RU2045268C1 - Antihistamine and antiallergic agent and method for preparing of glutaminate of hinuclidise-3-diphenylcarbinol as solution for injections - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: hinuclidyl-3-diphenylcarbinol is mixed with glutamic acid and with water at weight ratio 1:(1.25-1.3):0.25. The process is carried out at 40-50 C, into thus prepared solution of glutaminate salt being added 0.75 weight parts of water for injections. EFFECT: prepares novel preparation with improved quality. 3 cl, 5 tbl

Description

 The invention relates to medicine and relates to a new antihistamine and anti-allergic agent containing a salt of quinuclidyl-3-diphenylcarbinol, and a method for preparing its injection solution.

 In the literature of the salts of quinuclidyl-3-diphenylcarbinol, only its hydrochloride is described, known as an antiallergic drug called fencarol. In domestic allergological practice, diazaline preparations are used in the form of dragees (0.1 g each) and diphenhydramine in the form of tablets of 0.05 g (50 mg) and ampoule solutions (1% in 1 ml ampoule). In the course of a clinical study of the original domestic antihistamine anti-allergic drug fencarol (quinuclidyl-3-diphenylcarbinol hydrochloride) in the form of tablets of 0.025 g (25 mg), its advantages in therapeutic efficacy and tolerability were revealed in comparison with diphenhydramine, diazaline, and pipiphene and suprastin limited in import , tavegil. On this basis, the widespread medical use of fencarol was recommended (number on the State Register of Medicinal Products 76/788/2), however, it was pointed out that it is necessary to develop an injectable form of an effective domestic drug fencarol for use in acute and severe allergic reactions and in cases where impossible to use in the form of tablets. However, the physicochemical properties of diphenylcarbinol hydrochloride (quinuclidyl-3), i.e., phencarol, (primarily low solubility in water and pharmaceutical solvents) did not allow an injection solution with the required properties.

 The purpose of the invention is a new antihistamine and antiallergic drug of the quinuclidyl-3-diphenylcarbinol series, which has improved properties, and a method for preparing its solution for injection.

 As a result of chemical, pharmacological, and pharmaceutical studies of a large group of newly synthesized salts of a number of quinuclidyl-3-diphenylcarbinol, glutaminate of quinuclidyl-3-diphenylcarbinol was selected.

Глутаминат хинуклидил-3-дифенилкарбинола (госрегистрационный N 8155187) соединение новое, в литературе не описано. Соединение термически неустойчиво, но его водный раствор (по растворимости в воде он в 20 раз превосходит соответствующий гидрохлорид) представляет собой бесцветную прозрачную жидкость, устойчивую на свету и при нагревании (выдерживает стерилизацию, 120^оС), замерзает при пониженной температуре, но при комнатной вновь образует прозрачный раствор. По данным ТСХ не содержит примесей, содержание хинуклидил-3-дифенилкарбинола в 1 мл раствора составляет 0,0095 0,0105 г, содержание глутаминовой кислоты в 1 мл раствора 0,00595 0,00657 г.Thus, the goal is achieved by a new chemical compound, which is the glutamate of quinuclidyl-3-diphenylcarbinol of the formula I

Quinuclidyl-3-diphenylcarbinol glutamate (state registration N 8155187), the compound is new, not described in the literature. The compound is thermally unstable, but the aqueous solution (solubility in water, it is 20 times greater than the corresponding hydrochloride) is a colorless transparent liquid, stable to light and under heating (withstand sterilization, 120 ° ^C), freezing at low temperatures, but at ambient forms a clear solution again. According to TLC, it contains no impurities, the content of quinuclidyl-3-diphenylcarbinol in 1 ml of the solution is 0.0095 0.0105 g, the content of glutamic acid in 1 ml of the solution is 0.00595 0.00657 g.

The method of preparation of quinuclidyl-3-diphenylcarbinol glutaminate in the form of a solution for injection is that quinuclidyl-3-diphenylcarbinol is mixed with glutamic acid and water for injection in a weight ratio of 1: (1.25-1.3): 0.25 at a temperature of 40-50 ^about With, to the resulting solution of the resulting salt of glutaminate hinuclidyl-3-diphenicarbinol add 0.75 wt. including water for injection. The resulting solution is filtered, poured into ampoules and sterilized.

 Starting materials glutamic acid and quincoidyl-3-diphenylcarbinol are available.

