Method for preparing sulfated polysaccharides, and sulfated polysaccharides

Abstract

The present invention relates to a method for preparing sulfated polysaccharides, in which a mixture is prepared comprising at least one polysaccharide and at least one polar aprotic solvent. At least one sulfating agent, at least one acetylating agent, and at least one peroxydisulfate are added to the mixture, which is then subjected to a temperature treatment, thereby converting the at least one polysaccharide into at least one sulfated acetate polysaccharide. The at least one sulfated acetate polysaccharide is separated from the mixture and converted into a sulfated polysaccharide. The present invention further relates to sulfated polysaccharides that can be prepared using the method according to the present invention. The present invention further relates to microcapsules and a method for producing the microcapsules.

Description

[Technical Field]

[0001] The present invention relates to a method for preparing sulfated polysaccharides. A mixture comprising at least one polysaccharide and at least one polar aprotic solvent is prepared in this method. At least one sulfating agent, at least one acetylating agent, and at least one peroxydisulfate are added to the mixture, and the mixture is then subjected to a temperature treatment to convert at least one polysaccharide into at least one sulfated polysaccharide acetate sulfate. The at least one sulfated polysaccharide acetate sulfate is separated from the mixture and converted back into sulfated polysaccharides. The present invention further relates to sulfated polysaccharides that can be prepared using the method according to the present invention. The present invention further relates to microcapsules and methods for producing microcapsules. [Background technology]

[0002] Sodium cellulose sulfate is a water-soluble polymer of cellulose sulfate half-esters. Cationic polymers such as poly(diallyldimethylammonium chloride)(poly(DADMAC)) and corresponding polymer electrolyte complexes can be formed using an aqueous solution of sodium cellulose sulfate by adding droplets to an aqueous solution. This allows for the encapsulation of not only materials such as dyes and fragrances, but also living organisms such as cells, enzymes, and bacteria. Sodium cellulose acetate can be formed by esterification of the hydroxyl groups of cellulose with a sulfurizing agent such as anhydrous sulfuric acid, sulfuric acid, or derivatives thereof, and subsequent conversion to a neutral sodium salt of the azido half-ester.

[0003] A method for preparing sodium cellulose sulfate is generally known, in which sulfation is carried out in a heterogeneous phase without dissolving the polymer (heterogeneous), or in a homogeneous phase during the dissolution of the polymer (semi-homogeneous), or after the prior dissolution of the polymer (homogeneous).

[0004] Lukanoff et al. (Lukanoff, B. and Dautzenberg, H., Das Papier, 1994, 6, 287-298) further developed known heterogeneous preparation methods (US2,539,451 / US2,969,355) using sulfuric acid and propanol as reaction medium and sulfating agents. In such heterogeneous preparation methods, the reaction medium is first prepared from 96% sulfuric acid and isopropanol in a molar ratio of 1.8:1, for example, according to Bohlmann et al. (Chemie Ingenieur Technik, 2021, 74, 359-363). Here, the sulfation of cellulose is carried out at -5°C for a period of 150 minutes. The reaction mixture is separated from the formed cellulose sulfuric acid half-ester and washed with alcohol to interrupt the reaction. The washed product is then converted to a sodium salt using a sodium caustic alkali solution.

[0005] A substantial drawback of this heterogeneous sulfated cellulose process is that it is an exothermic reaction in a heterogeneous phase, which is difficult to control and inevitably leads to irregularities in the substituent distribution along and between polymer chains, thus impairing the solubility behavior of the resulting sulfated cellulose.

[0006] A further serious drawback of heterogeneous preparation methods is the rapid and powerful reduction in chain length of cellulose during sulfation. To mitigate this reduction in cellulose chain length, the sulfation reaction is interrupted, for example, by a washing step that removes sufficient heat and thus avoids further temperature increases. Nevertheless, the diffusion and expansion processes of cellulose, as well as its morphological structure, have a substantial influence on the reaction procedure, as the reaction proceeds while maintaining the overall solid structure of the cellulose.

[0007] To achieve complete water solubility of heterogeneously prepared sulfated cellulose without separating the insoluble portion in the DS range of less than 0.8, pre-activation of cellulose is proposed in DE4019116A1; however, nevertheless, only a very low viscosity product with a maximum of 8.5 mPas in 1% solution is obtained. If these sulfated celluloses were used to produce simple (symplex) microcapsules, it should be observed that only microcapsules with very low mechanical strength would be produced.

[0008] According to DE4021049, the water-insoluble portion is separated by an additional method step, but the resulting soluble portion with lower viscosity is washed away, allowing for the isolation of sulfated cellulose with higher viscosity from the accompanying reaction products (see Lukanoff, B. and Dautzenberg, H., Das Papier, 1994, 6, 287-298).

[0009] As a result, the heterogeneous preparation process yields a product with a relatively high degree of substitution (at least DS=0.7) and a non-uniform substituent distribution, and also yields low viscosity sodium cellulose sulfate despite using high molecular weight starting cellulose to convert the cellulose to complete water solubility.

[0010] A conventional method using organic solvent-soluble intermediate cellulose derivatives for the homogeneous sulfation of cellulose allows for better suppression of the reduction in cellulose chain length during the sulfation reaction. Since sulfation proceeds after or during the complete dissolution of the solid structure in a dipolar aprotic solvent, a more uniform substituent distribution is achieved. The final product has a higher solution viscosity and is already partially and completely water-soluble with a DS value of 0.25.

[0011] For example, using relatively low molecular weight cellulose acetate (DS=2.4; Cuoxam-DP approximately 250), the solution viscosity of synthesized sodium cellulose sulfate down to approximately 10 mPas (measured in a 2% solution in 2N NaOh using an Ubbelohde viscometer) can be obtained (see DE4435180).

[0012] The degree of polymerization of the commercially available cellulose acetate (Cuoxam-DP, approximately 200-350) used (which is too low to produce sulfated cellulose with a solution viscosity of over approximately 10 mPas in a 1% aqueous solution) is a substantial drawback. Setting the corresponding solution viscosity range of the resulting sodium cellulose sulfate for a given starting degree of polymerization of cellulose acetate remains desirable.

[0013] Acetosulfating of natural cellulose has long been known as a fundamental principle for the preparation of sulfated cellulose acetate, cellulose acetate, or sulfated cellulose by mixed esterification. In this regard, almost exclusively sulfuric acid with acetic anhydride in glacial acetic acid as the reaction medium has been used as the reactant (see, e.g., US2,683,143). Sodium chloride sulfonate has also been used as an alternative to sulfuric acid (US2,969,355). The results of Chauvelon et al.'s study on the preparation of water-soluble sulfated cellulose acetate (G. Chauvelon, Carbohydrate Research, 2003, 338, 743-750) showed the high degree of disorder in this heterogeneous reaction, to the point that the target product could only be obtained fractionally.

