RU2180557C2 - Anesthetic composition with prolonged effect - Google Patents

Abstract

FIELD: medicine, pharmacy. SUBSTANCE: invention relates to anesthetic agent with prolonged effect containing α-isomer of 1-allyl-2,5-dimethyl-piperidol-4 benzoic ester salt with succinic acid in the ratio 1:1 as an active component, inulin as a prolonging agent and sodium chloride isotonic solution as a pharmaceutical solvent taken in the definite ratio. Agent induces rapidly onsetting, deep and prolonged anesthesia without adverse effects, allergic and toxic responses. EFFECT: valuable medicinal properties of composition. 4 tbl

Description

 The invention relates to medicine, in particular to pharmacy, and in particular to an anesthetic composition of prolonged action.

 Various sustained release anesthetics are known.

 So, for example, a prolonged-acting anesthetic composition is known, which includes the β-form of dicaine, methyl cellulose, which provides prolonged anesthesia, and a pharmaceutical solvent used to prepare eye drops as an active active ingredient (RF Patent 2038076. Cl. A 61 K 9/08, 31 / 245, 1995).

 The disadvantage of this composition of prolonged anesthetic action is a narrow scope - as a local anesthetic for ophthalmology.

 Also known is the composition of a prolonged anesthetic effect using trimecaine as a active active ingredient, a prolonging agent - collagen in acetic acid solution (AS USSR 880426, Cl. A 61 K 9/08, 1981).

 However, this composition did not find wide practical application in medicine due to the limited scope (dentistry).

 The closest in technical essence and the achieved result is the composition of a prolonged anesthetic effect, in which richlocaine hydrochloride (benzoic ester - isomer of 1-allyl-2,5-dimethylpiperidol-4 hydrochloride) is used as an active active ingredient, and inulin and pharmaceutical solvent - distilled water. (Local anesthetic properties of some derivatives of piperidine, indole, benzimidazole and their combinations with inulin. Khankoeva A.I., Galenko-Yaroshevsky P.A., Prikhodko A.V. - // in the book. Russian National Congress. Man and medicine , Abstract, -21 - April 25, 1998 - M., 1998. -c.631).

 However, the above composition of a prolonged anesthetic effect has not found practical application due to insufficient prolongation.

 Rihlokain, used as an active active principle, is a new original drug of anesthetic effect, created by the authors of the proposed composition of prolonged action (Patent RK 3191 Cl. A 61 K 31/445. 1996). The drug is registered in the Republic of Kazakhstan, the registration certificate of the Republic of Kazakhstan - 5-000860 and the Russian Federation, registration numbers 95/250/2 and 95/250/8.

 Rychlokain is well established in surgical practice for infiltration and conduction anesthesia, in obstetrics and gynecology clinics for pudental anesthesia, in maxillofacial surgery, dentistry, bronchoscopy, phthisiology, ophthalmology. The drug causes a fast onset, deep and prolonged anesthesia, and has an analgesic effect, is active in scarred and purulent tissues, does not cause toxic and allergic reactions. However, richlocaine does not have a prolonged anesthetic effect.

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

 The problem is achieved by the proposed anesthetic composition of prolonged action, including an active active principle, a prolonging agent inulin, a pharmaceutical solvent is distilled water.

 As an active active principle, a salt of richlocaine (base) with succinic acid in a molar ratio of 1: 1 was used to obtain richlocaine hemisuccinate (benzoic ester - isomer 1-allyl-2,5-dimethylpiperidol-4-hemisuccinate) with concentrations wt.%: 0.25, 0.5, 1 and 2.

 The study of the mechanism of anesthetic action showed that local anesthetics in the action of the anesthetic are involved both forms of its molecule - a cation and a non-ionized base. The non-ionized base as a lipotropic substance ensures their penetration to the reaction site, and the cationic form - the interaction of the anesthetic substance with the neural formation at the injection site (Pryanishnikova N.T. The value of the physicochemical properties of drugs in their mechanism of action // short course in molecular pharmacology. - M.: Medicine, 1975.-S. 21-50). It has been established that the rate of anesthetic absorption and the degree of anesthesia caused by it are affected by the ability of the anesthetic to diffuse and adsorb, as well as its degree of ionization, surface activity, ratio of lipophilic and hydrophilic properties, solution concentration, pH value.

