Anesthetic composition of the prolonged action


(57) Abstract:

The invention relates to medicine, in particular to anestesiologia tool prolonged action, containing as active principle salt benzoic ether-isomer of 1-allyl-2,5-dimethylpiperidine-4 with succinic acid in the ratio of 1:1, prolonging agent - inulin and pharmaceutical solvent - isotonic solution of sodium chloride at a certain ratio. Means it was coming fast, deep and long-lasting diseases without side effects, allergic and toxic reactions. table 4.

The invention relates to medicine, in particular to the pharmacy, namely anestesiologia composition of prolonged action.

There are various anesthetic compositions of the prolonged action.

So, for example, known anesthetic composition of prolonged action, which includes active-form dikaina, methylcellulose, providing prolongation of anesthesia and pharmaceutical solvents used for the preparation of eye drops (RF Patent 2038076. CL. A 61 K 9/08, 31/245, 1995).

The disadvantage of this structure extended anestesiologia.

Also known composition of prolonged anesthetic action using as active trimekain, prolonging agent - collagen in acetic acid solution (A. C. the USSR 880426, CL. A 61 K 9/08, 1981).

However, this composition has not found wide practical application in medicine because of the limited scope (dentistry).

The closest in technical essence and the achieved result is the composition of prolonged anesthetic action, in which the active product used rihanana hydrochloride (benzoic ether - isomer of 1-allyl-2,5-dimethylpiperidine-4 hydrochloride), as prolonging agent - inulin and pharmaceutical solvent is distilled water. (Local-anesthetic properties of some derivatives of piperidine, indole, benzimidazole and their combinations with inulin. Chanaeva A. I., Galenko-Yaroshevsky P. A., Prikhodko, A. C. - // in the book. Russian national Congress. Man and medicine, proc. Dokl., -21 - April 25, 1998), 1998. -c.631).

However, the above composition of prolonged anesthetic action has not found practical application due to insufficient Strait preparation of anesthetic action, created by the authors of the proposed composition of the prolonged action (Patent of the Republic of Kazakhstan 3191 CL. A 61 K 31/445. 1996). The drug is registered in the Republic of Kazakhstan, registration card RK - 5-000860 and the Russian Federation, registration number 95/250/2 and 95/250/8.

Rihlokain well established in surgical practice for infiltration and block anesthesia, in clinics of obstetrics and gynecology for pudental anesthesia in oral and maxillofacial surgery, dentistry, bronchoscopy, pulmonology, ophthalmology. The drug is coming fast, deep and prolonged anesthesia, and has analgesic effect, active in the scar-modified and purulent tissues, does not cause toxic and allergic reactions. However, rihlokain not have a prolonged anesthetic effect.

The objective of the invention is the creation of an anesthetic composition of the prolonged action with a wide range of applications.

This object is achieved proposed anesthetic composition of prolonged action, including active active principle, prolonging agent-inulin, pharmaceutical solvent is distilled water.

As is Oseni 1:1, getting rihlokain of hemisuccinate (benzoic ether - isomer of 1-allyl-2,5-dimethylpiperidine-4-hemisuccinate) with concentrations in wt.%: 0,25, 0,5, 1 and 2.

Study of the mechanism of anesthetic action has shown that local anesthetics in action usual means to participate both forms of the molecule - cation and neionizirovanne basis. Neionizirovanne base as a lipotropic substance provides their penetration to the site of reaction, and the cationic form of the interaction of anaesthetic substances from nerve education at the injection site (N. Pryanishnikov.T. The value of physico-chemical properties of drug substances in the mechanism of their action // short course of molecular pharmacology. - M.: Medicine, 1975. -S. 21 - 50). It is established that the absorption rate of the anesthetic and the extent caused by anesthesia affect the ability of the anesthetic to the diffusion and adsorption, as well as the degree of ionization, surface activity, the ratio of the lipophilic and hydrophilic properties, the concentration of the solution, the pH value.

It should be noted that an anaesthetic drug activity increased with increasing pH from 3.6 to 7.25 (1. Maksimov, Century, Pashchenko C. H. , Rubin A. B. To the question about the molecular is N. T. Chervyakova I. C. Special principle of searching for new local anaesthetics // Pharmacological aspects of pain management: proc. Dokl. All-Union conference, Leningrad, 1983. -n-100 - 101).