[0014] Furthermore, it is known that N,N-dimethylformamide can be used as a reaction medium to enable the acetosulfation of cellulose that proceeds during dissolution. In this regard, acetic hydride / SO3 or acetic anhydride / chlorosulfuric acid is used as the reaction mixture (Wagenknecht et al., Das Papier, 1996, 50, 12, 712 - 720). After the alkaline splitting off of the unstable acetyl groups, substituted water-soluble sulfated cellulose with a DS value up to about 0.8 at the C6 position of mainly anhydroglucose units was obtained.

[0015] The disadvantage of sulfated cellulose synthesized previously in this way involves irregularities at DS values below 0.6, which results in the inhomogeneity of the aqueous solution and thus the instability in the production of simple membranes or stable polyelectrolyte complexes.

[0016] A further possibility for preparing sulfated cellulose by acetosulfation is described in EP1863851. The chain length reduction during precipitation is prevented by the corresponding defined neutralization conditions, and the degree of polymerization and, in relation to that, the solution viscosity of the sulfated cellulose obtained after preparation are determined.

[0017] The preparation of sulfated cellulose after dissolution in ionic liquids such as 1-ethyl-3-methylimidazolium acetate (EMIMAC) or 1-butyl-3-methylimidazolium chloride (BMIMCl) is described in DE102007035322. As a result of the high viscosity, this invention requires the addition of a co-solvent such as N,N-dimethylformamide (DMF). The use of ionic liquids can be cited as a disadvantage in addition to the increased labor in this preparation. The use of sulfated cellulose for medical and pharmaceutical applications is only possible after a complex purification process due to the use of ionic liquids. Furthermore, the use of ionic liquids on a large-scale technical scale is limited by their high production cost. Summary of the Invention Problems to be Solved by the Invention

[0018] Therefore, an object of the present invention was to provide a method capable of preparing a sulfated polysaccharide suitable for the production of microcapsules. Further, an object of the present invention was to provide a method for producing the corresponding microcapsules.

Means for Solving the Problems

[0019] This object is achieved by the features of claim 1 for the method of preparing a sulfated polysaccharide, by the features of claim 11 for the sulfated polysaccharide, by the features of claim 14 for the method of producing microcapsules, and by the features of claim 16 for the microcapsules. The dependent claims represent advantageous further developments.

[0020] Thus, according to the present invention, there is provided a method for preparing a sulfated polysaccharide, a) a mixture containing at least one polysaccharide and at least one polar aprotic solvent is prepared, b) at least one sulfating agent, at least one acetylating agent, and at least one peroxydisulfate are added to the mixture, and then the mixture is subjected to a temperature treatment, whereby at least one polysaccharide is converted into a sulfated acetate polysaccharide, c) at least one sulfated acetate polysaccharide is separated from the mixture, d) at least one sulfated acetate polysaccharide is converted into at least one sulfated polysaccharide.

[0021] In step a) of the method according to the present invention, first a mixture containing at least one polysaccharide such as cellulose and at least one polar aprotic solvent such as dimethylformamide is prepared. The mixture may be a dispersion. The mixture can be prepared, for example, by dispersing at least one polysaccharide in at least one polar aprotic solvent.

[0022] In step b), at least one sulfating agent, at least one acetylating agent, and at least one peroxydisulfate are added to the mixture (prepared in step a), and the mixture is then subjected to a temperature treatment to convert at least one polysaccharide into sulfated acetate polysaccharide. Here, preferably, at least one sulfating agent and at least one acetylating agent are added to the mixture first, followed by at least one peroxydisulfate. The temperature treatment can be carried out, for example, at a temperature in the range of -10°C to 150°C for a period of 1 minute to 30 hours. At least one sulfated acetate polysaccharide may be present in a dissolved form in the mixture.

[0023] In step c), at least one sulfated polysaccharide acetate (prepared in step b) is separated from the mixture. This can be done, for example, by precipitating the at least one sulfated polysaccharide acetate by adding the mixture to a precipitation medium (e.g., containing at least alcohol and water), and then separating the precipitated at least one sulfated polysaccharide acetate (from the mixture and the precipitation medium) by a mechanical separation process, for example by filtration.

[0024] In step d), at least one sulfated polysaccharide acetate is converted to at least one sulfated polysaccharide. This can be done, for example, by alkaline separation of the acetate groups. Sulfated polysaccharides particularly well suited for the production of microcapsules, especially those produced by droplet formation, can be prepared using the method according to the present invention, wherein the shell comprises a polyelectrolyte complex of a cationic polymer such as poly-(DADMAC) and a sulfated polysaccharide. Materials to be encapsulated, such as pharmaceutical active ingredients, can be encapsulated within such microcapsules. As a result, such microcapsules can be used as drugs, for example, in the process of implantation and in the process of injection.

[0025] The method according to the present invention is particularly characterized by the use of at least one peroxydisulfate. Surprisingly, it has been found that a significant increase in the degree of substitution, and consequently better solubility of the prepared sulfated polysaccharide in water, can be achieved by the addition of peroxydisulfate in the acetosulfation of the polysaccharide, while simultaneously significantly reducing the use of strong sulfating agents such as chlorosulfate. This is also advantageous because the use of strong sulfating agents, especially a larger portion thereof, can lead to a reduction in the polysaccharide chain. Therefore, an increase in the degree of substitution can be achieved by the use of at least one peroxydisulfate without increasing the risk of reduction in the length of the polysaccharide chain. Sulfated polysaccharides prepared using the method according to the present invention are particularly well suited for the production of microcapsules due to the increased degree of substitution and the resulting improvement in solubility in water. In contrast, these advantages cannot be achieved by the use of sulfates such as K2SO4 or Na2SO4 (instead of peroxydisulfate).

[0026] Peroxydisulfates are salts of peroxydisulfate that are used technically as bleaching and oxidizing agents, but are also used to initiate the polymerization of various alkenes, including styrene, acrylonitrile, and fluoroalkenes. Polymerization is initiated by homolysis of the peroxydisulfate. Sodium peroxydisulfate is also known to be used in soil and groundwater remediation, as well as in etching copper on printed circuit boards. Potassium and ammonium compounds are commonly used peroxydisulfates.