 It should be noted that the anesthetic activity of the drug increases with increasing pH from 3.6 to 7.25 (1. Maksimov G.V., Pashchenko V.Z., Rubin A.B. To the question of molecular mechanisms of action of local anesthetics . // Physiological Journal of the USSR -1989. T. 25. 2. -S. 184 - 188. 2. Pryanishnikova N.T. Chervyakova I.V. A Special Principle for the Search for New Local Anesthetics // Pharmacological Aspects of Anesthesia: Abstracts. All-Union Conference - L., 1983.-S. 100 - 101).

 Applicants unexpectedly discovered that the use of richlocaine (base) as the active principle, the benzoic ester of the 1-allyl-2,5-dimethylpiperidol-4 isomer with succinic acid in a 1: 1 molar ratio, applied to particles of inulin dissolved in water , leads to a significant increase in prolonged anesthetic action. The main advantages of the active principle are a higher degree of lipophysis of the anesthetic, which contributes to its better penetration into the tissues and thereby enhancing the anesthetic effect and increasing its duration; an increase in the surface activity of the molecule, which leads to better adsorption of it on the tissue, thereby causing anesthesia faster.

 It was also found that the cationic form of the active active principle - salts of succinic acid with benzoic ester of the α-isomer of 1-allyl-2,5-dimethylpiperidol-4 (richlocaine base) in a 1: 1 molar ratio most effectively ensures the interaction of the anesthetic with a neural formation , which leads to increased prolonged anesthetic effect.

 One of the significant advantages of the claimed composition is its prolonged anesthetic activity already at a concentration of 0.25% active active principle, the prototype is inactive at this concentration. It was found that an increase in the concentration of the active active principle of more than 2% is impractical due to a slight increase in the duration of the anesthetic effect.

 The inventive composition has a prolonged anesthetic effect for all types of anesthesia with much lower toxicity compared to known compounds. The combination of the active principle of the succinic acid salt of the benzoic ester of the α-isomer 1-allyl-2,5-dimetipiperidol-4 in the indicated ratio with inulin leads to an unexpected effect - a change in the dynamics of the anesthetic effect - a much earlier onset of anesthesia with a sufficient duration. In terms of the breadth of its therapeutic effect, it also surpasses the known formulations of anesthetic action, which allows it to be recommended for widespread use in surgical practice, gynecology and obstetrics, dentistry, maxillofacial surgery clinic, etc. The composition does not have side effects, does not cause allergic and toxic reactions .

 The proposed composition of the anesthetic effect is obtained as follows: the required amount of succinic acid salt with benzoic ester of the α-isomer of 1-allyl-2,5-dimethylpiperidol-4 (rhlocaine hemisuccinate) in the indicated ratio is loaded, the inulin and isotonic sodium chloride solution are mixed, mixed in for 30 minutes until a clear, colorless solution is formed, and then the isotonic sodium chloride solution is adjusted to a predetermined volume.

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

 Example 1. 0.25 g of richlocaine hemisuccinate, 2 g of inulin and isotonic sodium chloride solution are charged into a container. The mixture is mixed well until a clear, colorless solution is formed, and then the volume is adjusted to 100 ml with isotonic sodium chloride solution. Get the composition of a 0.25% solution of active active principle in an isotonic inulin solution.

 Example 2. The preparation of 0.5% of the composition as described in example 1.

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

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

Acute toxicity of the proposed composition was determined in experiments on mice with subcutaneous administration. Each dose was tested on 5 animals that were observed for 48 hours. The average lethal dose was determined - LD ₅₀ (VB Prozorovsky, MP Prozorovskaya, VM Demchenko. Express method for determining the average effective dose and its errors // Pharmacology and Toxicology - 1978. -T. 41, 4 .- p. 497 - 502.

Acute toxicity (LD ₅₀ ) of the claimed composition of prolonged anesthetic action is 1184.5 mg / kg, LD _{50 of the} prototype is 847.4.

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

Surface (terminal) anesthesia was examined on the cornea of the eyes of rabbits according to Rainier-Valet (N.T. Pryanishnikova, N.A. Sharov. Trimekain. Pharmacology and clinical application. -L .: Medicine, 1967. -239 p.)
The sensitivity of the cornea was determined using Frey's hair with a pressure force of 50 g / mm ² . The animals were placed in a box with a hole securing the head, and their eyelashes were cut. The test substance solution was instilled into the conjunctival sac of the rabbit eye twice with an interval of 1 min. Studies began from the third minute and were subsequently repeated every 5 minutes (within an hour) from the moment of installation. In each case, the minimum number of touches of the same strength and rhythm was noted, causing the eyelids to close. The absence of a corneal reflex for 1 min (100 touches) was regarded as an indicator of complete anesthesia. The Rainier index was taken as the average value calculated from the sum of the values obtained by testing the test substance for 1 min.

