RU2482883C1 - Method for preparing fibre polymeric composites with antimicrobial activity - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to macromolecular compound chemistry, to preparing polymeric compositions of fibre materials with the antimicrobial properties. The method consists in immobilising a bioactive polymeric complex of (N-(2-hydroxypropyl)methacrylamide-acrylic acid + gentamicin base) copolymer on phosphorus cellulose or carbon fibre materials. The method involves sorption for 24 hours at temperature 25°C from aqueous solutions of the various (0.06-0.5%) concentrations of the polymeric complex on the phosphorylated cellulose or carbon fibre materials containing the functional phosphorus groups in the acid or salt forms on its surface. The polymeric complex is attached in the structure of the fibre material with additional thermal processing at 90°C for 1.5 hours.

EFFECT: invention provides the biological compatibility of the material that exhibit the haemostatic, thromboresistant, antibacterial properties.

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Description

The invention relates to the chemistry of macromolecular compounds, to the production of modified cellulosic and carbon fiber materials having antimicrobial properties that can be used in medicine as fixative dressings, dressings, drains and implants for endoprosthetics.

Known methods for producing fibrous materials with antimicrobial properties, of which the most representative are the following.

Cellulose oxidized by nitrogen oxides was condensed with tubazide, rivalone, norsulfazole, and also with aminoglycoside antibiotics: kanamycin, streptomycin [ZhPKh, 1971, v. 44, No. 3, p.632]. The obtained antimicrobial materials were used in surgical operations. The disadvantages of this method is that such materials did not possess sorption properties and did not extract creatinine, uric acid, bilirubin, oligopeptides from biological fluids of the body.

Silver, copper, N-cetylpyridinium, streptomycin, hexachlorophene and pentachlorophenol ions were attached to cellulose (viscose) fibers and tissues modified by grafting with polyacrylic or polymethacrylic acids [Virnik A.D. Text. prom 1972, No. 5, p. 56-59]. Zones of growth inhibition of test microbes at the edges of the sample (2 × 2 cm in size) containing streptomycin were 5 mm for staphylococcus and 9 mm for E. coli. The disadvantages of this method are the complexity of the process of obtaining modified fibers, the uneven distribution of biologically active substances in the fiber, the toxicity of the material due to the presence of copper ions in it, limiting its use in medicine.

In the work [Chem-farm. g. 1998, vol. 32, No. 2, pp. 29-31] to a powder of water-insoluble microcrystalline cellulose obtained from cotton cellulose, a polymer antiseptic catapol was adsorbed from an aqueous solution, which is a complex of catamine AB antiseptic with a copolymer of N-vinylpyrrolidone with crotonic acid . The resulting suspensions were stirred for 5 minutes to 6 hours at room temperature, then filtered and dried. The amount of adsorbed substance was determined in the obtained samples. The disadvantages of this method is the rapid desorption, the maximum is achieved in 1 min and amounts to 24.6% of the adsorbed amount, significantly lower antimicrobial activity of catamine AB as compared with aminoglycoside antibiotics, and the fact that the obtained material cannot be used as an implant for endoprosthetics due to toxicity of catamine AB released in the body, which causes hemolysis of red blood cells.

The closest to the essence and the achieved result is a method of producing antimicrobial fibrous materials by attaching mycerin (antibiotic-aminoglycoside neomycin) to sulfo groups of modified cellulose [Snezhko DL and others. Izv. Universities. Technol. text. prom., 1968, No. 2, p.104-106] - prototype. Sulfonation of the cellulosic fibrous material (preliminary modification) was carried out by treating it with an aqueous solution of 2,4-di-chloro- (3 ', 6', 8'-trisulfo-1-naphthylamino) -8-triazine. For subsequent immobilization of mycerol on the fiber surface, a modified cellulose tissue containing 0.4% N and 0.7% S with an ion exchange capacity of 0.22 mEq / g was used. The tissue was treated for 30 min in solutions of base mycerin with concentrations from 50 to 2000 u / ml, after which it was removed, washed with water and dried. The antimicrobial activity of tissues increased with an increase in the concentration of mycerol from 50 to 2000 u / ml and was satisfactory in terms of the antibacterial activity of cellulose tissue. At the same time, it is known that the antibiotic mycerin has high nephro- and ototoxicity, and, as a result, has a damaging effect on the kidneys and hearing organs. This disadvantage is inherent in the fibrous antimicrobial materials obtained on its basis. Currently, the use of mycerol is limited.

The objective of the proposed technical solution is to reduce the toxicity of antimicrobial fibrous materials, improve their bactericidal properties, increase the strength of fixing antimicrobial substances in the structure of the fiber.

The task and a positive result are achieved in a method for producing antimicrobial polymer-composite fiber materials, including sorption of an antibiotic-aminoglycoside on modified fibrous materials from its aqueous solutions, using the polymer complex of an aminoglycoside with an N- (2-hydroxypropyl copolymer) to immobilize the antibiotic on a fibrous material ) methacrylamide with acrylic acid.

As an antibiotic-aminoglycoside, gentamicin base (GO) is used.

Cellulose phosphate or carbon phosphorus-containing fibrous material obtained by carbonization of cellulose phosphate in acid and salt forms are used as a substrate material for immobilizing the polymer complex.

Sorption of the polymer complex on modified fibrous materials is carried out from solutions of 0.06-0.5% concentrations for 24 hours at 25 ° C.

The polymer complex is fixed on modified fibrous materials with an additional heat treatment of 90 ° C, 1.5 hours

The fibrous materials used exhibit hemostatic and thromboresistant properties.

