Method cross-linkage carboxylating polysaccharides |
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IPC classes for russian patent Method cross-linkage carboxylating polysaccharides (RU 2230073):
                           
A method of obtaining modified chitosan emulsions and products on its basis / 2223279
The invention relates to chemical technology, particularly to a method for producing a gel or suspension of chitosan, and can be used in food, cosmetic, pharmaceutical and other industries
A method of producing chitosan / 2221811
The invention relates to a method of producing chitosan, which can be used as a sorbent, emulsifier, foaming agent
 The method of obtaining food biosorbent / 2219997
The invention relates to the microbiological industry, and specifically to methods for biosorbent by microbiological synthesis, which can be used as activator beer fermentation
 The way waste complex processing of chitin-containing raw material / 2207033
The invention relates to a method for integrated processing of chitin-containing raw materials with the aim of obtaining chitin/chitosan and enzymatic protein hydrolysates for use as the basis of microbiological culture media
 Photoallergen gel based on crosslinked hyaluronic acid and method thereof / 2197501
The invention relates to biocompatible fototienda gel based on crosslinked hyaluronic acid, which has specific physical properties, the methods of its production and its applications as biomedical materials
 The method of obtaining a modified hyaluronic acid / 2191782
The invention relates to the field of biochemistry and can be used in medicine
The method of preparation of a colloidal solution of chitosan / 2189751
The invention relates to the dairy industry, can be used in fish, meat and food processing industry
 The method of obtaining low molecular weight chitosan for radioprotective drugs / 2188829
The invention relates to medical biotechnology and can be used to create based on natural polysaccharides new radioprotectors
 The gel (and its variants) / 2134703
 The method of producing fibers or filaments of regenerated cellulose / 2221907
The invention relates to a method for producing filaments of regenerated cellulose and can be used for the manufacture of knitted, or nonwoven textile surfaces
 The method of microcrystalline cellulose / 2203995
 The method of microcrystalline cellulose / 2178033
The invention relates to the manufacture of cellulose derivatives, namely to obtain microcrystalline cellulose (MCC), which can be used in chemical, cosmetics, pharmaceutical, food industries and medicine
 Water-soluble carboxymethylcellulose derivatives of cellulose and method of production thereof / 2169736
The invention relates to new biologically active derivative of cellulose and methods of producing cellulose derivatives
 Method for continuous production of pulp chemical pulp digester continuous action / 2165433
The invention relates to a method for continuous production of pulp chemical pulp and cooking boiler continuous action
 The method of microcrystalline cellulose / 2163945
The invention relates to the manufacture of cellulose derivatives and relates to a method of microcrystalline cellulose, which can be used as filler in pharmaceutical and food industries, sorbent and filter material in the technique, the raw material for producing low-viscosity cellulose derivatives
 The method of microcrystalline cellulose / 2155192
The invention relates to the modification of cellulose, in particular to a method for producing microcrystalline cellulose(MCC),which finds application in food, pharmaceutical, cosmetic, porcelain, ceramic industry
The method of producing carboxymethyl cellulose / 2155191
The invention relates to the production of cellulose derivatives, in particular to a technology for production of carboxymethyl cellulose, which is widely used in the oil and gas industry for making mud used during drilling
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The invention relates to a method of cross stitching carboxylating polysaccharides and can be used in medical and pharmaceutical fields, and in cosmetology. The method includes receiving the activated carboxyl groups of the polysaccharide by reacting with a suitable activating the carboxyl group of agents in an anhydrous aprotic solvent. Followed by a stage of interaction of the polysaccharide with activated carboxyl groups and polyamine General formula: R1-NH-A-other2where a is a C2-C10alkalinous chain or polyoxyalkylene chain [ (CH2)n-O-(CH)2]mwhere n is equal to 2 or 3, m is from 2 to 10. R1and R2are the same or different and represent hydrogen, C1-C6alkyl, phenyl or benzyl. Poperechnaya polysaccharides receive the above method. The invention allows to obtain compounds with high biocompatibility, improved resistance to enzymatic systems. From the resulting polysaccharides can be formed in various forms (gels, films), and also achieved the ability to be sterilized chemically or physically without changing the product structure. 2 C. and 8 C.p. f-l is sidirovanii polysaccharides.
