Modified chitosan

FIELD: organic chemistry of natural compounds, chemical technology, medicine.

SUBSTANCE: invention relates to the group of chitosan-containing compounds. Invention relates to synthesis of modified chitosan of the following structure: wherein n = 150-1400. The modified chitosan possesses the bactericidal activity, in particular, antituberculosis activity.

EFFECT: valuable medicinal properties of modified chitosan.

1 tbl, 1 dwg, 3 ex

 

The invention relates to the field of chemical technology, namely the group of compounds containing chitosan. The resulting modified chitosan can be used in medicine, cosmetics, agriculture, veterinary, food and light industry.

Chitosan is a physiologically active compound of natural origin, widely used in cosmetics and medicines. It is produced by hydrolysis of chitin, the main component of the outer skeleton of arthropods:

n=150-1400

Chitin (from the French "chitine" and the Greek "chitone", which means "skin", "shell") is widely distributed in nature, it is part of the cell walls of fungi and bacteria, where does the support and a protective function.

According to the chemical structure of chitosan is a high molecular weight polymers (MM˜30000-260000 USD) from the group of polysaccharides built from the remnants of glucosamine (acetylglucosamine), interconnected β(1→4) glycosidic bonds. In its structure, physicochemical properties and biological role of chitosan is similar to the cellulose of plants.

In recent years in various fields of medicine and cosmetology has emerged a heightened interest in the use of chitosan as a mild remedy, obladayushzuyu antiseptic effect. Especially valuable is that chitosan, being a product of vital activity of living organisms are harmless to humans.

Known to be an effective antibacterial antibiotic streptomycin, which molecule is a tricyclic carbohydrate containing one of the two cycles guanidine groups [encyclopedia of medicine. 8th ed., edited Ufraw, M., "radar", 2001, str].

The structural formula of streptomycin has the following form:

Streptomycin by their chemical nature, as chitosan refers to the aminoglycosides, is an effective broad-spectrum antibiotic, active against Mycobacterium tuberculosis, the causative agents of plague, tularemia, brucellosis, dysentery, strepto-, fees and meningococci, produces radiant fungus (genus Streptomyces).

However, streptomycin is toxic enough and with long-term use affects the auditory nerve.

Closest to the proposed solution is the drug carboxymethylchitosan, obtained by the reaction of chitosan with monochloracetic acid (U.S. Pat. Of the Russian Federation No. 2185387, class 08 In 37/08, 2000).

The disadvantages of this drug include lack of bactericidal activity and complex method of receipt.

The technical purpose of this invention is to increase the bactericidal activity and the drug.

To solve the technical problem of the synthesized modified chitosan of the following structure:

where n=150-1400

Since the polymer forms of medications are generally preferred due to the strengthening effect due to the presence of many active groups located at the molecular distances, lower toxicity, and the effect of Deposit (longer therapeutic effect of the drug, it was considered useful to carry out guanidine amine groups of chitosan, turning them from inactive amine in high-performance guanidine.

The modified chitosan was obtained as follows. Due to the low thermal stability of chitosan as a soft guanidinium tool was selected carbodiimide (NH=C=NH) - tautomer Monomeric cyanamide (NH2CN).

As a source of chitosan materials have served two commercial sample of chitosan succinate companies CJSC "Bioprogress" and "Hemmed", freeze-dried method. Their molecular masses are according to ultrafiltration (osmosis on the membranes) 30000 26000 and; the degree of polymerization, respectively, n=150 and n=1400. The reaction was carried out with swollen chitosan succinate in a solution of acetonitrile containing the estimated quantity of 50% aqueous carbodiimide:

where n=150-1400

To complete the process the reaction mixture after 24 hours of exposure under normal conditions was heated for 10 hours at 40°C. the Modified chitosan differs from the original by more friable structure.

