DE19952073A1 - Process for the preparation of nanoparticulate chitosans or chitosan derivatives - Google Patents

Abstract

Proposed is a process for the preparation of nanoparticulate chitosans or chitosan derivatives having particle diameters in the range of 10 to 1000 nm, in which DOLLAR A (a) dissolves the chitosan or chitosan derivative in an acidic aqueous medium DOLLAR A (b) the pH the solution in the presence of a surface modifier so far raises that it comes to the precipitation of the chitosan. DOLLAR A The method enables a simple, independent of organic solvents producing agglomeration stable nanoparticles in dispersed or dry form.

Description

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

Unlike most hydrocolloids, those in the range of biological pH are chitosan under these conditions cationic bio The positively charged chitosan can be charged with opposite Surfaces interact and is therefore, for example, in kosmeti hair and body care products and pharmaceutical preparations (see Ullmann's Encyclopedia of Industrial Chemistry, 5th Ed., Vol. A6, Wein Heim, Verlag Chemie, 1986, pp. 231-332), where it is used as a moisturizer and film bildner application finds. The corresponding applies to derivatives of chitosan, in wel the basic character of the molecule is preserved. These include, for example wise alkoxylation of chitosan such as ethoxylates and propoxylates.

The properties and applications of chitosans and chitosans Derivatives depend significantly on the form in which these substances are present, esp especially in which particle size and in which consistency. A typical feature Chitosan is its low solubility in the neutral and alkaline pH range and generally in non-aqueous media. Furthermore characteristic is its out coined gelation tendency even at low concentrations, which is the hand The use of chitosan and its application in particular in cosmetics in many Makes cases problematic. Further, chitosan is included with other components For example, only limited compatibility in cosmetic formulations. It exists thus a need for chitosans, which in a good manageable and metered form before lie, are stable in storage and processable better than conventional product qualities and can be used in formulations.  

From the literature different attempts are known, the properties of Chitosan to influence its particle size and small chitosan particles for to use certain purposes. Thus, those described in DE 197 12 978 are suitable with an oil body loaded chitosan microspheres as drug depots, which Release the active ingredient in a time-delayed and controlled manner. The be there described microspheres make beads with a diameter of 0.01 to 6 mm represents.

From JP-A 09221502 chitosan nanospheres are known, which by Emul gure aqueous chitosan solutions in organic solvents in the presence of quaternary ammonium salts. WO-A 9801162 and the WO-A-9801160 describes chitosan nanospheres consisting of complexes of Chitosan exist with nucleic acids and produced by coacervation techniques become.

A disadvantage of the known from the prior art manufacturing process, which using an organic solvent is the often difficult Isolable ness of the nanoparticles. In addition, it is often not possible for the nanoparticles to be full constantly rid of the organic solvent, which is especially cosmetic and pharmaceutical applications severely restricts.

Another disadvantage of prior art fabrication methods is that that resulting in the production as by-products salts often difficult to remove are.

For a broader application, for example, in cosmetics and pharmacy exists a need for chitosan particles whose size is in the nanometer range, the Production without organic solvents is possible and not producible inevitably with a certain drug, such as nucleic acids in the case of both aforementioned WO documents or oil bodies in the case of DE 197 12 978, or a certain surfactant are preloaded. Furthermore, a Her Setting method for such particles are technically simple and inexpensive and in conventional and widespread technical facilities.

Surprisingly, it was found that the above-described Auf solve release by a manufacturing process in which an aqueous solution  of chitosans or chitosan derivatives in the presence of surface modifiers kationsmitteln fails.

The invention thus relates to processes for the preparation of nanoparticulate chitosans or chitosan derivatives having an average particle diameter in the Range of 10 to 1000 nm, preferably from 50 to 200 nm, in which one (a) dissolving the chitosan or chitosan derivative in an acidic aqueous medium (b) the pH of the solution in the presence of a surface modifier so far raises that it comes to the precipitation of chitosan.

Preferably, the process is carried out in the absence of organic solvents. The term organic solvents does not explicitly apply to the term "organic solvents" Method used surface modifiers and optionally in Step (a) of the method for dissolving the chitosan or chitosan derivative ver used organic acids.