 Glutamic acid is commercially available and approved for use as a medicine. Quinuclidyl-3-diphenylcarbinol is also a domestic raw material and is obtained by treating pharmacopoeial fencarol (quinuclidyl-3-diphenylcarbinol hydrochloride) with an aqueous solution of ammonia, followed by its isolation (extraction with an organic solvent, evaporation of the extract) and purification by recrystallization (see example 7).

 The starting components and temperature conditions for the preparation of the claimed medicinal product are necessary and sufficient conditions for the production of hinuclidyl-3-diphenylcarbinol glutaminate, which has better properties than the corresponding hydrochloride.

If these conditions are not met, the following is observed:
in the case of a decrease in the declared amount of glutamic acid (<1.25), a solution does not form (example 6) and thus the preparation cannot be obtained;
an increase in the amount of glutamic acid (> 1.3 wt. h) is unacceptable, since glutamic acid (2-aminoglutaric acid) is an independent highly active drug that is used in the treatment of diseases of the central nervous system (epilepsy, psychosis, reactive conditions, other mental and nervous diseases). When using glutamic acid, a number of side effects were noted, including dyspepsia, agitation.

 Also an essential condition of the proposed method is the procedure for mixing the starting components with water, namely, after mixing the starting components, water must be introduced in parts: first, in an amount of 0.25 wt. hours and after receiving the solution the rest (0.75 wt. hours).

 Failure to comply with this condition, for example, an increase in the amount of the first portion of water, leads to a significant slowdown in the process of solution formation (up to 60 min).

Preparation of the claimed agent at a temperature below ^{40 °} C and above ⁵⁰ ° C leads to the fact that in the first case the solution is not formed (the starting components are in suspension) and in the second case is inexpedient increase in temperature, since the starting components are completely reacted at a temperature of 40 to 50 ^{° C} to form the novel compounds (soluble salt) glutamate hinuklidil-3-difenilkarbinola.

 Obtaining the specified new compounds in the claimed conditions is not obvious.

It is known that glutamic acid is slightly soluble in cold water and soluble in hot water (80 to 90 ° ^C). In addition, it is also known that the base of quinuclidyl-3-diphenylcarbinol in water is practically insoluble. In this connection, the possibility of formation of new salts of the glutamic acid compounds at a lower temperature (40 50 ° ^C) than the temperature of dissolution itself glutamic acid (80 to 90 ° ^C), was unexpected.

 The following examples illustrate the inventive method for the preparation of quinuclidyl-3-diphenylcarbinol glutaminate as an injection and the preparation of the starting base of quinuclidyl-3-diphenylcarbinol.

PRI me R 1. Quinuclidyl-3-diphenyl-carbinol (pharmacopoeial) 1.0 g (1 parts by weight) Glutamic acid 0.626 g (1.25
wt. hours) Water for injection 25 ml I portion
(0.25 parts by weight)
75 ml II serving
(0.75 parts by weight)
The method of preparation of the claimed funds.

Quinuclidyl-3-diphenylcarbinol 1.0 g and glutamic acid 0.626 g are dissolved in 25 ml of water for injection at a temperature of 40-50 ^about C for 20 minutes with constant stirring. The resulting solution is adjusted with water for injection to 100 ml, stirred again, after which the solution is filtered, filled into clean ampoules prepared, sealed and sterilized ⁽¹²⁰ ° C 8 min).

 Quinuclidyl-3-diphenylcarbinol glutamate is obtained as an injection. This is a colorless transparent sterile liquid containing quinuclidyl-3-diphenylcarbinol 0.0098 g / ml, glutamic acid 0.00625 g / ml.

PRI me R 2. Quinuclidyl-3-diphenyl-carbinol (pharmacopoeial) 1.0 g (1 wt. Parts) Glutamic acid 0.65 (1.3 wt. Parts) Water for injection I portion 25 ml
(0.25 parts by weight)
II portion 75 ml
(0.75 parts by weight)
Preparation of the solution is carried out by a method similar to example 1.

 Quinuclidyl-3-diphenylcarbinol glutamate is obtained in the form of an injectable solution, which is a colorless transparent sterile liquid containing quinuclidyl-3-diphenylcarbinol 0.0099 g / ml, glutamic acid 0.00649 g / ml.

PRI me R 3. Quinuclidyl-3-diphenyl-carbinol (pharmacopoeial) 1.0 g (1 parts by weight) Glutamic acid 0.751 g (1.5
wt. hours) Water for injection I portion 25 ml
(0.25 parts by weight)
II portion 75 ml
(0.75 parts by weight)
The preparation of the solution is carried out by a method similar to example 1. The formation time of the solution is 20 minutes

 The resulting solution of quinuclidyl-3-diphenylcarbinol glutaminate is a colorless, clear, sterile liquid. The content of quinuclidyl-3-diphenylcarbinol is 0.0099 g / ml, glutamic acid is 0.0075 g / ml. The solution has an irritating effect.