The method according to the invention ensures a high degree of reproducibility of the products obtained in terms of the degree of cross-linkage, the homogeneity of the distribution Poperechnaya circuits and chemical-physical characteristics of the products and technological characteristics of the products obtained from them.
Reproducibility is particularly important for applications in medical and pharmaceutical fields, in dermatology and cosmetology.
The invention additionally relates to the products obtained by the above method, and their applications in medical and pharmaceutical fields, dermatology and cosmetology.
Background of the invention
The use of macromolecules in the medical/pharmaceutical field and, later, in dermatological and cosmetic area is well known. Macromolecules used in the preparation of pharmaceutical compositions as thickeners, lubricants, agents for film coating resistant to stomach, in particular, upon receipt of capsules, gels, colloids and various devices (e.g., contact lenses, items of gauze, and so on). Macromolecules are also used to obtain compositions with controlled release of active ingredients.
Reviews Oxford, 1990, Vol.1-6; 2) A. Wade and P. J. Wellers Editors - "Handbook of Pharmaceutical Excipients" - Ed. 1994, The Pharmaceutical Press.
These macromolecules belong to different chemical families, and can be synthetic or natural, or synthetic.
Examples of synthetic macromolecules include polyvinylpyrrolidone, polyoxyalkylene esters, polyvinyl alcohol, polymethacrylates. Examples of natural macromolecules include natural hyaluronic acid (HY) and cellulose.
Examples of semi-synthetic macromolecules include carbon-sulcicollis, widely used in food and personal hygiene items. These macromolecules are characterized by linear or slightly branched structure.
A very important modification to increase chemical, enzymatic and mechanical stability is ensured by cross-linking, which can be performed on both synthetic and natural (more or less modified) polymers.
Examples Poperechnaya polymers include polymers that are used to protect the tablets or capsules in the stomach (polymethacrylates), and polymers that are used as emulsifiers, suspendida agents, hardeners tablets (carbopol is in the surrounding area, to obtain invasive medical devices that must be administered parenterally, these polymers must meet a number of requirements of technical or procedural type.
Technical requirements include:
1) high biocompatibility;
2) resistance to enzyme systems, both tissue and plasma (for injectively songs), and gastrointestinal (oral compositions).
In some cases it may be desirable gradual degradation, for example, for a controlled release of the drug.
This stability is particularly important when the macromolecule is in the compositions/products that should exist for a long period of time, such as the artificial synovial fluid, tape, swabs or gels as anti-adhesion tissue during operations of various kinds; in tissue engineering (artificial organs); artificial skin in the treatment of burns and widely in aesthetic surgery;
3) the ability to form in various forms (gels, films, tampons and so on);
4) the ability to be sterilized chemically or physically without changing the product structure.
According to the regulatory requirements of part p that the production methods are standardized and that the main components have a very low internal variability.
Possible cause heterogeneity of macromolecules derived from the scatter of molecular masses. This heterogeneity becomes even higher in the cross-linkage. This can be a serious disadvantage depending on the application and applied the purposes of the final product.
EP-A-566118 (Kimberly-Clark) discloses Poperechnaya polysaccharides for use as superabsorbents for diapers and other products.
It describes a method based on cross-linking of cellulose through the formation of intermolecular amides, esters and ethers between polyamines, polyols and mixtures thereof and a carboxyl group of the polysaccharide.
The reaction is carried out by heating at 80 With a mixture of polysaccharide with a polyol and/or polyamines. This technique is undoubtedly an economical and suitable for large-scale production, where the requirements for reproducibility are less stringent.
In U.S. patent 5465055 disclosed Poperechnaya polysaccharides (hyaluronic acid and alginic acid), obtained by esterification of COOH-groups of the polysaccharide and Oh-groups of other molecules, without inserting Poperechnaya "branches".
In WO 91/9119 disclosed microcapsule barium ions.