Chitosans are biopolymers and are ge to the group of hydrocolloids counts. Chemically, these are partially deacetylated chitins different molecular weight. The chitosans are made from chi tin, preferably the shell remnants of crustaceans, as cheap raw materials be available in large quantities. The chitin usually becomes too next deproteinated by addition of bases, by addition of mineral acids de mineralized and finally deacetylated by addition of strong bases, the Molecular weights can be distributed over a broad spectrum. Appropriate Methods are for example made of macromol. Chem. 177, 3589 (1976) or the fran French patent application FR 2701266 A1. Preferably, such Types used, as described in the German patent applications DE 44 42 987 A1 and DE 195 37 001 A1 (Henkel) are disclosed, and the average molecule large, from 800,000 to 1,200,000 daltons, Brookfield viscosity (1 wt% in glycolic acid) below 5000 mPa.s, a degree of deacetylation in Range of 80 to 88% and an ash content of less than 0.3 wt .-% on point. Among chitosan derivatives in the context of the present invention are those Understand derivatives which are water-soluble at acidic pH, in the neutral but are sparingly soluble in water at alkaline pHs, d. H. the have an analogous solubility behavior as the chitosans themselves. Such chitosan derivatives  are, for example, alkoxylation products of chitosans with Ethylene oxide, propylene oxide or mixtures of both and derivatives which basi contain amino groups.

In the first step of the method according to the invention is a chitosan or Chito San derivative with the addition of an acid dissolved in water as a solvent. The Dissolution of the chitosan or chitosan derivative takes place by salt formation with a Mineral acid or an organic acid, for example with hydrochloric acid, sulfur acid, methanesulfonic acid, glycolic acid, lactic acid, salicylic acid, adipic acid or Ascorbic acid. Hydrochloric acid, glycolic acid and milk are preferred according to the invention acid. The order of assembly of the individual components is in the Preparation of the solution is not critical. Preferably, the chitosan or chito San derivative in water and with stirring with such an amount of acid re, as required to form a solution. Preferably, the dissolution takes place solution of the chitosan or chitosan derivative at pH values between 1 and 5. In ei Another preferred embodiment is the chitosan or chitosan derivative entered in an aqueous acid.

In the second step of the process, the pH of the aqueous solution of Chito sans or Chitosanderivats by means of an alkalizing agent in the presence of a Surface modifier raised so that it precipitated the nanoparticulate chitosan or chitosan derivative comes. As alkalizing agent are preferably aqueous solutions of hydroxides of alkali or alkaline earth metals or ammonia used. Preferably, the precipitate is below mecha Nischer mixing, for example by means of a stirrer performed. In the Precipitation becomes either the acidic solution of chitosan or chitosan derivative submitted and added the alkalizing agent, or it is turned vice versa It is essential to the invention that the precipitation of the acidic solution of chitosan or chitosan derivative in the presence of a surface modifier. In this case, the surface modifier can either in the acidic solution or the alkalizing agent. In a further embodiment of the The production process of the invention can be the acidic solution of chitosan or Chitosan derivatives, the alkalizing agent and the surface modifier, preferably in the form of aqueous solutions, also simultaneously combined with each other the.  

By surface modification agents are meant substances which are at the top surface of the finely divided particles physically adhere, but not or only with these react chemically to a slight extent. The individual on the surface adsor The above-described molecules of the surface modifiers are essentially free of intermolecular bonds with each other. Under surface modifiers are to be understood in particular dispersants. Dispersants are the subject For example, man under the terms emulsifiers, protective colloids, network medium, detergents, etc. known.