PRI me R 4 (to use a reduced amount of water). Quinuclidyl-3-diphenylcarbinol (pharmacopeic) 1.0 g (1 part by weight) Glutamic acid 0.626 g (1.25
wt. hours) Water for injection I portion 20 ml
(0.2 wt. H.)
II portion 80 ml
(0.8 parts by weight)
1.0 g of 3-Hinuklidil difenilkarbinola and 0.626 g of glutamic acid were dissolved with stirring in 20 ml of water for injection, heated to a temperature of 40 50 ° ^C. The formation of a homogeneous solution is observed, since the liquid phase of 20 ml (water for injection) inadequate to get a solution.

PRI me R 5 (for the use of an increased amount of water). Quinuclidyl-3-diphenylcarbinol (pharmacopeic) 1.0 g (1 part by weight) Glutamic acid 0.626 g (1.25
wt. hours) Water for injection I portion 50 ml
(0.5 parts by weight)
II portion 50 ml
(0.5 parts by weight)
Preparation of the solution is carried out by a method analogous to example 1, with the difference that the first portion of water for injection upon receipt of the solution is taken 50 ml, heated to 40 50 ^about C and mixed. In this case, the formation time of the solution increases to 50-60 minutes. After complete dissolution of the ingredients, bring the solution with water for injection to 100 ml (II portion of 50 ml) and mix again. The solution is filtered and poured into the prepared ampoules, sealed and sterilized at ¹²⁰ ° C 8 min.

 Quinuclidyl-3-diphenylcarbinol glutamate is obtained in the form of a solution for injection, which is a colorless transparent sterile liquid. The content of quinuclidyl-3-diphenylcarbinol is 0.001 g / ml, glutamic acid is 0.006098 g / ml.

PRI me R 6. Quinuclidyl-3-diphenyl-carbinol (pharmacopoeial) 1.0 g (1 wt. Parts) Glutamic acid 0.6 g (1.2 wt. Parts) Water for injection I portion 25 ml
(0.25 parts by weight)
II portion 72 ml
(0.75 parts by weight)
Preparation of the solution is carried out by a method similar to example 1.

 At this ratio, the formation of a clear solution is not observed, since part of the starting quinuclidyl-3-diphenylcarbinol does not react according to the quantitative data and is in suspension.

 PRI me R 7. Obtaining the starting base of quinuclidyl-3-diphenylcarbinol.

 40 g of 99.1% (or 39.6 g of 100%) pharmacopoeial fencarol (quinuclidyl-3-diphenylcarbinol hydrochloride), 100 ml of water, 200 ml of 25% aqueous ammonia are mixed.

The mixture was extracted with chloroform (10 x 300 ml). The chloroform extract is evaporated to dryness
34 g of 3-hinuklidil difenilkarbinola to which was added 850 ml of absolute ethanol, 1.7 g of activated carbon, boiled for 1 hour, filtered off charcoal, the solution is cooled first to room temperature then to 0 ± 4 ^{° C} and kept at this a temperature of 30 hours. The precipitate formed is filtered off, washed, squeezed and dried to constant weight.

Hinuklidil obtained 24.5 g of 3-difenilkarbinola as colorless crystals with a melting point of 233 235 ^o C (in the range of ^about 1.5 C). The content of the basic substance is 99.5%. The yield is 69% based on the initial phencarol.

The biological activity of the claimed drug is studied in comparison with fencarol and diphenhydramine. The study was conducted according to tests characterizing the antihistamine, antiserotonin, cholinolytic effect, toxicity (LD ₅₀ ) was determined upon single administration to different types of animals with different routes of administration.

 The study was subjected to aqueous solutions of the claimed drug in various concentrations.

 1. Antiallergic activity of the claimed compound.

 1.1. Experiments on isolated organs.

The antihistamine, antiserotonin and anticholinergic activity of the claimed compounds was studied in experiments on an isolated segment of the ileum of the guinea pig. Abbreviations caused by: histamine 1 ˙ 10 ^-8 g / ml; acetylcholine 1 ˙ 10 ^-8 1 ˙ 10 ^-7 g / ml; serotonin 1 ˙ 10 ^-7 g / ml, was recorded in isometric mode.

