Novel cross-linking reagents for producing chitosan-based biocompatible materials

FIELD: chemistry.

SUBSTANCE: articles based on biologically active polymer materials can be used in surgery when treating wounds and as materials for temporary replacement of body tissue, in biotechnology for obtaining matrices for growing cell cultures, in pharmaceuticals as carriers of enzymes and other biologically active compounds. The cross-linking reagents are 2,4-derivatives of 3-oxa glutaric dialdehyde (2,2'-oxydiacetaldehyde). These compounds can be obtained via periodate oxidation of monosaccharides, nucleosides and nucleotides.

EFFECT: low toxicity and biocompatibility of chitosan-based materials is achieved by using cross-linking reagents.

2 dwg, 12 ex

 

The invention relates to the field of biotechnology and medicine, namely the creation of polymeric materials based on chitosan with low toxicity and high biocompatibility, in particular, films, microcapsules, hydrogels, wound coverings, scaffolds etc. products on the basis of biologically active polymeric materials can be used in surgery in the treatment of wounds and as materials for temporary replacement of body tissues, in the field of biotechnology for producing matrices for growing cell cultures, in the pharmaceutical industry as carriers of enzymes and other biologically active compounds.

As reagents for cross-linking of chitosan using phthalic and amber dianhydride, diepoxide, crown-ethers, diphenylsulfone [Sereikaite I., Bassus D., Bubnis R. and others // Bioorganic chemistry, 2003, t, No. 3, s-257] aldehydes of various structure: glutaric aldehyde (HA), genipin [F.L. Mi, Y.C. Tan, H.C. Liang e.a. // J. Biomater. Sci. Polym. Ed., 2001, v.12, No. 8, p.835-850], formaldehyde [A. Singh, S.S. Narvi, P.K. Dutta and N.D. Pandey. // Bull. Mater. Sci., 2006, V.29, №.3, p.233-238], acetaldehyde, glyoxal, oligoethyleneglycols [Ohya Y., Cai R., Nishizawa, H., Nagy, K., Ouchi T. //S.T.P. Pharma Sci., 2000, v.10., No. 1., p.77-82]. As shown by the authors [S.J. Meade et al Bioorg. Med. Chem. 11, 853-862, 2003], on the basis of comparative study of the reactivity of aldehydes most readily reacts with amino groups glutaric Aldagi the (HA). The use of HA allows cross-linking of chitosan under mild conditions (low temperature, physiological pH).

Of polymer aminecontaining media in combination with HA was used as synthetic polymers (aminoplastic modified with diamines stiroldivinilbenzol polymers, as well as the product of copolymerization of ethylene with maleic anhydride)and artificial (aminocellulose), and amino compounds, polymers of natural origin (gelatin [Draye JP, Delaey Century, Van de Voorde, A., Van Den Bulcke, A., De Reu Century, Schacht E. // Biomaterials, 1998, v.18. p.1677-1687], albumin, protein feathers, casein, collagen and others).

The most promising polymer for creating biologically active polymeric material is biocompatible and biodegradable aminopolysaccharide coated chitosan [A.J.Varma et al. Carboh. Polymers, 55, 77-93,2004; J.Berger et al. Eur. J. Pharm. Biopharm. 57, 19-34, 2004; H. Yi et al. Biomacromolecules, 6, 2881-2894 2005; K. Kurita. Marine Biotech. 8, 203-226, 2006]. The solubility of chitosan in dilute aqueous solutions of acids, along with fiber - and film-forming ability and the presence of reactive amino groups facilitates the modification of this polymer and its processing of polymer products.

Previously on the basis of chitosan - HA (RF patent 2261911) was developed biocatalyst containing immobilized organophosphorous enzyme gidrolizuemye pastefire communication, before oznaczony removal of organophosphorus compounds with different surfaces, including the skin, and subsequent detoxification, as well as for use as PPE.

The gels obtained by sequential processing of chitosan-HA and then the sulfur dioxide in aqueous solution (US Patent 4125708)and tripolyphosphate and then HA (US Patent 5322935)proposed to use as fillers in the devices column type for purification of water from dissolved compounds containing ions of chromium and manganese, and for the manufacture of highly cross-linked membranes designed for the separation of components of liquid mixtures, such as water-alcohol (US Patent 5006255). The mixture of HA and chitosan with low molecular weight is an effective flocculant in the dehydration of sewage sludge (US Patent 4609470). Films based on chitosan, crosslinked HA or containing the carbonyl group of a crosslinking reagent by genipin (Mt F.-L., HuangC.-T., Liang, H.-F. et al. // J.Agr.Food Chem., 2006, v.54, p.3290-3296), proposed as coatings of various food products; chitosan film slow down the oxidation, microbial growth, loss of moisture, absorb odors, so you can use them as edible films for high-quality food storage.

