Means for terminal anesthesia

 

(57) Abstract:

The invention relates to medicine and can be used in anesthesiology, ophthalmology, dentistry, otolaryngology, surgery. The tool contains dikain hydrochloride, sodium chloride and dikain hydrochloride, chemically linked to a polymer carrier, glycidylether N-carboxymethyl chitosan in certain quantities. The ratio dikaina hydrochloride and indicated the polymer carrier is 1.4:1, respectively. A new tool has improved anaesthetic efficiency, high durability, minimal irritant effect and low toxicity. table 4.

The invention relates to medicine and especially to means for terminal anesthesia and can be used in anesthesiology, ophthalmology, dentistry, otolaryngology, surgery.

Known medicines used for terminal anesthesia including composition dikaina with epinephrine (Galenko-Yaroshevsky B. N. Comparative study of local anesthetic activity rihanana and lidocaine when socetanii with some agonists. Dis. on saisc. academic step. K. M. N. - Rostov-on-don, we dikaina of hemisuccinate in the experiment" In kN.: II Russian national Congress “Man and medicine”. Proc. Dokl. - M., 1995 - S. 31).

Closest to the application is the use of dikaina hydrochloride.

Its disadvantages include insufficient duration of action, high General toxicity and irritant effect.

The technical result of the present invention is to increase anaesthetic efficacy, reduced side effects.

The technical result is achieved by the fact that the composition of the proposed means for the terminal anesthesia is dikain hydrochloride, dikain hydrochloride, chemically linked to a polymer carrier, glycidylether.

N-carboxymethyl chitosan, which is formed when the ratio dikaina hydrochloride and indicated the polymer carrier of 1.4:1, respectively, and sodium chloride in the following ratio, wt.%: dikain hydrochloride - 20; dikain hydrochloride, chemically linked to a polymer carrier, glycidylether N-carboxymethyl chitosan, which is formed when the ratio dikaina hydrochloride and indicated the polymer carrier of 1.4:1, respectively - 65; sodium chloride - 15.

The tool is obtained in four steps.

Step 1. The depolymerization of chitosan by chemical means.

In the process of depolymerization of Israelis conducted chitinolytic complex bacteria of the species Bacillus sp. 739 known manner in an aqueous p-d XS 0.1 M Asón and 1% NaN3when the ratio of enzyme - substrate of 0.4, at 55C in the presence of sodium acetate buffer (pH 5,2) for 0.5 h (Ilyina A. C., B. N. Varlamov, Melent'ev, A. I. and other Depolymerization of chitosan chitinolytic complex bacteria of the genus Baccillus sp. 739. Applied biochemistry and Microbiology. 2001, T. 37, No. 2, S. 160-163).

2% Aqueous solution XS s M=60-70 kDa and degree of dezazetilirovanie 80%, containing 0,01% formic to you and 1% hydrogen peroxide, thermostatically at 70C for 15 to 20 minutes the Resulting solution was evacuated at 30-40C (a-0.7 kPa), the residue after vacuum was dissolved in water, measured shows the viscosity using a capillary viscometer - /from 1.5 to 1.6 DL/g, which corresponds to M=15-20 kDa. Obtained XS is a solid product, well soluble in water.

Step 2. N-Karboksimetilirovaniya chitosan

Chitosan with M=15-20 kDa and degree of dezazetilirovanie 80% dissolved in 50 ml of water and 0.01 formic acid at 20C. The solution was placed in a reactor with a reflux condenser and electronically and introduced to 0.47 g sodium Chloroacetic acid. The mixture thermostatically under stirring at 70 C for 3 hours the Reaction mass was evacuated at 70 C (-7 KP is (70%). Sodium salt of N-carboxymethyl--1,4-(2-amino-2-deoxy)-D-glucan (CMG) melts with decomposition at 150-C. Yield 1.3 g (80%).

Step 3. Glycidyloxy ether N-carboxymethyl chitosan

1 g CMH dissolved in 50 ml of water, the solution was placed in a reactor with a reflux condenser and electronically, the solution was injected into 1.1 ml of chloromethyloxirane (AP) with t Kip. = 116,1, n20d= 1,438, d2020= 1,81 in the form of a solution in 4 ml of ethanol; the ratio of the reagents KMH:EPH 1:4. The mixture thermostatically under stirring at 50C for 5 hours the Resulting reaction mass was evacuated at 70 C (-7 kPa). The residue after vacuum - slightly colored powder product, soluble in water and partially in water-alcohol mixtures. Received glycidyloxy ether KMH (GCMH) are marked with an admixture of sodium chloride. The mixture contains 82% GCMH and 18% of sodium chloride; the total yield of 1.36 g

Step 4. Chemical immobilization-dimethylaminoethanol ether N-butylaminoethyl acid hydrochloride (dikaina) in the structure GCMH