[0027] In the method according to the present invention, so-called sulfated acetate polysaccharides, such as sulfated cellulose acetate, are formed during synthesis. Unlike pure polysaccharides such as cellulose, this mixed ester is soluble in aprotic solvents such as DMF. Therefore, the synthesis used in the method according to the present invention is a semi-homogeneous synthesis, meaning that the polysaccharide is dissolved in the solvent during synthesis by modifying a derivative that is soluble in the solvent, unlike the polysaccharide itself. The solubility of sulfated acetate polysaccharides results in a uniform distribution of substituents along the polymer chain. Such a uniform distribution is beneficial in the dissolution process. Therefore, sulfated polysaccharides obtained using semi-homogeneous synthesis have improved solubility due to the uniform substituent distribution.

[0028] In contrast, heterogeneous synthesis (i.e., cellulose + solvent + reactant = two phases), often used in the prior art, typically yields a non-uniform distribution of substituents in anhydrous glucose units (AGU) (or anhydrous monosaccharide units or sugar units) and along the polysaccharide chain. For example, in the heterogeneous synthesis of sulfated cellulose with cellulose and sulfuric acid, AGUs have non-uniform substitutions at the 2, 3, and / or 6 positions. Furthermore, it is possible that some AGUs may be substituted two or even three times, while others may be completely unsubstituted along the polymer chain. Thus, such products may indeed have a total substitution degree DS of, for example, 0.7, but at the same time, they may have regions where the DS is significantly higher and other regions where the DS is significantly lower. Such products consequently have significantly poor properties, such as lower solubility in water and therefore less suitability for microcapsule formation.

[0029] In prior art, in homogeneous synthesis where the dissolution of polysaccharides in the solvent occurs before synthesis, and in semi-homogeneous synthesis where the dissolution of polysaccharides occurs during synthesis by modification of derivatives, there is typically a uniform distribution of substituents along the polymer chain, and often regioselective substitutions within AGUs (or anhydrous monosaccharide units). Therefore, in acetosulfation, substitutions often occur first, mainly at the C6 position.

[0030] In contrast, the method according to the present invention, based on a quasi-homogeneous system, yields a different regioselective substituent distribution within the AGU (or anhydrous monosaccharide unit). Therefore, substitutions occur, for example, not only primarily at the C6 position but also over a wider area at the C2 position, thus yielding a more uniform distribution of substituents within the AGU (or anhydrous monosaccharide unit), in addition to a uniform distribution of substituents along the polymer chain. Surprisingly, the specific regioselective substituent distribution resulting from the use of peroxydisulfate, and the resulting more uniform substituent distribution within the AGU (or anhydrous monosaccharide unit), along with the uniform distribution of substituents along the polymer chain, has been found to result in even better solubility in water of the prepared sulfated acetate polysaccharide. Sulfated polysaccharides prepared using the method according to the present invention are also particularly well suited for the production of microcapsules for this reason.

[0031] Overall, sulfated polysaccharides prepared using the method according to the present invention have a higher degree of substitution, a uniform substituent distribution, and a favorable regioselective substituent distribution (within AGU or anhydrous monosaccharide units) due to the specific preparation. These favorable properties result in very good solubility of the prepared sulfated polysaccharides in water, and thus sulfated polysaccharides prepared using the method according to the present invention are particularly well suited for the production of microcapsules.

[0032] A preferred variation of the method according to the present invention is characterized in that at least one polysaccharide is selected from the group consisting of cellulose, hemicellulose, chitosan, hyaluronic acid, hydroxyethylcellulose, hydroxypropylcellulose, methylhydroxyethylcellulose, methylhydroxypropylcellulose, methylhydroxybutylcellulose, ethylhydroxyethylcellulose, carboxymethylhydroxyethylcellulose, and mixtures thereof. The at least one polysaccharide is particularly preferably cellulose.

[0033] A more preferred variation of the method according to the present invention is that at least one polar aprotic solvent is - Tertiary carboxylic acid amides, for example, dimethylformamide, - Carboxylic acid esters, such as dimethyl carbonate, - Sulfoxides, for example, dimethyl sulfoxide, - Lactams, e.g., N-methyl-2-pyrrolidone, and - those mixtures It is selected from the group consisting of the following.

[0034] A further preferred variation of the method according to the present invention is characterized in that the mixture in step a) is prepared by dispersing at least one polysaccharide in at least one polar aprotic solvent. The mixture (or dispersion) thus obtained is preferably stirred before step b) at a temperature in the range of 10°C to 150°C, preferably 50°C to 120°C, and / or for a period of 1 minute to 10 hours, preferably 30 minutes to 5 hours.

[0035] A more preferred variation of the method according to the present invention is: - At least one sulfating agent is selected from the group consisting of sulfuric acid, chlorosulfuric acid, SO3 complex, sulfamic acid, sulfuryl chloride, and mixtures thereof, and / or - At least one acetylating agent is selected from the group consisting of acetic anhydride, acetyl chloride, and mixtures thereof, and / or - At least one peroxydisulfate is selected from the group consisting of potassium peroxydisulfate, ammonium peroxydisulfate, sodium peroxydisulfate, and mixtures thereof. It is characterized by the following.

[0036] A more preferred modification of the method according to the present invention, the mixture prepared in step a) contains at least one sulfating agent in an amount of up to 3 moles / mol AGU (or anhydrous monosaccharide units), preferably up to 2 moles / mol AGU (or anhydrous monosaccharide units), particularly preferably up to 1 mole / mol AGU (or anhydrous monosaccharide units), and most particularly preferably 0.5 moles / mol AGU (or anhydrous monosaccharide units).

[0037] A more preferred variation of the method according to the present invention is characterized in that, in step b), at least one sulfating agent and at least one acetylating agent are first added to the mixture, and then at least one peroxydisulfate is added to the mixture.

[0038] A further preferred modification of the method according to the present invention is that the temperature treatment in step b) is - At temperatures within the range of -10°C to 150°C, preferably 30°C to 100°C, and particularly preferably 45°C to 80°C, and / or - A period of 1 minute to 30 hours, preferably 30 minutes to 20 hours, and particularly preferably 3 hours to 10 hours. It is characterized by being checked.

[0039] A more preferred modification of the method according to the present invention, in step c), at least one sulfated polysaccharide acetate is precipitated by adding the mixture to a precipitation medium containing at least alcohol and water, and then separated from the mixture by a mechanical separation process, preferably by filtration. The at least one sulfated polysaccharide acetate is preferably washed once or more times with a washing solution after separation.

[0040] A further preferred modification of the method according to the present invention is characterized in that, in step d), at least one sulfated polysaccharide acetate is converted to at least one sulfated polysaccharide by alkaline separation of the acetate groups. At least one sulfated polysaccharide acetate is mixed with an alkaline solution, and the mixture thus produced is stirred for a period of 1 minute to 30 hours, preferably 1 hour to 20 hours, and particularly preferably 5 hours to 15 hours, thereby preferably achieving alkaline separation of the acetate groups. The mixture is then neutralized after stirring, at least one polysaccharide is separated, and it is preferably washed once or more times and dried.