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

• - Addition products of 2 to 60 moles of ethylene oxide and / or 0 to 5 moles of propy lenoxid to linear fatty alcohols with 8 to 22 C-atoms, to fatty acids with 12 to 22 C atoms and alkylphenols having 8 to 15 C atoms in the alkyl group;
• C _12/18 fatty acid _mono- and diesters of addition products 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 having 6 to 22 carbon atoms and their Ethylenoxi danlagerungsprodukte;
• - Alkyl mono- and oligoglycosides having 8 to 22 carbon atoms in the alkyl radical and their ethoxylated and / or propoxylated analogs;
• - Addition products of 15 to 60 moles of ethylene oxide with castor oil and / or ge hardened castor oil;
• - Polyol and in particular polyglycerol esters, such as. Polyglycerol polyricinoleate, Polyglycerol poly-12-hydroxy stearate or polyglycerol dimerate. Also suitable are mixtures of compounds of several of these classes of substances;
• - Addition products of 2 to 15 moles of ethylene oxide with castor oil and / or gehär tete castor oil;
• Partial esters based on linear, branched, unsaturated or saturated C _6/22 fatty acids, ricinoleic acid and 12-hydroxystearic acid and glycerol, polyglycerol, pentaerythritol, dipentaerythritol, sugar alcohols (for example sorbitol), alkyl glucosides (for example methyl glucoside , Butyl glucoside, lauryl glucoside) as well as polyglucosides (eg cellulose);
• Mono-, di- and trialkyl phosphates as well as mono-, di- and / or tri-PEG- alkyl phosphates and their salts;
• - lanolin alcohol;
• - 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 having 6 to 22 carbon atoms, methyl glucose and Polyols, preferably glycerol or polyglycerol and
• - polyalkylene.

The addition products of ethylene oxide and / or of propylene oxide with fatty alcohol hole, fatty acids, alkylphenols, glycerol mono- and diesters and sorbitan mono- and diesters of fatty acids or castor oil are known, commercially available These products are homolog mixtures whose middle alkoxy lierungsgrad the ratio of the amounts of ethylene oxide and / or propylene oxide and substrate with which the addition reaction is carried out corresponds.

C _8/18 alkyl mono- and oligoglycosides, their preparation and their use are known in the art. Their preparation is carried out in particular by imple mentation of glucose or oligosaccharides with primary alcohols having 8 to 18 carbon atoms. With respect to the glycoside, it is true that both monoglycosides in which a cyclic sugar residue is glycosidically bound to the fatty alcohol, as well as oli gomere glycosides having a degree of oligomerization preferably up to about 8 are suitable. The degree of oligomerization is a statistical mean, which is based on a homolog distribution typical for such technical products.

Typical examples of anionic emulsifiers are soaps, alkylbenzenesulfonates, Alkanesulfonates, olefinsulfonates, alkyl ether sulfonates, glycerol ether sulfonates, α- Methyl ester sulfonates, sulfo fatty acids, alkyl sulfates, alkyl ether sulfates such as example fatty alcohol ether sulfates, Glycerinethersulfate, Hydroxymischethersulfate, Mo Noglyceride (ether) sulfate, fatty acid amide (ether) sulfate, mono- and dialkyl sulfosucci nate, mono- and dialkylsulfo-succinamates, sulfotriglycerides, amide soaps, ethercar acids and their salts, fatty acid isethionates, fatty acid sarcosinates, fatty acids retauride, N-acyl amino acids such as acylglutamates and acylaspartates, Alkyl oligoglycoside sulfates, protein fatty acid condensates (especially vegetable Pro wheat-based products), and alkyl (ether) phosphates. If the anionic surfactants Polyglycoletherketten contain, these may be a conventional, preferably however, have a narrow homolog distribution.

Furthermore, zwitterionic surfactants can be used as emulsifiers. Zwitterionic surfactants are surface-active compounds which carry 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 dis N-alkyl-N, N-dime thylammoniumglycinate, for example Kokosalkyldimethylammoniumglycinat, N-acylamino-propyl-N, N-dimethylammoniumglycinate, for example Koko sacylaminopropyldimethylammonium glycinate, and 2-alkyl-3 carboxymethyl-3-hydroxyethyl-imidazolines having in each case 8 to 18 C atoms in the alkyl or acyl group and the cocoacylaminoethylhydroxyethylcarboxymethylglycinate. Particularly preferred is the known under the CTFA name Cocamidopropyl Betaine fatty acid amide derivative. Also suitable emulsifiers are ampholytic Tensi de. Ampholytic surfactants are understood as meaning those surface-active compounds which, apart from a C _8/18 -alkyl or -acyl group in the molecule, contain at least one free amino group and at least one -COOH or -SO 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-alkylsarcosines, 2-alkylaminopropionic acids and alkylaminoacetic acids each having about 8 to 18 C atoms in the alkyl group. Particularly preferred ampholytic surfactants are N-cocoalkylaminopropionate, cocoacylaminoethylaminopropionate and C _12/18 -acylsarcosine. In addition to the ampholytic come and quaternary emulsifiers into consideration, wherein those of the ester quats type, preferably methyl-quaternized Difettsäuretriethanolaminester salts, be particularly be.