In EP 190215 disclosed cross-linking of polymers (carboxylating starches, dextran, cellulose) di - or polyfunctional epoxides.
Was offered the following agents for cross-linkage of hyaluronic acid:
polyfunctional epoxides disclosed in U.S. patent 4716224, 4772419, 4716154;
the polyalcohol are disclosed in U.S. patent 4957744;
diphenylsulfone disclosed in U.S. patent 4605691, 4636524;
aldehydes are disclosed in U.S. patents 4713448 and 4582865;
carboxamide disclosed in U.S. patent 5356833;
polycarboxylic acids disclosed in EP-A-718312.
Disclosure of the invention
The invention relates to a method for Poperechnaya polysaccharides containing carboxyl groups, allowing full control of the degree of cross-linkage, as well as high reproducibility in terms of the constant characteristics of the final product.
The method according to the invention includes:
a) activating the carboxyl groups of the polysaccharide interaction with a suitable activating the carboxyl group of agents in an anhydrous aprotic solvent;
b) interaction of the polysaccharide with activated carboxyl groups with polyamines.
The obtained p the rim hydroxyl groups.
The products obtained by the method according to the invention can also be subjected to complexation with metal ions such as zinc ions, copper or iron.
Polysaccharide containing carboxyl groups, which can be used according to the invention can be natural, synthetic or semi-synthetic origin. Examples of these polysaccharides include hyaluronic acid (derived from tissues or bacteria), carboxymethylation, carboxymethylcellulose, carboximetilkrahmal, alginic acid, cellulose acid, N-carboxymethyl - or butylglycol or chitosans, heparins of various molecular weights, optional desulfation or succinylcholine, dermatosurgery, chondroitin sulfates, heparansulfate, polyacrylic acid.
Hyaluronic acid, carboxymethyl cellulose, heparin, alginic acid and polyacrylic acid are particularly preferred.
These Poperechnaya polymers obtained by other means, known or proposed for various applications (see, for example, EP 566118, WO 91/9119, U.S. patent 5465055, EP 190215, EP 718312, U.S. patent 4716224 discussed above).
Agents which activate carboxyl groups usually represent titrisol, chloromethylpyridine iodide (CMP-J), hydroxybenzotriazole, p-NITROPHENOL+p-nitrophenylacetate, N-hydroxysuccinimide and the like. Application chloromethylpyridine iodide is particularly preferred.
Polyamine preferably have the following General formula:
R1-NH-A-NH-R2
where R1and R2that are the same or different, represent hydrogen, radicals, C1-C6alkyl, phenyl or benzyl And is2-C10alkylenes chain, preferably2-C6alkylenes chain, optionally substituted by hydroxyl, carboxyl, halogen, CNS, amino groups; polyoxyalkylene chain formulas
[(CH2)n-O-(CH2)n]m
where n is 2 or 3 and m is an integer from 2 to 10; the radical C5-C7cycloalkyl; the radical aryl or hetaryl, preferably 1,3 - or 1,4-disubstituted benzene. And preferably represents C2-C6normal alkylen or chain formulas
[(CH2)n-O-(CH2)n]m.
The cross-linkage reaction is preferably carried out in a solvent selected from tetrahydrofuran, dimethylformamide or dimethyl sulfoxide, and the polysaccharide populinum organic base.
The transformation of inorganic salts such as sodium salt, in a suitable organic lipophilic salt can be carried out by known ion exchange methods in homogeneous phase or precipitation of the acid component, followed by separation of the latter and the formation of salts with the desired organic base.
The reaction of activated carboxyl groups is carried out in homogeneous phase and in an anhydrous polar aprotic solvent.
Polyamine, diluted in the same anhydrous solvent, are added to a solution of activated ester, maintaining the temperature from 0 to 30C. the Time of reaction cross-linkage is in the range from 1 to 12 h, depending on the optional presence of a suitable basic substances (e.g. triethylamine).