[0041] The present invention further relates to sulfated polysaccharides that can be prepared or are prepared using the methods according to the present invention. The sulfated polysaccharides according to the present invention have a specific regioselective substituent distribution within each AGU (or anhydrous monosaccharide unit), thereby differentiating the sulfated polysaccharides according to the present invention from already known sulfated polysaccharides due to the method according to the present invention, particularly due to the use of peroxydisulfate. The exact substituent distribution also depends to some extent on the polysaccharides used in each preparation, and therefore it is not possible to give a general substituent distribution that applies to all sulfated polysaccharides. As a result, the sulfated polysaccharides according to the present invention are characterized by the preparation process.

[0042] In polysaccharide chemistry, the degree of substitution indicates how many OH groups are substituted within a sugar unit (or anhydrous monosaccharide unit). In the case of cellulose, the DS value can be up to 3, meaning there can be three OH groups within a glucose unit (or AGU). In principle, and depending on the determination method, the degree of substitution is given as a total parameter in elemental analysis, such as in the determination of heteroatoms like sulfur and nitrogen. 13 Certain spectroscopic techniques, such as 13C-NMR spectroscopy, allow for the correlation of regioselectivity at structural units under specific conditions. Therefore, it may be possible to determine substitutions at the C6, C2, and C3 positions.

[0043] Regarding sulfated polysaccharides, the degree of substitution at each C position, for example, the degree of substitution at the C2 position DS2 or the degree of substitution at the C6 position DS6 of a sulfated polysaccharide, 13 This can be determined using 1C-NMR spectroscopy. Here, the NMR spectrum can be measured, for example, in D2O at 60°C. The substitution is 13 The cellulose sulfate can be quantified by integrating the signal from the 13C-NMR spectrum and normalizing it to the signal of a carbon atom, such as C1. Such a procedure is described, for example, by Zhant et al., "Synthesis and spectroscopic analysis of cellulose sulfates with regulable total degrees of substitution and sulfation patterns via 13C NMR and FT Raman spectroscopy," Polymer, 52(1), pp. 26-32.

[0044] A preferred embodiment of the sulfated polysaccharide according to the present invention is that the sulfated polysaccharide is - In a 1% solution of water, at least 0.5 mm 2 / s, preferably at least 2 mm 2 Having a solution viscosity of / s, and / or - Having a (total) substitution degree DS in the range of 0.15 to 1.8, preferably 0.5 to 1.3 (for example, via the sulfur content of the sulfated polysaccharide determined by elemental analysis, or 13 (Determined via 13C NMR spectroscopy) It is characterized by the following:

[0045] The viscosity of the solution can be determined, for example, using DIN 51562-1:1999-01. The degree of substitution DS, or total degree of substitution DS, indicates the proportion of C positions where substitution (from a hydroxyl group to a sulfate group) can occur, i.e., the proportion of the original polysaccharide where a hydroxyl group is present and substitution (from the original hydroxyl group to a sulfate group) has actually occurred. The (total) degree of substitution DS can take values ​​in the range of 0 to z, where z corresponds to the number of C positions in the anhydrous glucose unit of the polysaccharide where substitution (from a hydroxyl group to a sulfate group) can occur, i.e., where a hydroxyl group is present in the original polysaccharide. For example, the anhydrous glucose unit of cellulose contains three C positions where substitution (from a hydroxyl group to a sulfate group) can occur: C2, C3, and C6. The (total) degree of substitution DS of sulfated cellulose can consequently take values ​​in the range of 0 to 3, where the minimum value of 0 is no substitution at any position, and the maximum value of 3 is substitution at all C2, C3, and C6 positions in the polysaccharide. For example, a (total) substitution degree DS of 1.5 for sulfated cellulose means that the substitution (of the original hydroxyl group to the sulfate group) occurred at 50% or half of all possible substitution sites of the sulfated polysaccharide (i.e., the sum of all C2, C3, and C6 positions). Here, the (total) substitution degree DS does not allow any direct conclusions to be drawn about how high the degree of substitution is at individual C positions. For example, a (total) substitution degree DS of 1.5 for sulfated cellulose could mean that the substitution (of the hydroxyl group by the sulfate group) occurred at all of the C6 positions, half of the C2 positions, and not at the C3 position. Or, on the other hand, for example, a (total) substitution degree DS of 1.5 for sulfated cellulose could mean that the substitution (of the hydroxyl group by the sulfate group) occurred at half of the C6 positions, half of the C2 positions, and half of the C3 positions.

[0046] The degree of substitution DS or total substitution DS can be determined via the sulfur content of the sulfated polysaccharide, which can be determined using elemental analysis. The degree of substitution via sulfur content can be determined using the following formula (A). Formula (A) DS=(M PS ×S[%]) / (100×M S -ΔM×S[%]) In the formula, MS is the molar mass of the element to be determined, in this case sulfur, M PS is the molar mass of the polysaccharide used, and ΔM is the difference in molar mass between the new substituent (e.g., SO3) and the leaving group (e.g., H). The determination of such a degree of substitution is also described, for example, in Rohowsky et al., Carbohydr. Polymers, 2016, 142, 56 - 62.

[0047] Alternatively, the degree of substitution DS or the total degree of substitution DS can also be 13 determined using 13C - NMR spectroscopy. Here, the measurement of the NMR spectrum can be carried out at 60 °C in D2O. Then, 13 the signals from the 13C - NMR spectrum are integrated and normalized to the signal of a C atom, for example, C1, 13 and the degree of substitution can be determined from the 13C - NMR spectrum (see, for example, Zhang et al., Polymer, 52(1), 26 - 32). Substitution at individual C atoms in the AGU (or anhydro - monosaccharide unit) can also be 13 determined by 13C - NMR spectroscopy.

[0048] A further preferred embodiment of the sulfated polysaccharide according to the invention is characterized in that the sulfated polysaccharide has a degree of substitution DS2 at the C2 position of at least 0.2, preferably at least 0.3, particularly preferably at least 0.4, and / or a degree of substitution DS6 at the C6 position of at most 0.9, preferably at most 0.8, particularly preferably at most 0.7, very particularly preferably at most 0.6.

[0049] The degree of substitution at individual C positions, for example, the degree of substitution DS2 at the C2 position and the degree of substitution DS6 at the C6 position of the sulfated polysaccharide, 13 can be determined using 13C - NMR spectroscopy. Here, the measurement of the NMR spectrum can be carried out at 60 °C in D2O. Then, 13 the signals from the 13C - NMR spectrum are integrated and normalized to the signal of a C atom, for example, C1, 13The degree of substitution can be determined from the 1C-NMR spectrum (see, for example, Zhang et al., Polymer, 52(1), pp. 26-32).