The choice of copolymers of N- (2-hydroxypropyl) methacrylamide (GPMA) as carrier polymers of gentamicin in polymer complexes is due to the fact that GPMA copolymers containing a small number of units of another comonomer, like poly-GPMA, are non-toxic and biocompatible. The chemical addition of gentamicin to water-soluble non-toxic reactive polymers allows you to change their pharmacokinetics and increase their effectiveness. It is significant that gentamicin, being chemically bound to the carrier polymer, has less cytotoxicity compared to

A distinctive feature of the proposed technical solution is also that the modified fibrous materials used as a substrate material are non-toxic, biocompatible, and are sorbents with a high ion-exchange capacity (SOEs are an order of magnitude higher than for sulfonated cellulose used in the prototype). This creates the conditions for improving the adsorbability of antimicrobial preparations with a fibrous substrate and, as a consequence, increases the bacterial resistance of the obtained polymer-fibrous materials. Cellulose phosphate and phosphorus-containing carbon fiber are approved for medical use.

Heat treatment of the resulting polymer-composite fiber material leads to additional system structuring due to the ongoing process of grafting the polymer complex to the functional groups of modified fibers, ensuring the safety of antimicrobial properties and increasing the resource of its use.

The method is illustrated by the specific examples of its implementation.

Example. Prepare a 0.06% aqueous solution of the polymer complex of gentamicin base (TO) with a copolymer of N- (2-hydroxypropyl) methacrylamide with acrylic acid (AK) containing 22.3 mol.% Units of COOH groups, with a molecular weight of 25000. The complex contains 25.7 wt.% GO. A piece of phosphorylated cellulose tissue weighing 0.5 g is placed in a bottle with a ground lid. The prepared solution of the GO polymer complex is added to the bottle by the calculation of the bath modulus 1:10. The sample is kept in solution in a tightly closed bottle for 24 hours at a temperature of 25 ° C. Then the fabric is removed, the excess solution is drained and then dried under vacuum at a temperature of 40 ° C for 5 hours, then the heating is turned off and left under vacuum for another 16-18 hours. Additional heat treatment is carried out at a temperature of 90 ° C for 1.5 hours The results are tabulated.

Table. Production conditions and antimicrobial properties of polymer-composite fibrous materials with antimicrobial activity. The exposure time of the substrate material in solutions of the polymer complex is 24 hours at a temperature of 25 ° C. No. Backing material The concentration of the polymer complex,% The diameters of the zones of inhibition of growth of test cultures around the disks, mm Staphylococcus aureus Pseudomonas aeruginosa Escherichia coli No heating Heat* Without
heating Heat No heating Heat one cellulose phosphate 0.06 2 3 3 four 5 6 2 phosphor-containing carbon fabric with surface acid groups 0.06 3 four 2 3 6 7 3 phosphorus-containing carbon cloth (salt form) 0.06 four 5 6 8 8 9 four cellulose phosphate 0.125 four 7 5 7 5 6 5 phosphorus-containing carbon with surface acid groups 0.125 5 7 5 5 8 9 6 phosphorus-containing carbon cloth (salt form) 0.125 7 9 8 9 10 eleven 7 cellulose phosphate 0.25 7 7 5 8 6 7 8 phosphorus carbon tissue with surface acid groups 0.25 7 7 5 8 8 9 9 phosphorus-containing carbon cloth (salt form) 0.25 8 9 9 10 10 12 10 cellulose phosphate 0.50 8 9 7 8 10 10 eleven phosphorus-containing carbon with surface acid groups 0.50 8 9 7 8 10 eleven 12 phosphorus-containing carbon cloth (salt form) 0.50 9 10 10 eleven 12 fourteen * Additional heat treatment at 25 ° C for 1.5 hours

Thus, as can be seen from the table, the obtained polymer-composite fibrous materials have high antimicrobial activity against the main causative agents of wound infection. For all samples, the diameters of growth inhibition zones of all used test cultures increased with increasing concentration of the immobilized GO polymer complex in solution, reaching a maximum at a concentration of 0.5%. Additional heat treatment of polymer-composite fiber materials increased their antimicrobial properties. Moreover, the antimicrobial activity in relation to all studied test cultures depended on the substrate material used. The most pronounced antimicrobial effect was obtained by immobilizing the polymer complex of GO on phosphorus-containing carbon materials in acidic and, especially, in salt form, due to the fixation in the structure of the fiber through ionic bonds between amino groups of GO and surface phosphate groups of carbon material. It is significant that the adsorbed GOs on fibrous materials and its polymer complex differ markedly in the kinetics of desorption. GO is completely desorbed in 6 hours, under the same conditions, the GO polymer complex is desorbed from the tissue substrate much more slowly: by 34.2% in 48 hours. The data indicate that the polymer complex is more firmly fixed in the structure of the phosphorus-containing carbon material, compared to GO, which can to provide a prolonged antimicrobial effect of the implant from a polymer-composite fibrous material containing a polymer complex GO. Limited tests carried out on the obtained polymer-composite fibrous materials in the form of a wound dressing showed that their use inhibits the development of purulent infection and promotes the regeneration of the skin.

Claims (2)

1. A method of producing polymer composite materials with antimicrobial activity, including sorption of the polymer complex of gentamicin base with a copolymer of N- (2-hydroxypropyl) methacrylamide with acrylic acid on a modified fibrous material, characterized in that cellulose phosphate or carbon is used as the modified fibrous material phosphorus-containing fibrous material exhibiting hemostatic and thromboresistant properties, while sorption is carried out from solutions of concentrations of 0.06-0.5% during of 24 hours at 25 ° C and additional heat treatment is carried out at a temperature of 90 ° C for 1.5 hours. 2. The method according to claim 1, characterized in that the carbon phosphorus-containing fibrous material is obtained by carbonization of cellulose phosphate in acid and salt forms.