As surface modifier suitable protective colloids are z. Natural water-soluble polymers such as. Gum arabic, starch, water-soluble derivatives of water-insoluble polymeric natural products such. As cellulose ethers such as methyl cellulose, hydroxyethylcellulose, carboxymethylcellulose or modified carboxy methylcellulose, hydroxyethyl starch or hydroxypropyl guar, as well as synthetic water-soluble polymers, such as. As polyvinyl alcohol, polyvinylpyrrolidone, polyalky glycols, polyaspartic acid and polyacrylates.

Particularly suitable as surface modifiers are, in particular, the nonionic surfactants. To be particularly effective, the nonionic surfactants of Type of alkyl glycosides, ethoxylated alkyl glycosides and addition Pro from 10 to 60 moles of ethylene oxide and / or 0 to 5 moles of propylene oxide to linear Fatty alcohols having 8 to 22 carbon atoms proved.  

In general, the surface modifiers are in a concentration of 10 to 500, but preferably 50 to 250 wt .-%, based on the chitosans or chitosan derivatives.

In the precipitation according to the invention of the acidic chitosan or chitosan derivative Solution by raising the pH, a suspension forms, which as Neutralization product contains a salt. A desalting of the product and an up Concentration can be carried out by methods familiar to the person skilled in the art, for example example by dialysis and / or centrifugation, preferably first Dialysis followed by centrifugation. Preferably, the Main amount of water removed by centrifugation, taking with the supernatant at the same time most of the salts formed during the process and the excess, not needed for occupying the surface of the nanoparticles Surface modifier is removed. The final removal of the Residual moisture, if desired, via common drying methods, special It prefers a freeze-drying.

Powders produced by nanoparticulate chitosans or chito in this way sanderivates typically still contain water contents in the range from 1 to 10% by weight, Salts in the range of 0 to 3 wt .-%, and levels of Oberflä chenmodifikationsmittel in the range of 1 to 5 wt .-%, each based on the Ge total weight of nanoparticles. Depending on the method of separating the excess Surface modifiers may also contain levels of surface modification average of up to 30% by weight. It is thus according to the teachings of the invention possible to produce nanoparticles containing more than 90% by weight of a chito san or chitosan derivative. According to the invention, chitosans or Chitosan derivatives obtained in the form of dry powders, which are easy to handle and are stable even after prolonged storage, especially not for agglomeration or sticking tend. They can be dissolved in water or other Lösungsmit using mechanical energy to redisperse nanoparticulate dispersions yaw.

In WO 9100298 a process for continuous production is microcrystalline chitosan, in which, as described, chitosan as a dispersion of particles in a size range between 0.1 and 50 microns is obtained. Out This dispersion is intended by drying a powdery product with particle sizes  between 1 and 100 microns can be obtained. Embodiments which this information could be based in the description will not be delivered. In the Embodiments are as a process product only gels with chitosan keep a maximum of about 10%. The reworking of this WO document has show that the doctrine revealed there only to flaky to gel-like products with chitosan particle sizes well above 1 micron, which after drying provide clumped, agglomerated products with further increased chitosan particle size, Which is difficult to handle and in the sense of the task of the present Invention are not useful.

Another object of the present invention are nanoparticulate chitosans or chitosan derivatives, which according to the erfindungsge described above are made in accordance with the method.

Those prepared by the method described in the present invention For example, nanoparticulate chitosans or chitosan derivatives can be used to prepare use of cosmetic and / or pharmaceutical preparations become. Such preparations include, for example, hair shampoos, hair lotions hair sprays, bubble baths, creams, lotions or ointments. As another recipe Turbine components can be used in cosmetic and / or pharmaceutical preparations contain adjuvants, as is customary in such preparations be used, such as. Preservatives, bactericides, antioxidants, par foams, foams, dyes, pigments, thickeners, wetting agents and / or moisturizing substances, surfactants, emulsifiers, plasticizers, fats, Oils, waxes, silicones, sequestering agents, anionic, cationic, nonionic or amphoteric polymers, alkalizing or acidifying agents, alcohols, butadiene lyols, softeners, light stabilizers, electrolytes or organic solvents. you che substances such. As emulsifiers, in the preparations on the one hand as Adju vans, but also as surface modifier of Nanopar be included.