[0050] A particularly preferred embodiment of the sulfated polysaccharide according to the present invention is characterized in that the sulfated polysaccharide is sulfated cellulose, and the sulfated cellulose has a degree of substitution at the C2 position of at least 0.2, preferably at least 0.3, particularly preferably at least 0.4 (DS2), and / or a degree of substitution at the C6 position of up to 0.9, preferably up to 0.8, particularly preferably up to 0.7, and very particularly preferably up to 0.6 (DS6).

[0051] The present invention also relates to sulfated polysaccharides (preferably sulfated cellulose) having a degree of substitution at the C2 position of at least 0.2, preferably at least 0.3, particularly preferably at least 0.4 (DS2), and / or a degree of substitution at the C6 position of up to 0.9, preferably up to 0.8, particularly preferably up to 0.7, and very particularly preferably up to 0.6 (DS6).

[0052] The present invention further relates to a method for producing microcapsules, - Using the method according to the present invention for preparing sulfated polysaccharides, at least one sulfated polysaccharide is prepared, or - The present invention provides at least one sulfated polysaccharide, Next, e) An aqueous solution of at least one sulfated polysaccharide is prepared, f) At least one material to be encapsulated is added to an aqueous solution of at least one sulfated polysaccharide, thereby producing a suspension. g) At least a portion of the suspension is droplet-formed, thereby generating droplets of the suspension. h) A droplet of the suspension is dropped into a solution of at least one cationic polymer, and the cationic polymer forms a polyelectrolyte complex with a sulfated polysaccharide, thereby converting the droplet into a microcapsule containing the material to be encapsulated.

[0053] A preferred variation of the method according to the present invention for generating microcapsules is, in the method, a) A mixture comprising at least one polysaccharide and at least one polar aprotic solvent is prepared, b) At least one sulfating agent, at least one acetylating agent, and at least one peroxydisulfate are added to the mixture, and the mixture is then subjected to temperature treatment so that at least one polysaccharide is converted to a sulfated acetate polysaccharide. c) At least one sulfated polysaccharide acetate is separated from the mixture, d) At least one sulfated polysaccharide acetate is converted to at least one sulfated polysaccharide, e) An aqueous solution of at least one sulfated polysaccharide is prepared, f) At least one material to be encapsulated is added to an aqueous solution of at least one sulfated polysaccharide, thereby producing a suspension. g) At least a portion of the suspension is droplet-formed, thereby generating droplets of the suspension. h) A droplet of the suspension is dropped into a solution of at least one cationic polymer, and the cationic polymer forms a polymer electrolyte complex with a sulfated polysaccharide, thereby converting the droplet into a microcapsule containing the material to be encapsulated. It is characterized by the following:

[0054] The generated microcapsules preferably have a diameter of 0.1 μm to 1,000,000 μm, particularly 1 μm to 10,000 μm, and most preferably 10 μm to 1,000 μm.

[0055] A more preferred variation of the method according to the present invention is: - The aqueous solution of at least one sulfated polysaccharide prepared in step e) is a 0.5% to 10% solution of at least one sulfated polysaccharide in water, and / or - At least one of the materials to be encapsulated is of biological or non-biological origin, and / or - In step f), one or more substances selected from the group consisting of carrier materials, additives, solvents, such as DMSO, preservatives, salts, glycerin, and mixtures thereof are added to an aqueous solution of at least one polysaccharide, and / or - At least one cationic polymer is selected from the group consisting of polyethylenediamine, polypiperazine, polyarginine, polytriethylamine, spermine, polydimethylallylammonium, polydiallyldimethylammonium, polyvinylbenzyltrimethylammonium, cationic chitosan, derivatives of cationic chitosan, and mixtures thereof, and / or - A solution of at least one cationic polymer is an aqueous solution of at least one cationic polymer. It is characterized by the following.

[0056] The at least one material to be encapsulated may be of biological origin, or it may be of non-biological origin. For example, the at least one material to be encapsulated may be at least one active pharmaceutical ingredient. For example, the at least one material to be encapsulated may be at least one substance used as a drug. Active pharmaceutical ingredients or drugs can be encapsulated in microcapsules and then implanted or injected.

[0057] Alternatively, the at least one material to be encapsulated may be at least one substance that is neither a pharmaceutical active ingredient nor a drug. Furthermore, the present invention relates to a microcapsule comprising at least one encapsulated material and a shell surrounding the at least one encapsulated material, wherein the shell contains a polymer electrolyte complex of at least one cationic polymer and at least one sulfated polysaccharide according to the present invention.

[0058] Preferably, the microcapsules according to the present invention can be produced or generated using the method according to the present invention for producing microcapsules. The microcapsules according to the present invention preferably have a diameter of 0.1 μm to 1,000,000 μm, particularly preferably 1 μm to 10,000 μm, and most particularly preferably 10 μm to 1,000 μm.

[0059] The present invention also relates to microcapsules according to the present invention for use as a drug, in the process of transplantation, or in the process of injection. The present invention further relates to the use of microcapsules according to the present invention as drugs in the process of transplantation or in the process of injection. [Modes for carrying out the invention]

[0060] The present invention will be described in more detail with reference to the following figures and examples, but the present invention is not limited to the parameters specifically shown. [Examples]

[0061] Embodiment 1 Disperse 5g (atro) of cellulose (cotton linter) in 150ml of N,N-dimethylformamide (DMF) and stir at 85°C for 2 hours.

[0062] Sulfation was initiated by adding 4 mL of chlorosulfuric acid (1 mol / mol AGU) and 70 mL of acetic anhydride (12 mol / mol AGU) to 80 mL of DMF. Subsequently, a suspension of 8.3 kg of K2S2O8 (0.5 mol / mol AGU) in 50 mL of DMF was added. Synthesis was carried out at a temperature of 65°C. The polymer dissolved in the solvent after 1-2 hours.

[0063] The polymer solution was gradually poured (within 10 minutes) into a precipitation medium at room temperature consisting of 21 g of sodium hydroxide (NaOH), 42 g of H2O, and 10 g of sodium acetate added to 750 mL of ethanol, and precipitation was carried out after 5 hours with continuous stirring. Stirring was continued for 1 hour after the completion of precipitation. The mixture was then filtered and washed three times with a washing solution consisting of 4% (w / w) sodium acetate in an ethanol-water mixture (1:1, w / w) using 300 mL of each solution. The polymer or precipitate product was then stirred in an alkaline solution (8 g of NaOH, 16 g of 60, 200 mL of ethanol) for 12 hours to separate the acetate groups. After neutralization with an ethanol acetate solution (pH setting of 6-9), the product was washed three times with 300 mL of ethanol each, and the washed product was dried in a vacuum drying rack.