Basically the final product produce by the deposition of organic salts, adding another solvent to the reaction solvent, or by distillation of the latter, followed by centrifugation, washing with distilled water, re-dispersion in solution of the desired alkali (e.g. sodium, potassium), followed by washing with water and the final drying of the main salt in vacuum or by lyophilization.
The degree Poperechnaya carboxyl group, because the activation and reaction cross-linkage are mainly quantitative.
Poperechnaya polysaccharides, obtained according to the invention, can be subjected to the sulfation may present hydroxyl groups usually by interaction with a complex of pyridine-sulfur trioxide in dimethylformamide.
The reaction is carried out in a heterogeneous phase at a temperature of 0-10With over a period of time in the range from about 0.5 to about 6 hours
Received the degree of sulfation is within wide limits with respect to the hydroxyl groups in General and can be adjusted by changing the temperature and reaction time. Mainly the degree of sulfation (defined as equivalents of sulfate groups/g) can be in the range of 1 10-6up to 610-6EQ/g when the degree of cross-linkage, equal to 0.5.
Poperechnaya polymers obtained according to the invention, optionally sulfated, capable of forming a complex with metal ions such as zinc ions, copper or iron.
These complexes can be obtained by dissolving or dispersing until complete swelling of the product in water and EXT is tion or inorganic metal salt, for example CuCl2, ZnCl2, Fe2(SO4)3; after stirring for 12-24 h complex allocate by centrifugation or sedimentation after adding another solvent (such as ethanol or acetone) or by distillation in a vacuum, isolated crude product is washed thoroughly with distilled water to remove excess ions. Then the complexes lyophilized. The content of metal ions varies depending on operating conditions, in particular the molar ratio of polymer to ions, concentration and pH of the solutions; reaction time and, especially, the degree of crosslinking.
The method according to the invention with suitable regulation of the degree of cross-linkage and/or sulfation allows you to get Poperechnaya karboksilirovanie polysaccharides in a wide range of forms, with different properties, such as viscoelasticity, degree of hydration, the ability to form complexes with metal ions, the ability to form hydrogels, the ability to form into films or tampons, the mechanical strength of the final materials.
This allows to apply them in many medical fields, in human and veterinary medicine and in dermocosmetology.
Diaminopropanol.
1,210-3mol salt TION and carboxymethylcellulose in relation to the disaccharide glycosides of the unit is dissolved in 30 ml of DMF in an atmosphere of N2and under stirring. 0.32g chloromethylpyridine iodide (1,210-3mol), dissolved in 2 ml of DMF, is added dropwise to the solution, maintaining at a temperature of 0With on the ice.
The molar ratio was 1 to 1, as carboxymethylcellulose has one carboxyl functional group on the disaccharide glycosides of the unit. After 20 min the solution add 2 ml Poperechnaya 1,3-diaminopropane (0,006 mol) and immediately after 0.5 ml of triethylamine. Get a solid jelly-like product, which is washed with DMF, then put in the H2O until complete swelling.
Then spend alternating wash EtOH and N2O. After the last wash EtOH product is dried by freezing.
- IR (film; cm-1): 1650 ; without bending at about 1400.
- SD (degree of swelling in water and at room temperature over 15 min; gravimetric determination; calculated by:
where Ws= mass of hydrated GE is ktoi with a pore size 15-35 MK.
- Size of the product when exposed to rabbit PRP (plasma rich in platelets) shows a very low presence of platelets or aggregates compared with equivalent product obtained with polypropylene low density (EU standard).
EXAMPLE 2: the Gel of carboxymethyl cellulose, 50% poperechnogo 1,3-diaminopropanol
1,210-3mole of carboxymethyl cellulose in relation to dis-charidee unit is dissolved in 30 ml of DMF in an atmosphere of N2and under stirring. 0.24 g of chloromethylpyridine iodide (1,210-3mol), dissolved in 2 ml of DMF, is added dropwise to the solution, maintaining at a temperature of 0With on the ice. The molar ratio equal to 2:1.
After 20 min the solution add 2 ml Poperechnaya 1,3-diaminopropane (310-3mol) and immediately after 0.5 ml of triethylamine. Get a solid jelly-like product, which is washed with DMF, then put in the H2O until complete swelling.