The use of HA in obtaining various physical forms of polymer materials based on chitosan, in particular biotechnological and medical purposes, with different types of biological activity due to its ability when interacting with the aminopolysaccharide coated to form a high water-holding capacity durable biocompatible porous structure [Vikhoreva GA, kildeeva NR, M. Ustinov, Nocevkina YU. // Chem. fibers, 2002, No. 6, S. 29-33; Vikhoreva GA, Sablikova E.A., kildeeva NR // Chem. fiber, 2001, No. 3, ñ.38-42; A.S. Acharya, Suseman L.G., J.M. Manning /A J. Biol. Chem., 1983, v.285, No. 4, p.2296-2302; Jameela S.R., Jayakrishnan A. //Biomaterials, 1995, No. 16, p.769-775].

The study of the process of cross-linking of chitosan HA showed the presence in the samples of cross-linked chitosan products crotonic condensation HA [V.Crescenzi et al. // Biomacromolecules. 2003, v.4, p.1045-1054; Pairing. Kida. Diss. Moscow, 2007], which contains the carbonyl group and the C=C-bond.

Crotonic condensation HA catalyzed by amino groups, so in the case of chitosan HA is spent not only on the stitching aminopolysaccharide coated, but also on the growth of the oligomeric chains HA, length and structure to control not possible (figure 1). Figure 1 shows the structure of the products crotonic condensation HA and products of the interaction of HA with chitosan. The presence in the composition of the resulting hydrogels reactive carbonyl group and C=C-bonds limits the use of the system chitosan - aliphatic dialdehyde in biomedical purposes.

In this regard, Wasim what is important to search for new cross-linking reagents, able, like HA, effective to react with chitosan to form hydrogels, but not forming this oligomeric products.

The objective of this invention is to provide a chitosan-based non-toxic and biocompatible materials for medical and biotechnological purposes, as well as new sorption-active materials.

This task is solved by the use of new cross-linking reagent, 2,4-derivatives of 3-oxoglutarate aldehyde (2,2'-oxadiazolidine). The introduction of the electronegative oxygen atom at the 3-position of the HA, and the presence of substituents in the 2,4-positions prevent Alderney and crotonic condensation and the formation of irregular products.

These compounds can be obtained easily controllable periodic destruction by oxidation of nucleosides, nucleotides and sugars (such as derivatives of ribose, arabinose, erythrose, glucose, galactose, arabinose). It should be noted that obtaining derivatives of 3-oxoglutarate aldehyde is carried out in aqueous solutions under mild conditions, the reaction can be monitored using TLC or NMR spectroscopy. The methodology for conducting the reaction is very simple: to a solution of compound with a diol group in the water add a small excess of NaIO4and incubated for 10-30 min at 20°C [Snikolov, Hijackable. // Chemistry of natural compounds, 1987, p.40-43; Ermolinskiy BS, Mikhailov, S.N. //Bioorgan, chemistry. 2000, t, s-504] (figure 2). 2 shows the reaction scheme for the controllable periodic destruction of oxidation, which is used to obtain derivatives of 3-oxoglutarate aldehyde. It should be noted that these derivatives can also be obtained controllable periodic destruction by oxidation of compounds with trialname groups, in this case using 2 equivalent NaIO4.

Features of the proposed use of the new cross-linking reagents are: 1) the structure dialdehyde derivatives of monosaccharides, nucleosides and nucleotides eliminates the possibility of crotonic condensation of the dialdehyde, leading to the formation of a double C=C-bonds and the formation of toxic products with unpredictable composition; 2) the presence of a crosslinking reagents additional functional groups (phosphate group and heterocyclic bases) gives the possibility of their use not only as a cross-linking reagents, and modifying connections, providing additional functionalization of chitosan; 3) the use of the reagents opens up new possibilities: a) the creation of new biocompatible materials based on chitosan; b) the implementation in the process of knitting is not only covalent, and ionic interactions; C) leads to the production of new sorption-active materials.

Listed below are the specific instances of implementation of the proposed technical solution.

Example 1. Controllable periodic destruction oxidation uridine

0.899 g (4.2 mmol) of periodate sodium was dissolved in 8 ml of water was then added with stirring 0.976 g (4 mmol) uridine and the solution kept at room temperature. According to TLC in the system chloroform - ethanol 4:1, the reaction ends after 1 hour. Reactional the mixture was left in the refrigerator for 20 hours at 0°C, the precipitated white crystalline precipitate NaIO3was filtered and received a 0.5 M solution dialdehyde derivative of uridine (oxUrd), which ispolzovali the crosslinking of chitosan. The solution dialdehyde derivative of uridine is stable when stored in the refrigerator for several months.