Applicants unexpectedly discovered that the use of active rihanana (base) - benzoic ether-isomer of 1-allyl-2,5-dimethylpiperidine-4 with succinic acid in a molar ratio of 1:1, deposited on particles of inulin dissolved in water, leads to a significant increase in prolonging anesthetic action. The main advantages of active are more highly ipofisario anesthetic that promotes better penetration of it in tissue and thereby strengthening the anaesthetic effect and increase its duration; the increased surface activity of the molecule, resulting in better adsorption it on the fabric, thus faster causing anesthesia.

Also it was found that the cationic form of the active salts of succinic acid with benzoic ether-isomer of 1-allyl-2,5-dimethylpiperidine-4 (rihanana base) in a molar ratio of 1:1 of the most effectively ensures the interaction of anaesthetic substances nervous the public benefits of the proposed structure is its prolonged an anaesthetic activity already at a concentration of 0.25% active, the prototype in this concentration is inactive. Found that increasing the concentration of active product more than 2% is impractical due to the slightly increasing the duration of anesthetic action.

The inventive composition has a prolonged anesthetic effect in all types of anesthesia at a much lower toxicity compared to known compositions. The combination of active salt of succinic acid, benzoic ether-isomer of 1-allyl-2,5-dimethirimol-4 in a specified ratio with insulin leads to an unexpected effect - changing the dynamics of anesthetic action is significantly earlier onset of anesthesia with sufficient duration. The breadth of therapeutic action he is also superior to known compounds anesthetic action that can be recommended for wide application in surgery, gynecology and obstetrics, dentistry, clinic of maxillofacial surgery, etc., the Composition does not have side effects, does not cause allergic and toxic reactions.

The proposed composition of anesthetic action is obtained as follows: in the capacity segregation of hemisuccinate) in the ratio indicated, inulin and isotonic sodium chloride solution, stirred for 30 min before the formation of a clear, colorless solution and then isotonic sodium chloride solution adjusted to a specified amount.

The composition has a slightly bitter taste, odourless, pH 5.0.

Example 1. In the capacity load of 0.25 g of rihanana of hemisuccinate, 2 g of inulin and isotonic sodium chloride solution. The mixture was well stirred until formation of a transparent colorless solution and then the volume was adjusted to 100 ml of isotonic sodium chloride solution. Get a composition of 0.25% solution active in isotonic inulin.

Example 2. Preparation of 0.5% of the composition similar to that described in example 1.

Example 3. In the conditions of example 1 receive 1% of the composition.

Example 4. In the conditions of example 1 receive 2% of the composition.

Acute toxicity of the proposed composition was determined in mice after subcutaneous administration. Each dose was tested on 5 animals were observed for 48 hours. Determined the median lethal dose LD50(C. B. Prozorovskii, M. P. Prozorovskaya, C. M. Demchenko. Rapid method for determination of the average effective dose and its error // Pharmacology and toxic the anesthetic action is equal 1184,5 mg/kg, LD50prototype - 847,4.

Thus, the claimed composition is less toxic (1.4 times) in comparison with the composition of the prototype.

Surface (terminal) anesthesia were investigated on the cornea of rabbits on Rainier-Jack (N.T. Pryanishnikova, N. A. The balls. Trimekain. Pharmacology and clinical use. -L.: Medicine, 1967. -239 C.)

The sensitivity of the cornea were determined using Frey hairs with the force of a pressure of 50 g/mm2. Animals were placed in a box with a hole, the locking head, and cut her eyelashes. A solution of the substance was instillirovti in the conjunctival SAC of the eye of the rabbit twice with an interval of 1 minute of Research started with the third minute and was repeated every 5 min (within hours) after the instillation. In each case noted the minimum number of touches of the same strength and rhythm, causing the closure of the eyelids. The absence of corneal reflex for 1 min (100 touches) was regarded as an indicator of full anesthesia. For index Rainier took an average value calculated from the sum of the values obtained during the test analyte within 1 min.

