RU2205638C1 - "bravegyl" antihistamine product - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: the suggested product is designed as solution for injections and contains clemastine fumarate as active substance and additional substances - sorbitol, 94%-ethanol, sodium citrate dihydrate to achieve certain pH value, and water for injection - at certain quantitative ratio of ingredients. Antihistamine product suggested is nontoxic and causes no local irritating action during its injection. EFFECT: higher efficiency. 2 dwg, 6 tbl

Description

 The invention relates to medicine and relates to the creation of an antihistamine drug in the form of a solution for injection based on clemastine fumarate.

Clemastine belongs to antihistamines from the group of benzhydryl ethers. It is an antagonist of H ₁ receptors, selectively inhibits histamine H ₁ receptors and reduces capillary permeability. The drug has a pronounced antihistamine and antipruritic effect, characterized by a quick start and a significant duration of up to 12 hours.

 Known pharmaceutical compositions of complex composition, including for injection, containing as active substance clemastine fumarate (US p. 5770618, A 61 K 31/40, 1998).

 The closest in technical essence and the achieved result is the antihistamine Tavegil, the active substance of which is clemastine fumarate. "Tavegil" is known in tablet dosage form, as well as in the form of an injection solution in 2 ml ampoules containing 2 mg of the drug base (2.68 mg of fumarate) in an aqueous solution of propylene glycol (Mashkovsky MD Medicines. M., 1993, part 1, p. 355).

 The aim of the present invention is the creation on the basis of clemastine fumarate of domestic antihistamine nontoxic funds in the form of a solution for injection.

To solve this problem, an antihistamine, called "Bravegil", is made in the form of a solution for injection and contains as active substance clemastine fumarate at a concentration of 1 mg / ml, and as excipients sorbitol, ethanol 94 ^o , propylene glycol, sodium citrate dihydrate to adjust pH and water for injection.

The solution includes these ingredients in the following ratio, wt./about. %:
Clemastine Fumarate - 0.1-0.2
Sorbitol - 3-6
Ethanol 94 ^o - 4-10
Propylene glycol - 20-40
Sodium Citrate Dihydrate Solution 5% - To pH 6.3
Water - Else
Example. Preparation of Bravegil Injection Solution.

In 1 ml of solution for injection "Bravegil" contains, g:
Clemastine fumarate (in terms of 100% substance) - 0.00134
Sorbitol - 0.045
Ethanol 94 ^o - 0.07
Propylene glycol - 0.3
Sodium Citrate Dihydrate Solution 5% - To pH 6.3
To prepare the Bravegil solution in water for injection, taken in an amount of ~ 30-70% of the total volume, sorbitol is loaded with stirring. Stirring is continued until sorbitol dissolves. Then load ethanol, propylene glycol, clemastine fumarate. It is stirred until complete dissolution, a sample is taken to determine the pH and its value is adjusted to 6.3 ± 0.1 with sodium citrate solution. Bring the volume of the solution to the desired value with water for injection, check the content of the basic substance, refractive index, pH.

 We conducted a study of the experimental preparation of Bravegil injection solution - in comparison with the Tavegil injection solution of Novartis Pharma, Switzerland.

 Conducted the determination of the absorption spectrum of the preparations "Bravegil" and "Tavegil". In FIG. 1 and 2, overview absorption spectra of drug solutions are presented. Optical activity is observed in the wavelength range from 200 to 300 nm. From the drawings it can be seen that the absorption spectra of the experimental drug and the comparison drug completely coincide. At a wavelength of 220-230 nm, a fuzzy absorption peak is observed. With an increase in the wavelength in the region from 260 to 300 nm, the optical density monotonically decreases to zero.

Determination of acute toxicity of the drugs was performed in mice. A total of 72 non-linear mice weighing 16–20 g were used. They were divided into six groups of six animals each. The preparations were administered to animals in the tail vein in increasing doses from 35 to 70 mg / kg. In the table. Figures 1 and 2 show the results of determining the acute toxicity of Tavegil and Bravegil preparations. LD ₅₀ for the comparison drug was 56.7 ± 4.5 mg / kg, for the experimental preparation - 55.4 ± 5.0 mg / kg.