[0064] The sulfated cellulose prepared in this manner has a total substitution degree of 0.8 DS (determined by the sulfur content of the sulfated cellulose determined by elemental analysis using formula (A)), and 14 mm 2 It has a viscosity of / s (determined according to DIN51562-1:1999-01). Further properties of the prepared sulfated cellulose can be seen in Table 1.

[0065] Furthermore, the prepared sulfated cellulose in D2O 13 The 1C-NMR spectrum was recorded at a temperature of 60°C. The obtained spectrum is shown in Figure 1. 13 From the 1C-NMR spectrum, it was determined that the prepared cellulose acetate has a substitution degree of 0.30 (DS2) at the C2 position and a substitution degree of 0.49 (DS6) at the C6 position. The determination was made as follows: 13 This was done by integrating the signal from the ¹¹C-NMR spectrum and normalizing it to the signal of a ¹¹C atom, e.g., C1 (see, for example, Zhang et al., Polymer, 52(1), pp. 26-32). Thus, the (total) substitution degree DS of 0.79 is 13 Obtained from the 1C-NMR spectrum, this correlates to a (total) substitution degree of 0.8, determined within rounding accuracy via sulfur content.

[0066] Embodiment 2 Disperse 5g (atro) of cellulose (cotton linter) in 150ml of N,N-dimethylformamide (DMF) and stir at 85°C for 2 hours.

[0067] Sulfation was initiated by adding 2 mL of chlorosulfuric acid (0.5 mol / mol AGU) and 70 mL of acetic anhydride (12 mol / mol AGU) to 80 mL of DMF. Subsequently, a suspension of 14 g of (NH4)2S2O8 (1 mol / mol AGU) in 50 mL of DMF was added. Synthesis was carried out at a temperature of 75°C. The polymer dissolved in the solvent after approximately 1-2 hours.

[0068] Precipitation and preparation were carried out after 6 hours as described in Example 1. The sulfated cellulose prepared in this manner has a total substitution degree of 1.2 (determined by the sulfur content of the sulfated cellulose determined by elemental analysis using formula (A)), and 2 mm 2 It has a viscosity of / s (determined according to DIN51562-1:1999-01). Further properties of the prepared sulfated cellulose can be seen in Table 1.

[0069] Furthermore, the prepared sulfated cellulose in D2O 13 The 1C-NMR spectrum was recorded at a temperature of 60°C. The obtained spectrum is shown in Figure 2. 13 From the 1C-NMR spectrum, it was determined that the prepared cellulose acetate has a substitution degree of 0.35 (DS2) at the C2 position and a substitution degree of 0.77 (DS6) at the C6 position. The determination was made as follows: 13 This was done by integrating the signal from the 1C-NMR spectrum and normalizing it to the signal of the C atom, e.g., C1 (see, for example, Zhang et al., Polymer, 52(1), pp. 26-32). Thus, the (total) substitution DS of 1.12 is 13 Obtained from the 1C-NMR spectrum, this correlates with a (total) substitution degree of 1.2, determined within rounding accuracy via sulfur content.

[0070] Embodiment 3 5g (atro) of microcrystalline cellulose (MCC) was dispersed in 150ml of DMF and stirred at 85°C for 3 hours.

[0071] Sulfation was initiated by adding 2.5 g of trioxide / pyridine sulfate complex (0.5 mol / mol AGU) dissolved in 50 mL of DMF to 70 mL of acetic anhydride (12 mol / mol AGU). Synthesis was carried out at a temperature of 60°C. Subsequently, a suspension of 14 g of (NH4)2S2O8 (4 mol / mol AGU) in 50 mL of DMF was added. The polymer dissolved in the solvent after 1-2 hours.

[0072] Precipitation and preparation were carried out after 4 hours as described in Example 1. The sulfated cellulose prepared in this manner has a total substitution degree of 0.85 DS (determined by the sulfur content of the sulfated cellulose determined by elemental analysis using formula (A)), and 1 mm 2 It has a viscosity of / s (determined according to DIN51562-1:1999-01). Further properties of the prepared sulfated cellulose can be seen in Table 1.

[0073] Embodiment 4 5g (atro) of cellulose (rice husk pulp) was dispersed in 150ml of DMF and stirred at 85°C for 3 hours.

[0074] Sulfation was initiated by adding 1.2 ml of sulfuric acid (0.7 mol / mol AGU) and 70 ml of acetic anhydride (12 mol / mol AGU) to 80 mL of DMF. Subsequently, a suspension of 8.3 kg of K2S2O8 (0.5 mol / mol AGU) in 50 mL of DMF was added. Synthesis was carried out at a temperature of 50°C. The polymer dissolved in the solvent after approximately 1-2 hours.

[0075] Precipitation and preparation were carried out after 8 hours as described in Example 1. The sulfated cellulose prepared in this manner has a total substitution degree of 1.0 DS (determined by the sulfur content of the sulfated cellulose determined by elemental analysis using formula (A)), and 10 mm2 It has a viscosity of / s (determined according to DIN51562-1:1999-01). Further properties of the prepared sulfated cellulose can be seen in Table 1.

[0076] Embodiment 5 5g (atro) of cellulose (eucalyptus pulp) was dispersed in 150ml of DMF and stirred at 85°C for 3 hours.

[0077] Sulfation was initiated by adding 2 mL of chlorosulfuric acid (0.5 mol / mol AGU) and 70 mL of acetic anhydride (12 mol / mol AGU) to 80 mL of DMF. Subsequently, a suspension of 14 g of (NH4)2S2O8 (4 mol / mol AGU) in 50 mL of DMF was added. Synthesis was carried out at a temperature of 75°C. The polymer dissolved in the solvent after approximately 1-2 hours.

[0078] Precipitation and preparation were carried out after 6 hours as described in Example 1. The sulfated cellulose prepared in this manner has a total substitution degree DS of 1.3 (determined by the sulfur content of the sulfated cellulose determined by elemental analysis using formula (A)), and 22 mm 2 It has a viscosity of / s (determined according to DIN51562-1:1999-01). Further properties of the prepared sulfated cellulose can be seen in Table 1.

[0079] Embodiment 6 5g (atro) of arabinoxylan (birch) was dispersed in 150ml of DMF and stirred at 85°C for 3 hours.

[0080] Sulfation was initiated by adding 1.2 mL of chlorosulfuric acid (0.5 mol / mol AGU) and 70 mL of acetic anhydride (12 mol / mol AGU) to 80 mL of DMF. Subsequently, a suspension of 5.4 kg of K2S2O8 (0.5 mol / mol AGU) in 50 mL of DMF was added. Synthesis was carried out at a temperature of 55°C. The polymer dissolved in the solvent after approximately 1-2 hours.