IR-spectroscopic study of the obtained polymer (see drawing) shows the appearance of the structure of the modified chitosan (curve 1) a significant number guanidino groups: intensive bandsandwhen ˜3350 and 1600-1650 cm-1. For comparison, the drawing shows a range of grandravine polyethylenimine containing guanidine band (curve 2). The IR spectrum of initial chitosan bands at 3350 and 1600 cm-1does not contain [chitin and chitosan]. Since we had no method osmoticheskogo the determination of molecular mass to determine the molecular weight of the modified chitosan was used the following method. Sample source modified chitosan was dissolved in 2% acetic acid and determined their characteristic viscosity. The equality of the obtained values (ηRef=0,41 DL/l; ηmod=0,43 DL/l) indicates that during the reaction, the degradation of the polymer chains of chitosan did not take place. In turn, a small increase in the molecular is Arnau mass due to modifications of about 20%, also not so much to affect the characteristic viscosity.

The emergence of guanidino groups in the chitosan is logged chemical analysis: colorimetry with eosin.

By the method of serial dilution of the antibacterial activity grandravine chitosan. Bacteriostatic activity on the strain of Pseudomonas aeruginosa was 0,075%, bactericidal 0,15%.

Due to the proximity grandravine chitosan to streptomycin drug was also tested for anti-TB activity. It also noted increased efficiency, due to the polymeric nature of the drug (compared with streptomycin) and compared to the unmodified chitosan.

Provide examples illustrate the practical implementation of the synthesis grandravine chitosan.

Example 1

A portion of 25 g (0.1 mole) of chitosan succinate (n=150) was ground in a coffee mill in a fine yellow powder and was mixed in a flask with 100 ml of acetonitrile, containing 4.5 g (0.1 mole) carbodiimide. After swelling of chitosan in a solution of acetonitrile during the day the reaction mixture to complete the reaction was heated with occasional stirring at a temperature of 40°C. the Modified chitosan was separated by filtration, then washed with 50 ml distillirovanna the water on the filter and dried in air.

Received guanidine of modificat chitosan is a volumetric light powder light yellow color, it is difficult soluble in water and slightly better in 2% acetic acid solution.

Example 2

A portion of 25 g of commercial chitosan succinate (n=150) was purified by presidenial. To this end it was dissolved in 1.5 liters of 2% aqueous solution of acetic acid. Complete dissolution of the sample chitosan requires at periodic stirring ˜48 hours. The obtained homogeneous solution of chitosan acetate decantation from a small residue, which may include nephrolitiasis chitin and protein impurities. A clear solution was added with vigorous stirring to 2 liters of a 15% aqueous solution of ammonia. The reaction mixture was left for a day and then gently decantation of the upper clear solution. To the precipitate, having a form of white wool was added 1.5 l of distilled water, thoroughly mixed, and again left for the day. The operation of the washing and decanting was repeated three times until the complete disappearance of the smell of ammonia. After that sediment base of chitosan was obezvozhivani on the centrifuge and neutralized by adding dropwise 5 g glacial acetic acid, thorough mixing in a mortar and drying in air to constant weight. Exit 20,

The obtained chitosan acetate used in the reaction with the carb what diimides by the method of example 1. The degree of guanidine purified chitosan higher (75%)than neprevzojdennogo (60%), according to the colorimetric determination with eosin.

Sample of 0.5 g of the modified and the original chitosan was dissolved in 100 ml of 2% aqueous solution of acetic acid and measured the results of the specific viscosity of the obtained solutions. Close values obtained viscosities ηRef=0.4 ηmod=0,3 indicates the absence of destruction of the chain of chitosan at grandravine.

Example 3

Portion 5 g of the commercial chitosan succinate (n=1400) modified by treatment of 1 g of the carbodiimide in 20 ml of acetonitrile by the method of example 1. The modified chitosan was washed on the filter and dried to constant weight.

Weighed to 0.1 g of the modified and the original chitosan was dissolved in 100 ml of 2% aqueous solution of acetic acid and measured the results of the specific viscosity of the obtained solutions. Close values obtained viscosities ηRef=1,0 ηmod=0,9 indicates the absence of destruction of the chain of chitosan at grandravine.

Antitubercular activity grandravine chitosan
MedicationDose, %Duration
30 min1 hour 24 hours
Succinate grandravine chitosan0,5+--
0,25++-
Acetate grandravine chitosan0,5---
0,25+--
Streptomycin1,0+--
0,5++-
Unmodified chitosan2,0++-
(succinate)1,0+++

The modified chitosan of the following structure:

where n=150-1400.



 

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