 The clinical picture of poisoning was basically the same for both drugs. Starting from a dose of 40 mg / kg, the development of impaired coordination of movements was observed in animals, progressing with an increase in the dose of the drug. At higher doses, clonicotonic convulsions developed immediately after administration of the drug and death occurred within 1-5 hours. Animals died mainly during the first days after administration of the drug.

Subacute toxicity of the drugs was studied in outbred white rats weighing 180-220 g. The drugs were administered to animals intravenously in the volumes and dilutions indicated in the table. 3. Based on the fact that the therapeutic dose is 0.5 mg / kg, and a ten-fold therapeutic dose is 5 mg / kg, laboratory animals were divided into five groups:
group 1 - 10 - multiple therapeutic dose of the drug "Bravegil";
group 2 - therapeutic dose of the drug "Bravegil";
group 3 - 10 - multiple therapeutic dose of the drug "Tavegil";
group 4 - therapeutic dose of the drug "Tavegil";
group 5 - intact animals (physiological saline).

 The duration of drug administration was 14 days. During the experiment, the degree of intoxication was assessed by the general condition of the animals, the state of the coat, changes in the number of uria, defecations, salivation, tremors, seizures, changes in the frequency and rhythm of respiration.

 After the end of drug administration, animals were slaughtered and their anatomical autopsy followed by weighing of the abdominal cavity and brain organs. For light-optical analysis, samples were taken of the kidneys, liver, spleen, thymus and brain tissue. In addition, biochemical and hematological parameters such as total protein, glucose, urea, alanine transaminase activity (ALT), aspartotransaminase (ACT), alkaline phosphatase, hemoglobin concentration, platelet and white blood cell counts were determined in animals.

 When laboratory animals were introduced into the experimental animals for 14 days, the experimental drug and the comparison drug in both doses did not record a single fatal case. Both drugs did not cause signs of intoxication. When evaluating the general toxic effect, there were no differences between the Bravegil and Tavegil preparations.

 Studies of biochemical blood parameters, the results of which are presented in table. 4 showed that statistically significant differences are noted only for ALT and ACT. An increase in the activity of hepatic enzymes was noted only in groups of animals that received drugs in a 10-fold therapeutic dose. There was no significant difference between the experimental preparation and the comparison drug. An increase in the activity of “hepatotropic” enzymes most likely can be a reflection of the hepatotoxic effect and is probably mediated by an increase in the permeability of the cell membrane of hepatocytes, which leads to an increased release of enzymes from the cytoplasm of liver cells.

 The results of determining hematological parameters are given in table. 5, from which it can be seen that the integral indicators for both drugs and for both studied doses are not significantly different.

 In addition, the values of biochemical and hematological parameters in the experimental groups of animals do not differ significantly from the same indicators obtained for the control group of animals that were injected with saline.

 The leukocyte blood count in laboratory animals in response to the administration of drugs in both doses remained practically unchanged (Table 6).

 As a result of a pathoanatomical autopsy, laboratory animals showed no pathological changes in the liver, spleen, thymus, kidneys, and brain tissue. A comparative histological analysis showed that the preparations "Bravegil" and "Tavegil" when they are administered in therapeutic and 10-fold therapeutic doses do not cause cytomorphological changes in the organs of the abdominal cavity and brain tissue.

 Studies of the local irritant effect of the preparations have been carried out. It was evaluated by the status of the abdominal wall of laboratory animals. In response to the administration of Bravegil and Tavegil solutions, the development of visible signs of inflammation was not observed. The histological preparations in the experimental and control groups of animals are almost identical.

Claims (1)

An antihistamine, characterized in that it is an injection and contains the active substance clemastine fumarate and excipients - sorbitol, ethanol 94 ^o , propylene glycol, sodium citrate dihydrate to adjust the pH and water for injection - in the following ratio of ingredients, wt. /about.%:
Clemastine fumarate - 0.1 - 0.2
Sorbitol - 3 - 6
Ethanol 94 ^o - 4 - 10
Propylene glycol - 20 - 40
Sodium Citrate Dihydrate Solution 5% - To pH 6.3
Water - The rest

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