The inventive compound, fencarol and diphenhydramine were introduced into the solution at concentrations (from 1 ˙ 10 ^-9 to 1 ˙ 10 ^-5 g / ml) 3 minutes before the introduction of the agonist (histamine, acetylcholine or serotonin).

The antihistamine, anticholinergic and antiserotonin activity of the drugs was judged by their ability to reduce bowel spasm. The effective concentration of the studied drug, reducing intestinal spasm by 50% (EC ₅₀ ) was calculated by the Litchfield-Wilcoxon method based on 4 6 experiments.

 The results of the study are presented in table. 1.

 1.2. Experiments on anesthetized animals.

 The effect of the claimed compounds in comparison with fencarol and diphenhydramine on the bronchoconstrictive effect of histamine (10 μg / kg), serotonin (5 μg / kg) and acetylcholine (10 μg / kg), administered intravenously, was studied by the modified method of Concet-Rossler in 19 anesthetized guinea pigs weighing 300 400 g

The activity of the drugs was judged by their ability to prevent the development of bronchospasm; then calculated the value of the ED ₅₀ and the standard error of the arithmetic mean by the method of Litchfield-Wilcoxon based on 4 6 experiments.

 The results are presented in table. 2.

 1.3. Experiments on non-narcotic animals.

 The antihistamine activity of the claimed compound was studied in 96 guinea pigs weighing 300,350 g in comparison with fencarol and diphenhydramine with intramuscular injection. The animals were placed in a special chamber in which the aerosol of a 1% histamine solution was inhaled for 300 s.

 Antihistamine activity was judged by the ability of the drugs to protect animals from the action of histamine, i.e. increase the latent period of histamine intoxication (from the start of histamine inhalation to the appearance of clonic-tonic seizures, c) and prevent the death of animals caused by histamine. The inventive compound, fencarol and diphenhydramine were administered intramuscularly 30 minutes before the start of histamine inhalation.

 The results of the study are given in table. 3.

 2. Antiexudative activity.

In experiments on 370 white rats of both sexes weighing 140 160 g, the effect of the claimed compound in comparison with phencarol and diphenhydramine on impaired vascular permeability and the development of edema caused by subplanter administration was determined;
1 μg of serotonin creatinine sulfate in 0.1 ml of 0.9% NaCl solution;
5 μg of compound 48/80 (histamine liberator) in 0.1 ml of 0.9% NaCl solution;
0.1 ml of a 6% solution of dextran;
1% solution of carrageenin in 0.1 ml of 0.9% NaCl solution.

 The inventive compound and comparison preparations were administered orally and intramuscularly 1 hour before the experiment. Edema was measured plethysmometrically 30 minutes after administration of dextran, serotonin or compound 48/80 and 3 hours after administration of carrageenin.

Antiexudative activity was judged by the calculated value (ED ₅₀ ).

 The results of the study are given in table. 4.

3. Toxicity (LD ₅₀ ) of the claimed compounds with a single administration.

 The inventive compound, fencarol and diphenhydramine were administered to mice orally in doses of 150 to 140 mg / kg in the form of a 1% and 2% aqueous solution with an interval between doses of 50 mg / kg; intravenously in doses of 15 to 75 mg / kg (at concentrations of 0.1 to 0.5%) with an interval between doses of 5 mg / kg. A total of 160 mice were used.

 In rats, the inventive compound was administered intravenously at doses of 30; 40; fifty; 60; 70 mg / kg (concentration of solutions 1 1.5%); intramuscularly (to the thigh muscle) in doses of 100 to 200 mg / kg with an interval between doses of 25 mg / kg (concentration of solutions 2%).

 Inside the rats, the claimed compound was administered in the form of 1 2% solution in doses of 200 to 400 mg / kg (with an interval between doses of 50 mg / kg), and phencarol in the same doses and concentrations as a homogeneous suspension in water with the addition of an emulsifier Tween 80.

 A total of 120 rats were used.

The death of animals during 5 days was taken into account. The LD ₅₀ value was calculated by the Litchfield-Wilcoxon method.

 The results of the study are presented in table. 5.

The results obtained in these experiments indicate that the claimed compound practically does not differ from phencarol and diphenhydramine in antihistamine, anticholinergic and antiserotonin activity (the existing differences in EC ₅₀ are not statistically significant).

 From the table. 2 shows that the anti-histamine and anti-serotonin activity of the claimed compound is superior to diphenhydramine, and inferior to it in its effect on the bronchoconstrictor effect.