When the terminal method of analgesia in experiments on rabbits hall of 0.25%, while the composition of the prototype when this concentration is inactive. 0.5%, 1% and 2% concentrations of the inventive composition is superior to the prototype 1.3, 1.2 and 1.2 times, respectively, at a much lower toxicity, when using a 5% concentration of the active beginning of an anaesthetic activity did not undergo significant changes, however, the increase in concentration can cause weak irritating effect and adverse reactions (see table.1).

Infiltration anesthesia was studied in experiments on Guinea-males. (N. So Pryanishnikova, N. A. Balls Trimekain. Pharmacology and clinical use. -L. : Medicine, 1967. -239 C.) After removal of hair in the back region of the Guinea pigs in 2 zones intradermally in a volume of 0.25 ml were injected with freshly prepared solutions of the studied compounds and reference drugs. Pain sensitivity shot area of the skin was investigated by a touch of the injection needle, a series of 6 injections at intervals of 3 - 4 hours every 5 minutes Total number of touches needles that do not cause reactions of the animal in the form of twitching of the skin or vocalizations for 30 min, was regarded as an index of infiltration anesthesia solution at a given concentration, mnogo compounds were calculated based on the dependence of dose the effect is reflected in the graph, the ordinate axis which inflicted indexes infiltration anesthesia, and the abscissa shows the logarithm of the investigated concentrations. Determined the mean effective concentration (EC50).

In experiments on rabbits analyte was injected subcutaneously (2 ml) in the region of the anterior abdominal wall. On the skin of the stomach of animals (removing hair) was attached using rubber belt platinum electrodes. The irritation caused by using a rectangular electric pulses (with a duration of 0.3 MS, 50 Hz, amplitude 5, 10, 15, 20, 25, 30, 35 In intervals of 1 min and the duration of each stimulus - 2) from the pacemaker ES-50-1. An indicator of pain response were the changes in the rhythm and amplitude of breathing of the animal, which was recorded with the help of the device N-338 1-8. Change threshold electrical stimulation of the skin, infiltrated with a solution of the analyte, judged the time of onset of anesthesia, its depth and duration.

Results of research in infiltration anesthesia of the proposed structure and prototype are shown in table 2 and 3.

Thus, the claimed composition according to the breadth of therapeutic action ol the composition is considerably larger than the prototype.

Conduction anesthesia was investigated in experiments on the tibial nerve of male mice, the nerves of the rats tail, the lower dental and sciatic nerves of rats and rabbits (N.T. Pryanishnikova, N. A. Balls (Trimekain. Pharmacology and clinical use. -L.: Medicine, 1967. - 239 S.) in experiments on mice, the solutions of the investigated compounds were administered in a volume of 0.1 ml into the lower third of the tibia from the medial side in the direction of the tibia at a depth of 2 to 3 mm (see table.4). For each of the selected 4 - 8 concentrations of substances used 6 mice. To identify motor paralysis that occurred in the limb after the introduction of a substance (or reference drug) and was an indicator block anesthesia, used metal grid, on which were placed the animal. When turning the grid in the horizontal plane 360oclearly defined depression grasp reflex limb - mouse lost the ability to hold onto the grid. Re-testing every 5 min was allowed to determine the total duration of anesthesia. The results of this research were constructed curve dose - effect, where the y-axis was applied to the logarithms of the concentrations, and on the x - axis duration of motorway the duration of conduction anesthesia of the inventive composition is superior to the prototype 1.6 times, has the advantage on the time of onset of anesthesia and has no irritant effect unlike the prototype.

Thus, the proposed new composition of prolonged anestesiologi steps will give you the opportunity to expand the Arsenal analiziruemykh funds.

An anaesthetic agent with a prolonged action, containing the active principle, prolonging agent inulin and pharmaceutical solvent, characterized in that the active agent it contains 0.25-2 g of salt, derived from benzoic ether-isomer of 1-allyl-2,5-dimethylpiperidine-4 and succinic acid, taken in the ratio 1: 1, and as a pharmaceutical solvent it contains isotonic solution of sodium chloride, which bring the total volume to 100 ml and contains inulin 2,0,


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