[0081] Precipitation and preparation were carried out after 6 hours as described in Example 1, except that the final washing step was performed using a dialysis tube. The sulfated arabinoxylan thus prepared has a total substitution degree DS of 0.9 (determined by the sulfur content of the sulfated arabinoxylan determined by elemental analysis using formula (A)), and 2 mm 2 It has a viscosity of / s (determined according to DIN51562-1:1999-01). Further properties of the prepared sulfated arabinoxylan can be seen in Table 1.

[0082] [Table 1]

[0083] Total substitution degree DS in Table 1 S This was determined via the sulfur content of sulfated cellulose, which was determined by elemental analysis using formula (A). (Total) substitution degree DS in Table 1. NMR teeth, 13 By integrating the signal from the 1C-NMR spectrum and normalizing it to the signal of a C atom, for example, C1, 13 The values ​​were determined using 13C-NMR spectroscopy (see, for example, Zhang et al., Polymer, 52(1), pp. 26-32). The viscosity values ​​in Table 1 were determined according to DIN 51562-1:1999-01. The cloudiness values ​​in Table 1 were determined using DIN EN ISO7027-1:2016-11.

[0084] Microcapsules were successfully produced using all of the sulfated polysaccharides prepared according to Examples 1-6. In Example 6, only amorphous microcapsules were obtained from the sulfated polysaccharide.

[0085] Embodiment 7 An aqueous solution (1% w / w) is prepared from the corresponding portion by weight of the sulfated cellulose prepared in Example 1. After the substance is completely dissolved, the material to be encapsulated is added to an aqueous solution of at least one sulfated polysaccharide to form a suspension. The sulfated cellulose solution is then added dropwise to a 1% commercially available polydiallyldimethylammonium chloride solution (polyDADMAC solution). Uniform, round, spherical particles (microcapsules) are obtained. The material to be encapsulated is encapsulated within the obtained microcapsules. The obtained capsules are shown in photographs in Figures 3 and 4. Specific embodiments of the present invention are as follows. [Aspect 1] A method for preparing sulfated polysaccharides, a) A mixture comprising at least one polysaccharide and at least one polar aprotic solvent is prepared, b) Adding at least one sulfating agent, at least one acetylating agent, and at least one peroxydisulfate to the mixture, and then subjecting the mixture to a temperature treatment, the at least one polysaccharide is converted to a sulfated acetate polysaccharide. c) At least one sulfated polysaccharide acetate is separated from the mixture, d) A method for converting at least one sulfated polysaccharide acetate into at least one sulfated polysaccharide. [Aspect 2] The method according to embodiment 1, characterized in that the at least one polysaccharide is selected from the group consisting of cellulose, hemicellulose, chitosan, hyaluronic acid, hydroxyethylcellulose, hydroxypropylcellulose, methylhydroxyethylcellulose, methylhydroxypropylcellulose, methylhydroxybutylcellulose, ethylhydroxyethylcellulose, carboxymethylhydroxyethylcellulose, and mixtures thereof. [Aspect 3] The above-mentioned at least one polar aprotic solvent is - Tertiary carboxylic acid amides, for example, dimethylformamide, - Carboxylic acid esters, such as dimethyl carbonate, - Sulfoxides, for example, dimethyl sulfoxide, - Lactams, e.g., N-methyl-2-pyrrolidone, and - those mixtures The method according to embodiment 1 or 2, characterized by being selected from the group consisting of the following. [Aspect 4] The method according to any one of embodiments 1 to 3, wherein the mixture in step a) is prepared by dispersing the at least one polysaccharide in the at least one polar aprotic solvent, and the mixture thus obtained is preferably stirred for a period of 1 minute to 10 hours, preferably 30 minutes to 5 hours, at a temperature in the range of 10°C to 150°C, preferably 50°C to 120°C, before step b). [Aspect 5] - The at least one sulfurizing agent is sulfuric acid, chlorosulfuric acid, SO₂ 3 Being selected from the group consisting of complexes, sulfamic acid, sulfuryl chloride, and mixtures thereof, and / or - The at least one acetylating agent is selected from the group consisting of acetic anhydride, acetyl chloride, and mixtures thereof, and / or - The at least one peroxydisulfate is selected from the group consisting of potassium peroxydisulfate, ammonium peroxydisulfate, sodium peroxydisulfate, and mixtures thereof. The method according to any one of embodiments 1 to 4, characterized by the above. [Aspect 6] The method according to any one of embodiments 1 to 5, characterized in that, in step b), the at least one sulfating agent and the at least one acetylating agent are first added to the mixture, and then the at least one peroxydisulfate is added to the mixture. [Aspect 7] The temperature treatment in step b) - At temperatures within the range of -10°C to 150°C, preferably 30°C to 100°C, and particularly preferably 45°C to 80°C, and / or - A period of 1 minute to 30 hours, preferably 30 minutes to 20 hours, and particularly preferably 3 hours to 10 hours. The method according to any one of embodiments 1 to 6, characterized in that it is carried out. [Aspect 8] The method according to any one of embodiments 1 to 7, wherein in step c), the at least one sulfated polysaccharide acetate is precipitated by adding the mixture to a precipitation medium containing at least alcohol and water, and then separated from the mixture by a mechanical separation process, preferably by filtration, and the at least one sulfated polysaccharide acetate is preferably washed once or more times with a washing solution. [Aspect 9] The method according to any one of embodiments 1 to 8, characterized in that in step d), the at least one sulfated polysaccharide is converted to the at least one sulfated polysaccharide by alkaline separation of the acetate group. [Aspect 10] The method according to embodiment 9, characterized in that the at least one sulfated polysaccharide acetate is mixed with an alkaline solution, the mixture thus produced is stirred for a period of 1 minute to 30 hours, preferably 1 hour to 20 hours, and particularly preferably 5 hours to 15 hours, thereby achieving the alkaline separation of the acetate groups, and preferably the mixture is neutralized after stirring to separate the at least one polysaccharide, washed once or more times, and dried. [Aspect 11] A sulfated polysaccharide that can be prepared or prepared using the method described in any one of embodiments 1 to 10. [Aspect 12] - In a 1% solution of water, at least 0.5 mm 2 / s, preferably at least 2 mm 2 Having a solution viscosity of / s, and / or - Having a degree of substitution DS in the range of 0.15 to 1.8, preferably 0.5 to 1.3. A sulfated polysaccharide according to embodiment 11, characterized by the above. [Aspect 13] Degree of substitution DS at the C2 position is at least 0.2, preferably at least 0.3, and particularly preferably at least 0.4. 2 , and / or a degree of substitution DS at the C6 position of up to 0.9, preferably up to 0.8, particularly preferably up to 0.7, and most particularly preferably up to 0.6. 6 A sulfated polysaccharide according to embodiment 11 or embodiment 12, characterized by having the following properties. [Aspect 14] A method for producing microcapsules, wherein at least one sulfated polysaccharide is prepared using the method described in any one of embodiments 1 to 10, or at least one sulfated polysaccharide as described in any one of embodiments 11 to 13 is provided. Next, e) An aqueous solution of at least one of the sulfated polysaccharides is prepared, f) At least one material to be encapsulated is added to the aqueous solution of the at least one sulfated polysaccharide, thereby generating a suspension. g) At least a portion of the suspension is dropletized, thereby generating droplets of the suspension, h) A method wherein the droplets of the suspension are dropped into a solution of a cationic polymer, the cationic polymer forming a polyelectrolyte complex with the sulfated polysaccharide, thereby converting the droplets into microcapsules containing the material to be encapsulated. [Aspect 15] - The aqueous solution of the at least one sulfated polysaccharide prepared in step e) is a 0.5% to 10% solution of the at least one sulfated polysaccharide in water, and / or - The at least one material to be encapsulated is of biological origin or non-biological origin, and / or - In step f), one or more substances selected from the group consisting of carrier materials, additives, solvents, such as DMSO, preservatives, salts, glycerin, and mixtures thereof are added to the aqueous solution of the at least one polysaccharide, and / or - The at least one cationic polymer is selected from the group consisting of polyethylenediamine, polypiperazine, polyarginine, polytriethylamine, spermine, polydimethylallylammonium, polydiallyldimethylammonium, polyvinylbenzyltrimethylammonium, cationic chitosan, derivatives of cationic chitosan, and mixtures thereof, and / or - The solution of the at least one cationic polymer is an aqueous solution of the at least one cationic polymer. The method according to embodiment 14, characterized by the above. [Aspect 16] A microcapsule comprising at least one encapsulating material and a shell surrounding the at least one encapsulating material, wherein the shell contains a polymer electrolyte complex of at least one cationic polymer and at least one sulfated polysaccharide as described in any one of embodiments 11 to 13. [Aspect 17] The microcapsule according to embodiment 16, characterized in that it can be produced or is produced using the method described in embodiment 14 or embodiment 15. [Aspect 18] Microcapsules according to embodiment 16 or 17 for use as a drug, for use in the process of transplantation, or for use in the process of injection.