Example 2. Controllable periodic destruction oxidation disodium salt of adenosine-5'-monophosphate

To a solution of 0.782 g (2 mmol) of disodium salt of adenosine-5'-monophosphate in 2.5 ml of water was added under stirring 4.2 ml of a 0.5 M solution of periodate sodium (2.1 mmol) at room temperature. The mixture was stirred 2 hours at room temperature and the mixture was left in the refrigerator for 20 hours at 0°C. the Precipitated white crystalline precipitate NaIO3was filtered and received a 0.3 M solution dialdehydes derived adenosine-5'-monophosphate (oxAMP). The solution dialdehydes derived stable when stored in the refrigerator for months.

Example 3. Controllable periodic destruction oxidation of methyl β-D-ribofuranoside

0.899 g (4. mmol) periodate sodium was dissolved in 8 ml of water, then added with stirring 0.648 g (4 mmol) of methyl β-D-ribofuranoside and the solution kept at room temperature. According to TLC in the system chloroform - ethanol 4:1, the reaction ends after 1 hour. Reactional the mixture was left in the refrigerator for 20 hours at 0°C, the precipitated white crystalline precipitate NaIO3was filtered and received a 0.5 M solution dialdehydes derived methyl β-D-ribofuranoside, which is used for the crosslinking of chitosan. The solution dialdehydes derived stable when stored in the refrigerator for several months.

Example 4. Obtaining a solution of 3-oxoglutarate aldehyde (2,2'-oxadiazolidine)

0.450 g (2.1 mmol) of periodate sodium was dissolved in 5 ml of water, then added with stirring 0.208 g (2 mmol) of 1,4-anhydromannitol and the solution kept at room temperature. According to TLC in the system chloroform - ethanol 5:1, the reaction ends after 1 hour. Reactional the mixture was left in the refrigerator for 20 hours at 0°C, the precipitated white crystalline precipitate NaIO3was filtered and received a 0.4 M solution of 3-oxoglutarate aldehyde, which ispolzovali the crosslinking of chitosan. A solution of 3-oxoglutarate aldehyde stable when stored in the refrigerator for several months.

Example 5. Obtaining a hydrogel of chitosan

To 2.5 g of 3%-aqueous solution of chitosan with molecules of the nuclear biological chemical (NBC weight of 460 kDa in 2%acetic acid (pH 4,1) add 0.4 ml of 0.5m oxUrd. The resulting gel has the following composition, wt. %: chitosan - 2,43, oxUrd - 1,54, the rest to 100%. The ratio oxUrd/NH2is 0.67 mol/mol. Gelation is completed within 120 minutes.

Example 6. Obtaining a hydrogel of chitosan

3%solution of chitosan (molecular weight of 460 kDa) in 2%acetic acid titrated 10M NaOH to pH 5.0. To 2.5 g of this solution was added 0.4 ml of 0.5m oxUrd. The resulting gel has the following composition, wt. %: chitosan - 2,43, oxUrd - 1,54, the rest to 100%. The ratio oxUrd/NH2is 0.67 mol/mol. Gelation is completed within 60 minutes.

Example 7. Obtaining a hydrogel of chitosan

To 2.5 g of 2%solution of chitosan with molecular weight of 460 kDa in 2%acetic acid (pH 4,1) type of 0.64 ml of 4 mm oxUMP. The resulting gel has the following composition, wt.%: chitosan - 1,60, oxUMP was 0.026, the rest to 100%. The ratio oxUMP/NH2is 0.01 mol/mol. Gelation is completed within 10 minutes.

Example 8. Obtaining a hydrogel of chitosan.

To 2.5 g of 2%solution of chitosan with a molecular mass of 190 kDa in 2%acetic acid (pH 4,1) type of 0.64 ml of 4 mm ohmr. The resulting gel has the following composition, wt. %: chitosan - 1,60, kamr - 0,028, the rest to 100%. The ratio ohmr/NH2is 0.01 mol/mol. Gelation is completed in 14 hours.

Example 9. Obtaining a hydrogel containing immobilized trypsin/p>

To 2.5 g of 3%-aqueous solution of chitosan with a molecular mass of 190 kDa in 2%acetic acid (pH 4,1) add 0.2 ml of an aqueous solution of trypsin (5 mg/ml) and 0.4 ml of 0.5m oxUrd. The resulting gel has the following composition, wt. %: chitosan - 2,43, oxUrd - 1,54, trypsin - 0,032, the rest to 100%. The ratio Urd/NH2chitosan is 0.67 mol/mol. Gelation is completed within 120 minutes. The gel has activity equal to 90 units/g of dried gel.