 Compared with fenkarol, the claimed compound is superior to fenkarol in antihistamine and antiserotonin activity, and is comparable to it in its effect on the bronchoconstrictor effect of acetylcholine.

 These data indicate greater than the effects of diphenhydramine (antihistamine and antiserotonin) of the claimed compound and, as a consequence of this, the possibility of its use in allergic patients with concomitant diseases in which the appointment of anticholinergic drugs is contraindicated.

 As can be seen from the table. 3, the anti-histamine activity of the claimed drug in 1% concentrations is comparable to fencarol, and in other concentrations it exceeds fencarol and diphenhydramine.

 From the data table. 4 it is seen that the claimed compound with both routes of administration by antiexudative activity on dextran and carrageenin models of aseptic inflammation is comparable to fencarol and superior to diphenhydramine.

 From the table. 5 shows that the claimed compound as well as fenkarol and diphenhydramine can be classified as moderately toxic substances.

 A study of the pharmacokinetics of quinuclidyl-3-diphenylcarbinol glutaminate.

 The content of quinuclidyl-3-diphenylcarbinol in rat blood serum after intramuscular injection was studied: there is no statistically significant difference in the concentration of the test substance in blood serum or in the dynamics of its changes with intramuscular injection of two different salts. The drug is rapidly absorbed into the bloodstream and rapidly excreted. The maximum concentration of quinuclidyl-3-diphenylcarbinol in the blood is observed 30 minutes after administration, after 1 h only small amounts remain in the blood.

 The study of acute toxicity and local irritant effects of the claimed drug.

 The study of acute toxicity in the experiment was carried out on 60 non-linear white male mice weighing 18 to 20 g. The drug was administered intravenously once in doses of 40; fifty; 60; 80; 100 and 120 mg / kg.

It was found that the LD _{50 of the} claimed drug is 64 mg / kg, phencarol 62 mg / kg, diphenhydramine 29 mg / kg.

 The study of tolerability and local irritating effects of the claimed drug was carried out on 80 non-linear white male rats weighing 140 150 g.

 The drug was administered intramuscularly in a volume of 0.1 ml daily for 10 days alternately in the right and left hind paw. During the experiment, the general condition and behavior of animals, the dynamics of body weight, changes in the injection site were observed. The inventive preparation was compared with known antihistamines: diphenhydramine (1% solution), suprastin (2% solution), pipolphen (2.5% solution).

 It was found that animals tolerate ten times the administration of the claimed compound: pathological changes in behavior and general condition were not observed, the functions of the main organs and systems were not violated, the weight of the animals increased to 150 160 g. According to the local irritating effect, we will formulate the claimed drug with the following drugs: all cases at the injection site marked swelling, multiple hemorrhages in the muscle. Identified changes are reversible a week after discontinuation of the thigh tissue preparation practically unchanged.

 Thus, when compared with fencarol, the inventive drug glutaminate quinuclidyl-3-diphenylcarbinol has advantages in physicochemical properties, which makes it possible to obtain it in the form of a dosage form for parenteral administration of ampouled injection solutions.

 A pharmacological study allows us to conclude that the claimed compound in experiments on isolated organs does not differ in spectrum of action from phencarol and exhibits high anti-histamine activity, combined with moderate antiserotonin properties. At the same time, fencarol and the claimed compound are superior to diphenhydramine.

 With intravenous and especially intramuscular administration, the claimed compound is superior to diphenhydramine and fencarol in antihistamine and antiexudative activity, i.e. precisely by those indicators that determine the antiallergic properties of the drug. Fenkarol (registration number 76/788/2) has established itself as a highly effective drug superior to diphenhydramine.

 An injection dosage form of quinuclidyl-3-diphenylcarbinol glutaminate with high pharmacological activity distinguishes the claimed compound from phencarol in tablets and makes it possible to use the drug to stop acute and severe allergic reactions, to use it when it is impossible to use tablets (unconscious patient, allergic laryngeal edema esophagus, etc.).

Claims (2)

 1. Glutaminate quinuclidyl-3-diphenylcarbinol as an antihistamine and anti-allergic agent. 2. A method of preparing quinuclidyl-3-diphenylcarbinol glutaminate in the form of an injection, characterized in that quinuclidyl-3-diphenylcarbinol is mixed with glutamic acid and water for injection in a weight ratio of 1 (1.25 1.3) 0.25 at 40 50 ^o C, to the resulting solution of the salt of glutaminate quinuclidyl-3-diphenylcarbinol add 0.75 wt. including water for injection.

Images