifiers, plasticizers, fats, oils, waxes, silicones, sequestering agents, anionic, cationic, nonionic or amphoteric polymers, Alkalizing or acidifying agents, alcohols, polyols, softeners, light stabilizers, electrolytes or organic solvents. Some fabrics, such as B. emulsifiers, can be contained in the preparations on the one hand as an adjuvant, but independently as a surface modification agent of the nanoparticles.

The amount of the nanoparticulate chitosans or chitosan derivatives in the cosmetic and / or pharmaceutical preparations is chosen so that the concentration of the chitosans or chitosan derivatives contained in the nanoparticles - d. H. without taking into account the surface modification agents contained in the nanoparticles - is between 0.1 and 20, preferably between 0.5 and 2% by weight, based on the preparations.

The invention accordingly furthermore relates to cosmetic and / or pharmaceutical preparations which contain nanoparticulate chitosans or chitosan derivatives produced by the process according to the invention in the concentrations mentioned above.

The following examples are intended to explain the subject of the invention in more detail:

Examples

Example 1: Production of nanoparticulate chitosan (variant 1):

¹ > Chitosan DCMF®, Henkel KGaA / Düsseldorf

²⁾ VE = fully desalinated

³ > the solution is adjusted to pH = 12 with aqueous NaOH

100 g of solution I are added dropwise to 700 g of solution II with vigorous stirring. The pH after the end of the dropping is between 9 and 11. A fluffy precipitate forms. The precipitate settles out after a while, the supernatant liquid is decanted off and the rest is centrifuged. To remove the salt, the product is dialyzed using a dialysis tube. The subsequent freeze-drying provides a fluffy, colorless chitosan powder which can be redispersed in water to particle sizes between 50 and 200 nm. The analysis of the chitosan powder shows a water content of 8%, a NaCl content of 2.9% and a dehydol content of 3%.

Example 2: Production of nanoparticulate chitosan (variant 2):

100 g of solution I are added dropwise to 700 g of solution II with vigorous stirring. The pH after the end of the dropping is between 9 and 11. A fluffy precipitate forms. The precipitated system is desalinated using ultrafiltration and concentrated to puncture resistance (12% solids content). Part of the emulsifier dehydol is also removed by the ultrafiltration. Freeze drying gives a dry powder which has a surfactant content of 24% by weight and an NaCl content of less than 0.1% by weight. This powder is redispersible in water to particle sizes between 50 and 200 nm.

Claims

claims

1. Process for the preparation of nanoparticulate chitosans or chitosan derivatives with an average particle diameter in the range from 10 to 1000 nm, in which

(a) dissolving the chitosan or chitosan derivative in an acidic aqueous medium

2. The method according to claim 1, characterized in that the production takes place in the absence of organic solvents.

3. The method according to claim 1 or 2, characterized in that the average particle diameter is in the range of 50 to 200 nm.

4. The method according to any one of claims 1 to 3, characterized in that the chitosan derivative is an ethoxylate, propoxylate or a mixed alkoxylate of a chitosan.

5. The method according to any one of claims 1 to 4, characterized in that one uses an acid which is selected from the group formed by hydrochloric acid, glycolic acid and lactic acid.

6. The method according to any one of claims 1 to 5, characterized in that a surface modifier is used which is selected from the group of nonionic surfactants, preferably from the group which is formed by alkyl glycosides, ethoxylated alkyl glycosides and fatty alcohol ethoxylates.

7. The method according to any one of claims 1 to 6, characterized in that the surface modifiers are used in amounts of 50 to 250 wt .-%, based on the chitosan or chitosan derivative.

8. The method according to any one of claims 1 to 7, characterized in that after process steps (a) and (b) as a further process step, dialysis and / or centrifugation is carried out.

9. The method according to any one of claims 1 to 8, characterized in that drying is carried out as the final step.

10. The method according to claim 9, characterized in that the drying is freeze-drying.

11. Nanoparticulate chitosans or chitosan derivatives, produced by a process of claims 1 to 10.

12. Cosmetic and / or pharmaceutical preparations, characterized in that they contain a nanoparticulate chitosan or chitosan derivative produced according to one of claims 1 to 10 in a concentration between 0.1 and 20% by weight, based on the preparation.