Then spend alternating wash EtOH and N2O. After the last wash EtOH product is dried by freezing.
- IR (film; cm-1): 1650 ; and without Asia platelets: as reported in example 1.
EXAMPLE 3: the alginic acid Gel, 50% (100% in relation to the disaccharide glycosides units), poperechnogo 1,3-diaminopropanol
Sol TION and alginic acid obtained from the sodium salt by ion exchange on a strong cation exchange resin (Dovex) N+form (i.e., the acid form), followed by neutralization with tetrabutylammonium hydroxide (TBA-OH) and the final lyophilization.
1,210-3mol relative to the monosaccharide unit is dissolved in 30 ml of DMF in an atmosphere of N2and under stirring. 0.36g chloromethylpyridine iodide (1,210-3mol), dissolved in 2 ml of DMF, is added dropwise to the solution, maintaining at a temperature of 0With on the ice. The molar ratio equal to 1:1.
After 20 min the solution was added 610-3mol Poperechnaya 1,3-diaminopropane (0,024 mol) and immediately after 0.5 ml of triethylamine. Get a solid jelly-like product, which is washed with DMF, then placed in N2About until complete swelling.
Then spend alternating wash EtOH and N2O. After the last wash EtOH product is dried by freezing.
- IR (film; cm-1): 1635 (wide)
EXAMPLE 4: Obtaining hyaluronic acid, poperechnogo with CLD=0,05 (5% of the available carboxyl groups). Poperechnikami agent: 1,3-propandiamine. Sodium salt of hyaluronic acid (110-3mol relative to the disaccharide glycosides unit) was transferred to salt TWAS one of the following ways:
a) 1% aqueous solution of sodium hyaluronate transferred to N+form with strong N+-cation exchange resin (Amberlite IR 120); the final solution was treated with 0.5% solution of TBA-HE to a pH of about 9;
b) 1% aqueous solution of sodium hyaluronate, transferred to salt TION processing weak cationic resin in the TBA+form (Amberlite IRC 50).
In both cases, the final solutions lyophilized. Then salt TBA dissolved in 15 ml of anhydrous DMF, in an atmosphere of N2and when 0With, kept the salt solution TION is added dropwise 0.02 g chloromethylpyridine iodide (CMPJ) in 2 ml of anhydrous DMF.
Then to the reaction mixture is added 0.1 ml of triethylamine and then add dropwise a solution of 1,3-diaminopropane (d=0,88 in large excess so that it is easier to hold the cross-linking of the activated carboxyl groups) in 2 ml of anhydrous DMF. When the addition was completed, the reaction mixture plumage is car Ried out in DMF, which is then removed by distillation; the residue is treated with ethanol, ethanol-water and at the end of the water.
Then the product lyophilized and the residue is subjected to analysis.
- IR (film; cm-1): 1630 ; 1740 , polysaccharide); 3200 (-NH-).
- SD (degree of swelling in water and at room temperature over 15 min; gravimetric determination; calculated by:
where Ws= mass of hydrated gel; Wd= mass of dry gel): 31,000.
- The degree of cross-linkage: 0,05 (5% initially available carboxyl groups).
EXAMPLE 5: Receiving hyaluronic acid, crosslinked with CLD=0,05 (5% of the available carboxyl groups). Poperechnikami agent: 1,6-diaminohexane. Activator: chloromethylpyridine iodide.
Poperechnaya derivative produced by the method and under the conditions described in example 4, using the same HY the same activator, but instead of 1,3-diaminopropane - 1,6-diaminohexane.
- IR (film; cm-1): 1630 (- -NH-); 1740 (- HE polysaccharide); 3200 (- -).
EXAMPLE 6: Getting poperechnogo hyaluronic acid with CLD=0,05 (5% of the available carboxyl groups). Papachristou get in the manner and under the conditions described in example 4, and using the same activator, but instead of 1,3-diaminopropane - 0,0’-bis-(2-aminopropyl) PEG 500.