The amount of nanoparticulate chitosans or chitosan derivatives used in the Cosmetic and / or pharmaceutical preparations are chosen so that the Concentration of the chitosans or chitosan derivatives contained in the nanoparticles - d. H. without consideration of the surface modifiers contained in the nanoparticles  between 0.1 and 20, preferably between 0.5 and 2,% by weight, based on the preparations.

Another object of the invention are therefore cosmetic and / or phar pharmaceutical preparations which are prepared by the process according to the invention Asked nanoparticulate chitosans or chitosan derivatives in the above ge contained concentrations.

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

Examples example 1 Preparation of nanoparticulate chitosan (variant 1)

Solution I: Solution II: 3% chitosan ¹⁾ 1% Dehydol TA 40 (fatty alcohol C _16-18 + 40 EO) 96% H ₂ O SU ²⁾ NaOH dil. = <PH = 12 ³⁾ 1% HCl conc. ad 100% H ₂ O VE 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 with vigorous stirring in 700 g of solution II. The pH value after completion of the dropping is between 9 and 11. It forms flocculent precipitation.

The precipitate settles down after some time, the supernatant becomes liquid decanted and the rest centrifuged. The product is removed to remove the salt dialyzed by dialysis tubing. The subsequent freeze-drying provides a fluffy colorless chitosan powder, which in water to particle sizes zwi 50 and 200 nm is redispersible.

The analysis of the chitosan powder gives a water content of 8%, a NaCl Content of 2.9% and a content of dehydol of 3%.

Example 2 Production of nanoparticulate chitosan (variant 2)

Solution I: Solution II: 3% chitosan 1% Dehydol TA 40 (fatty alcohol C _16-18 + 40 EO) 96% H ₂ O VE NaOH dil. = <PH = 12 1% HCl conc. ad 100% H ₂ O VE

100 g of solution I are added dropwise with vigorous stirring in 700 g of solution II. The pH value after completion of the dropping is between 9 and 11. It forms flocculent precipitation.

The precipitated system is desalinated by ultrafiltration and until the puncture resistance (12% solids) concentrated. Part of the emulsifier Dehydol is replaced by the Ultrafiltration also removed. Freeze-drying gives a dry one Powder having a surfactant content of 24% by weight and a NaCl content of less than 0.1% by weight having. This powder is water in particle sizes between 50 and 200 nm redispersible.

Claims (12)

1. A process for the preparation of nanoparticulate chitosans or chitosan derivatives having an average particle diameter in the range of 10 to 1000 nm, in which

• a) dissolves the chitosan or chitosan derivative in an acidic aqueous medium
• b) raising the pH of the solution in the presence of a Oberflächenmodifikationsmit means so far that it comes to the precipitation of chitosan.

2. The method according to claim 1, characterized in that the preparation in Absence of organic solvents takes place. 3. The method according to claim 1 or 2, characterized in that the middle Particle diameter 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 Chitosans is. 5. The method according to any one of claims 1 to 4, characterized in that one an acid 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 one uses a surface modifier selected from the group the nonionic surfactants, preferably from the group 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 one the surface modifier 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 the process steps (a) and (b) as a further process step a dialysis and / or centrifugation takes place.   9. The method according to any one of claims 1 to 8, characterized in that as final step, a drying takes place. 10. The method according to claim 9, characterized in that the drying a Freeze-drying is. 11. Nanoparticulate chitosans or chitosan derivatives prepared according to Ver Driving of claims 1 to 10. 12. Cosmetic and / or pharmaceutical preparations, characterized gekennzeich net, that it is a nanoparticulate prepared according to any one of claims 1 to 10 res chitosan or chitosan derivative in a concentration between 0.1 and 20 wt .-%, based on the preparation included.