Claims

1. A method for preparing sulfated polysaccharides, a) A mixture comprising at least one polysaccharide and at least one polar aprotic solvent is prepared, b) Adding at least one sulfating agent, at least one acetylating agent, and at least one peroxydisulfate to the mixture, and then subjecting the mixture to a temperature treatment, the at least one polysaccharide is converted to a sulfated acetate polysaccharide. c) At least one sulfated polysaccharide acetate is separated from the mixture, d) The at least one sulfated polysaccharide acetate is converted to at least one sulfated polysaccharide, A method wherein at least one polysaccharide is selected from the group consisting of cellulose, arabinoxylan, and mixtures thereof.

2. The above-mentioned at least one polar aprotic solvent is - Tertiary carboxylic acid amide, - Carboxylic acid ester, - Sulfoxide, - Lactam, and - Those mixtures The method according to claim 1, characterized in that it is selected from the group consisting of the following.

3. The method according to claim 1 or 2, characterized in that the mixture in step a) is prepared by dispersing the at least one polysaccharide in the at least one polar aprotic solvent.

4. - The above at least one sulfurizing agent is sulfuric acid, chlorosulfuric acid, SO ３ Being selected from the group consisting of complexes, sulfamic acid, sulfuryl chloride, and mixtures thereof, and / or - The at least one acetylating agent is selected from the group consisting of acetic anhydride, acetyl chloride, and mixtures thereof, and / or - The at least one peroxydisulfate is selected from the group consisting of potassium peroxydisulfate, ammonium peroxydisulfate, sodium peroxydisulfate, and mixtures thereof. A method according to any one of claims 1 to 3, characterized by the above.

5. The method according to any one of claims 1 to 4, characterized in that, in step b), the at least one sulfating agent and the at least one acetylating agent are first added to the mixture, and then the at least one peroxydisulfate is added to the mixture.

6. The temperature treatment in step b) - At temperatures within the range of -10°C to 150°C, and / or - Periods ranging from 1 minute to 30 hours The method according to any one of claims 1 to 5, characterized in that it is carried out.

7. The method according to any one of claims 1 to 6, characterized in that, in step c), the at least one sulfated polysaccharide acetate is precipitated by adding the mixture to a precipitation medium containing at least alcohol and water, and then separated by a mechanical separation process, thereby separating the at least one sulfated polysaccharide acetate from the mixture.

8. The method according to any one of claims 1 to 7, characterized in that in step d), the at least one sulfated polysaccharide is converted to the at least one sulfated polysaccharide by alkaline separation of the acetate group.

9. The method according to claim 8, characterized in that at least one sulfated polysaccharide acetate is mixed with an alkaline solution, and the mixture thus produced is stirred for a period of 1 minute to 30 hours, thereby achieving the alkali separation of the acetate groups.

10. A method for producing microcapsules, wherein at least one sulfated polysaccharide is prepared using the method described in any one of claims 1 to 9. Next, e) An aqueous solution of at least one of the sulfated polysaccharides is prepared, f) At least one material to be encapsulated is added to the aqueous solution of the at least one sulfated polysaccharide, thereby generating a suspension. g) At least a portion of the suspension is dropletized, thereby generating droplets of the suspension. h) A method wherein the droplets of the suspension are dropped into a solution of a cationic polymer, the cationic polymer forming a polyelectrolyte complex with the sulfated polysaccharide, thereby converting the droplets into microcapsules containing the material to be encapsulated.

11. - The aqueous solution of the at least one sulfated polysaccharide prepared in step e) is a 0.5% to 10% solution of the at least one sulfated polysaccharide in water, and / or - The at least one material to be encapsulated is either a material of biological origin or a material of non-biological origin, and / or - In step f), one or more substances selected from the group consisting of carrier material, additive, solvent, preservative, salt, glycerin, and mixtures thereof are added to the aqueous solution of the at least one polysaccharide, and / or - The at least one cationic polymer is selected from the group consisting of polyethylenediamine, polypiperazine, polyarginine, polytriethylamine, spermine, polydimethylallylammonium, polydiallyldimethylammonium, polyvinylbenzyltrimethylammonium, cationic chitosan, derivatives of cationic chitosan, and mixtures thereof, and / or - The solution of the at least one cationic polymer is an aqueous solution of the at least one cationic polymer. The method according to claim 10, characterized by the above.

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