1 g GCMH dissolved in 20 ml of water was placed in a reactor with a stirrer, the solution was introduced 1 g dikaina dissolved in 4 ml of water, the reaction mass was stirred at 20 ° C for 1.5 h, the Ratio of the reaction-spri 70C (-7 kPa), the residue after vacuum - solid product with a decomposition temperature of 130-140°C, soluble in water and partially in spirtovodnogo mixture; solubility in water 3-3,5 g in 100 ml; pH rastafara 6-6,5;Relsolution at a concentration of 1 g/DL - 1,162. In the composition of the obtained product contains 1,09 g (65%) of drug polymer, 0.31 g (20%) is not associated with the polymer dikaina hydrochloride, 0.26 g (15%) sodium chloride solution.

Quantitative determination dikaina hydrochloride comprising means for terminalling anesthesia.

0.4 g of the Substance was dissolved in 11 ml of water and 10 ml of diluted hydrochloric acid, added water to a total volume of 80 ml and 1 g of potassium bromide. With constant stirring was titrated with 0.1 M solution of sodium nitrite at the rate of 2 ml/min (0.5 ml up to an equivalent amount), then, with a rate of 0.05 ml/min at 18C. The equivalence point was determined using the internal display (tropaeolin 00): 1 ml of 0.1 M solution of sodium nitrate corresponds to C15H24N2O2·HCl.

For titration spent 2,62 ml of 0.1 M solution of sodium nitrate. This corresponds to the content dikaina hydrochloride in the sample substance 0.4 g 0,0788 g - 19,85%.

The study of infrared spectra dikaina hydrochlo the IR spectra of glycidylether N-carboxymethyl chitosan and dikaina hydrochloride. In preparation for spectral analysis tool for terminal anesthesia was exhaustively extracted in relation dikaina hydrochloride. In the IR spectra dikaina hydrochloride, chemically bound to the polymer carrier by glycidylether N-carboxymethyl chitosan, revealed the presence of absorption bands: 850, 730 cm-1- out-of-plane deformation relationships of the C-H in benzene ring; 1600 cm-1- plane stretching vibrations of the carbon-carbon bonds of the benzene ring; 3030 cm-1- stretching vibrations of =C-H of benzene ring.

These bands are absent in the spectrum structure of glycidylether N-carboxymethyl chitosan, but typical spectra dikaina hydrochloride. This shows the connection to the structure of N-carboxymethyl chitosan dikaina hydrochloride.

The structural formula dikaina hydrochloride, chemically bound to the polymer carrier, glycidylether N-carboxymethyl chitosan.

Biological activity

All studies were conducted in accordance with the “Manual on experimental (preclinical) study of new pharmacological substances”. - M., 2000, S. 176-178.

The study depth Ter is in the method of Setnikar in experiments on rabbits grey suit weight 2.5-3 kg Each concentration was tested in eight animals. It is established that the tool causes a pronounced effect.

Table 1 presents data in units of Rainier, the terminal depth of anesthesia in rabbits with double instillation into the conjunctival SAC two drops with an interval of 60 s solutions and dikaina hydrochloride.

Found that the product has a minimal irritant. For five points (+++++ there were desquamation of the epithelium of the cornea 40%; four points(++++) - 30%; three points (+++) - 20%; two points (++) -10%; one point(+) - 5%; (±) - 5% in some animals in the group there has been no reaction.

Table 3 presents data irritants tools and dikaina hydrochloride.

Study duration terminal anesthesia in equal concentrations on substance dikaina revealed a significant superiority before dikaina.

Table 4 presented the data about the duration of the terminal anesthesia.

The study of the acute toxicity was carried out on 72 white mice weighing 19-21 g percutaneously. Installed half-lethal dose LD50tools and dikaina, is equal to the th terminal anesthesia, high duration, minimal irritant effect and lower toxicity, excelling on these parameters, the prototype.

The use of the proposed tool allows to increase the duration of the manipulation in connection with the increase in the length of the terminal anesthesia and a half to two and a half times at the same concentration of the substance dikaina used to reduce the concentration of solutions in connection with increasing depth of the terminal anesthesia, to increase the volume of the fluids used in connection with a reduction in acute toxicity and irritant.

Means for terminal anesthesia containing dikain hydrochloride, characterized in that the composition additionally includes dikain hydrochloride is chemically linked to a polymer carrier, glycidylether N-carboxymethyl chitosan, which is formed when the ratio dikaina hydrochloride and indicated the polymer carrier of 1.4:1, respectively, and sodium chloride in the ratio, wt.%:

Dikain hydrochloride 20

Dikain hydrochloride, chemically linked to a polymer carrier, glycidylether N-carboxymethyl chitosan, which is formed when the ratio dikaina hydrochloride to the specified polymer wear the

 

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