 When the terminal method of pain relief in experiments on rabbits, the claimed composition has a pronounced anesthetic effect at a concentration of active active principle of 0.25%, while the composition of the prototype at this concentration is inactive. In 0.5%, 1% and 2% concentrations, the claimed composition exceeds the prototype 1.3, 1.2 and 1.2 times, respectively, with much lower toxicity, and when using 5% concentration of the active principle, the anesthetic activity did not undergo significant changes , however, an increase in concentration can cause a mild irritant effect and adverse reactions (see table 1).

Infiltration anesthesia was studied in experiments on male guinea pigs. (N.T. Pryanishnikova, N.A. Sharov Trimekain. Pharmacology and clinical use. -L.: Medicine, 1967. -239 p.) After removal of hair in the back of 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 preparations. The pain sensitivity of the anesthetized skin area was investigated by touching the injection needle with a series of 6 injections at intervals of 3 to 4 hours every 5 minutes. The total number of needle touches that did not cause an animal reaction in the form of twitching of the skin or vocalization for 30 minutes was regarded as the index of infiltration anesthesia of the solution at this concentration, the maximum value of which was expressed by the number 36 (6 trials for 6 injections). The relative activity of the test compound was calculated based on the dependence of the dose — the effect shown on the graph, the ordinate axis of which infiltration anesthesia indices were applied, and the abscissa showed the logarithms of the concentrations studied. The average effective concentration (EC ₅₀ ) was determined.

 In experiments on rabbits, the test substances were injected subcutaneously (2 ml) into the region of the anterior abdominal wall. Platinum electrodes were attached to the skin of the animal’s abdomen (after removing the hairline) using a rubber belt. Irritation was applied using rectangular pulses of electric current (0.3 ms in duration, 50 Hz in frequency, 5, 10, 15, 20, 25, 30, 35 V in amplitude with an interval of 1 min and a duration of each stimulus of 2 s) from an electric stimulator -50-1. An indicator of the pain reaction was changes in the rhythm and amplitude of the animal’s breathing, which were recorded using the N-338 1-8 device. By changing the threshold of electrical skin irritation infiltrated with a solution of the test substance, we judged about the time of anesthesia, its depth and duration.

 The results of the study of infiltration anesthesia of the claimed composition and prototype are shown in table 2 and 3.

 Thus, the claimed composition in breadth of therapeutic action exceeds the prototype by 1.82 times.

 By the time of onset of anesthesia and its duration, the claimed composition significantly exceeds the prototype.

Conduction anesthesia was investigated in experiments on the tibial nerve of male mice, rat tail nerves, lower dental and sciatic nerves of rats and rabbits (N.T. Pryanishnikova, N.A. Sharov (Trimekain. Pharmacology and clinical use. -L .: Medicine, 1967. - 239 pp.) In experiments on mice, solutions of the studied compounds were injected in a volume of 0.1 ml into the lower third of the lower leg from the medial side in the direction of the tibia to a depth of 2 - 3 mm (see table 4). 4 to 8 concentrations of the substance were used in 6 mice each. iterated paralysis, arising in the limb after injection (or reference preparation) and is an indication of conduction anesthesia, using a metal mesh on which was placed the animal When turning the grid in a horizontal plane at 360 ^o clearly defined depression grasping reflex limb -. Mouse lost the ability to retain in Repeated tests every 5 min allowed to determine the total duration of anesthesia. Based on the results of the studies, a dose-response curve was constructed — the effect where the logarithms of the concentrations were applied to the ordinate axis and the duration of motor paralysis to the abscissa axis. Indices of conduction anesthesia were determined by the least squares method.

 The total duration of conduction anesthesia of the claimed composition exceeds the prototype by 1.6 times, has an advantage in time of onset of anesthesia and does not have an irritating effect, unlike the prototype.

 Thus, the proposed new composition of prolonged anesthetic action will make it possible to expand the arsenal of anesthetics.

Claims (1)

 A prolonged-acting anesthetic containing an active principle, an inulin prolonging agent and a pharmaceutical solvent, characterized in that it contains 0.25-2 g of salt obtained from the benzoic ester of the α-isomer of 1-allyl-2,5-dimethylpiperidol -4 and succinic acid, taken in the ratio 1: 1, and as a pharmaceutical solvent it contains an isotonic sodium chloride solution, which is adjusted to a total volume of 100 ml and contains 2.0 g of inulin.

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