Example 10. Obtaining microcapsules based on chitosan

Microcapsules were obtained by means of high-frequency (200 Hz) breaker jet molding composition is a joint solution of chitosan with a molecular mass of 300 kDa and oxUrd, in warm (60°C) vegetable oil. The ratio oxUrd/NH2were 0.4 and 2 mol/mol. To complete the process of gelation capsules kept in oil for 5-10 minutes under stirring. The obtained microcapsules with a diameter of 300-500 μm, had a spherical shape. The degree of swelling in water of the microcapsules obtained when the ratio oxUrd/NH2=2.0 mol/mol, 300%, and at oxUrd/NH2=0.4 mol/mol - 2000%.

Example 11. The receiving space of the modified films based on chitosan

To 45 g of 2%solution of chitosan with molecular weight of 460 kDa in 2%acetic acid (pH 4,1) type of 11.26 ml of 2 mm dialdehydes derived METI the β-D-ribofuranoside. After mixing, the solution was poured into a Petri dish with a diameter of 10 cm and left overnight at 40°C. the Obtained film has the following composition, wt.%: chitosan - 95,40, dialdehydes derived methyl β-D-ribofuranoside - 0,80, the rest to 100%. The ratio dialdehydes derived methyl β-D-ribofuranoside /NH2was 0.005 mol/mol. The thickness of the laminated film 50 μm, the degree of swelling in water of 800%.

Example 12. Having surface modified films based on chitosan

A solution of chitosan (2%) by weight of 45 g with molecular weight of 467 kDa in 2%acetic acid (pH of 4.1) was poured into a Petri dish of 10 cm diameter and leave for 5 days at 25°C. the thickness of the formed film was 50 μm. Molded film was filled with 20 ml of 0.1 M aqueous solution of NaOH to neutralize the acetic acid, and then after washing with distilled water and placed 11.3 ml of 4 mm 3-oxoglutarate aldehyde for 2 hours. The thickness of the obtained film is 83 μm, the degree of swelling in water of 1000%.

Example 13. Obtaining fibrous biocatalyst based on chitosan

Woven cellulosic material (cotton calico) weight 1.2 g were placed in a 3%solution of chitosan with a molecular mass of 190 kDa (2.55 g)containing 0.2 ml of an aqueous solution of α-chymotrypsin (5 mg/ml) and 0.40 ml of 0.5m oxUrd. Calico was pressed and held in the air in techenie minutes. The resulting biocatalyst had the following composition, wt. %: protein - 2,05, chitosan - 12,92 insoluble carrier -51,37, oxUrd - 0,032, the rest to 100%. The activity of the biocatalyst was 87%/year

Cross-linking reagents to obtain chitosan-based biocompatible and non-toxic materials for biomedical and biotechnological purposes, as well as new sorption-active materials constituting 2,4-derived 3-oxoglutarate aldehyde (2,2'-oxadiazolidine).



 

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5 tbl

FIELD: production of new materials.

SUBSTANCE: proposed nanocomposite can be used as component contributing to charges of consumer properties of materials made on its base. Nanocomposite includes fibrils of filler-chitin individualized to nanosizes with distance between fibrils from 709 to 20-22 nm and water-soluble polymeric matrix in interfibril space. Degree of filling of nanocomposite is 0.05-0.25% mass. Fibrils are arranged in parallel and they have cross size of 4 nm. Method of production of nanocomposite comes to the following: free-radical polymerization in water medium of at least one monomer of row of acrylic acid, salt of acrylic acid, acrylamide is carried out in presence of filler. Initiator is chosen from the row of water-soluble peroxides, hydroperoxides or their salts, potassium persulfate. Individualization to nanosizes of fibrils is done simultaneously with process of polymerization and/or with combination of said process with mechanical disintegrating action by disintegrating or pressing, or pressing with abrasion shift. Nanocomposite is obtained in form of film, being pervaporation membrane.

EFFECT: enlarged range of filling, ease of production.

22 cl, 1 tbl, 9 ex, 2 dwg

FIELD: medicine.

SUBSTANCE: composite contains a reactive ceramic phase of triple-substituted calcium phosphate and an organic phase containing polyvinyl alcohol hydrogel. The mechanical properties and injectability of said material can be adjusted by varying the concentration of two phases.

EFFECT: preparation of the new injectable composite applicable as a bone filler.

9 cl, 2 tbl

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