- IR (film; cm-1): 1630 ; 1740 , polysaccharide); 3200 ).
SD: 31,000.
EXAMPLE 7: Getting Poperechnaya hyaluronic acid with CLD=0,3 (30% of the available carboxyl groups). Poperechnikami agent: 1,3-propandiamine. Activator: chloromethylpyridine iodide.
0.6 g of the salt of hyaluronic acid and tributylamine (110-3mol relative to the disaccharide glycosides of the unit) is dissolved with stirring in 30 ml of DMF under nitrogen atmosphere. To the stirred solution is added dropwise to 0.08 g chloromethylpyridine iodide (3,510-4mol), dissolved in 2 ml of DMF, supporting with 0C. Therefore, the molar ratio is approximately 3:1.
After 20 min, add 2 ml of 1,3-diaminopropane (0,024 mol), then 0.5 ml of triethylamine. Get a solid glutinously product, then the product is allowed to swell in water and again washed with ethanol.
The final product after lyophilization shows under the scanning microscope heterogeneous sample with Gladkikh available carboxyl groups).
- IR (film; cm-1): 1740 ; 1630 ; 1610 ; 1560 ( .
EXAMPLE 8: Obtaining hyaluronic acid, poperechnogo with CLD=0,5 (50% of the available carboxyl groups). Poperechnikami agent: 1,3-propandiamine. Activator: chloromethylpyridine iodide.
0.6 g of the salt of hyaluronic acid and tributylamine (WELL, TBA) (110-3mol relative to the disaccharide glycosides of the unit) is dissolved with stirring in 30 ml of DMF under nitrogen atmosphere. 0.15 g of chloromethylpyridine iodide (CMPJ) (610-6mol), dissolved in 2 ml of DMF, is added dropwise to the solution while 0C. the Molar ratio is 2HY.TBA:1 CMPJ. After 20 min the solution add 2 ml of 1,3-diaminopropane (0,024 mol). Then add 0.5 ml of triethylamine. Get a solid jelly-like product and washed thoroughly with DMF. After distillation of DMF product allow to swell in water and washed with ethanol before lyophilization.
The resulting product has a degree of cross-linkage of 0.5 and it shows under the scanning microscope granular appearance with large holes in between. When bootrom few microns.
-IR (film; cm-1): 1740 ; 1630 ; 1610 ; 1560 .
The gels are subjected to swelling in PBS and evaluate the maximum ability to swell.
SD = 23,500.
NMR = (13C; ppm): 29,3 and 39.3 (communications-CH2-CH2-CH2-propandiamine); 172,5
Rheological properties valued on the rheometer Bohlin VOR at a temperature of 23±0,1C, showed that the dynamic elastic modulus G’ (100 PA at 10 Hz), the same for the two considered concentrations (10 and 20 mg/ml), is always higher than the dynamic coefficient of viscosity (G” 40 PA to 20 mg if 10 Hz and 20 PA for 10 ml at 10 Hz).
Examples 9-12
The methods disclosed in the previous examples, get Poperechnaya derivatives of hyaluronic acid, having the characteristics summarized in the following table 1, starting with10-3mol (0.6 g) salt of hyaluronic acid and tributylamine.
The obtained derivatives had the following characteristics (see table 1).
Example 13: the Sulfation 50% poperechnogo HY
Derivative obtained in example 8, was dispersed in 5 ml DMF with vigorous, paramasivan mesilat within 3 hours The reaction is quenched by adding an excess of N2About (50 ml) and the pH adjusted to 9 with 0.1 M NaOH.
The product is washed thoroughly with ethanol and N2O and then lyophilized.
The infrared spectrum shows, in addition to the bands original product peak at 1260 cm-1and a stronger band at 1025 cm-1.
The gel swelled in PBS with SD=33,000. 13C-NMR high-resolution displays signals in the H2On at 37S, are shown in table 2. The intensity of the NMR-signals at 29,3 and to 38.8 ppm (-CH2-) and signal 172,5 ppm (CONH) confirms the degree of cross-linkage, equal to about 50%.
Rheological properties characterized by a dynamic elastic modulus G’ (2500 PA with 20 mg and 1000 PA with 10 mg at 10 Hz), which is always higher than the dynamic viscosity coefficients G (600 PA with 20 mg and 150 PA with 10 mg at 10 Hz), and significantly higher than the corresponding values obtained with desulfuromonas HY (13 at 50% example 5). This connection has a clotting time (TT) is higher (61±5) than in control (14,0) and the corresponding compounds without cross-linkage (14,6).
The compound is also active in PRP test using rabbits under stress.
EXAMPLE 14: the Sulfation of alginic acid gel
Poperechnyy product after treatments
To 100 ml Poperechnaya product dispersed in 5 ml of DMF, add a solution of SO3-pyridine (800 mg in 2 ml DMF). The reaction should be carried out with 0 10-5
50% poperechnyy gel: 210-5
100% poperechnyy gel: 310-5
SD:
5% poperechnyy gel: 1910-3
50% poperechnyy gel: 910-3
100% poperechnyy gel: 710-3
EXAMPLE 15
Using the same methodology, synthesize sulfated derivatives 50% Poperechnaya products of examples 10, 11 and 12.
Colorimetric of hamerow 8 and 13.
EXAMPLE 16: the Sulfation of carboxymethylcellulose gel.
Following the method and conditions described in example 14, receive a sulfated derivative.
Equivalents SO3groups/g:
a - CMC 5% Poperechnaya: 810-6
b - CMC 50% Poperechnaya: 710-6
s - CMC 100% Poperechnaya: 410-6
SD:
and: 2010-3
b: 1210-3
s: 9l0-3
Claims 1. A method of obtaining a cross-linked polysaccharides containing carboxyl groups, comprising (a) activating the carboxyl groups of the polysaccharide by reacting with a suitable activating the carboxyl group of agents in an anhydrous aprotic solvent; (b) interaction of the polysaccharide with activated carboxyl groups with polyamines, where the polyamine has the following General formula: R1-NH-A-NH-R2, where R1and R2that are the same or different, represent hydrogen, radicals With1-C6alkyl, phenyl or benzyl; And is2-C10alkylenes chain, Pradhana, CNS, amino groups; polyoxyalkylene chain formulas [(CH2)n-O-(CH2)n]m, where n is 2 or 3, m is an integer from 2 to 10; radical With5-C7cycloalkyl; the radical aryl or hetaryl, preferably 1,3 - or 1,4-disubstituted benzene. 2. The method according to p. 1, where the polysaccharide is chosen from hyaluronic acid, derived from tissues or bacteria, carboxymethylcysteine, carboxymethyl cellulose, carboxymethyl amylum, alginic acid, cellulose acid, N-carboxymethyl - or butylglycol or chitosans; heparins of various molecular weights, optional desulfation or succinylcholine, dermatosurgical, chondroitin sulfates, heparansulfate, polyacrylic acids. 3. The method according to p. 1 or 2, where the agent activating the carboxyl group, selected from carbonyldiimidazole, carbonitrile, chloromethylpyridine iodide, hydroxybenzotriazole, p-NITROPHENOL, p-nitrophenylacetate, N-hydroxysuccinimide. 4. The method according to one of paragraphs.1-3, where the polysaccharide forms a salt with lipophilic cations. 5. The method according to p. 4, where the lipophilic cation is tributyl or tetralkylammonium. 6. The method according to one of paragraphs.1-5, where the reaction cross-scientists cross-linked polysaccharide is additionally subjected to the sulfation of hydroxyl groups by interacting with a complex of pyridine/sulfur trioxide. 8. The method according to p. 7, where the sulfation reaction is carried out in dimethylformamide in a heterogeneous phase at 0-10With over a period of time from about 0.5 to about 6 hours
9. The method according to one of paragraphs.1-8, where cross-linked, optionally sulfated, polysaccharide optionally subjecting the reaction of formation of the complex with aqueous solutions of ions of copper, zinc or iron.
10. Cross-linked polysaccharides, obtained by the method according to PP.1-9.
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