Antihypoxic agent and method thereof

 

(57) Abstract:

Usage: in medicine, as antihypoxic funds. Essence: antihypoxic agent contains, mass. h: 3,5-diamino-1,2,4-thiadiazole 1, succinic acid 0,3-0,6, poliglyukin 0.7 to 1.3 and the sodium hydroxide to pH 5.5oC-8.5 in. The method of obtaining antihypoxic funds includes the following stages: dissolution in water at a temperature of 50 to 75oC 3,5-diamino-1,2,4-thiadiazole with polyglycine, adding a solution of succinic acid, titrating the mixture with a solution of sodium hydroxide to a pH of 5.5oC-8,5, keeping at the temperature of a solution, cooled, sterile filtration and freeze-drying to obtain a sterile lyophilized powder. New antihypoxic agent is characterized by improved properties: sufficient solubility in water, stability during storage, neutral reaction, the possibility of sterilization and high antihypoxic activity in combination with less severe irritant effect when injecting. 2 C. p. F.-ly, 4 PL.

The invention relates to medicine and medical industries, in particular to medicines, and with whom odara his antihypoxic activity proposed for use in medicine as a drug for protection against hypoxia. It is effective in all forms of hypoxia and can be used for burns, traumatic and hemorrhagic shock, mechanical injury, hemorrhage, ischemic and hemorrhagic stroke, disorders of cerebral and peripheral circulatory, respiratory failure, for use in operations on the heart and in other cases.

For the clinical study proposed and approved by the decision of the Pharmacological Institute of the USSR Ministry of health (Protocol No. 11, dated April 23, 1976) is a drug called "antisol", i.e. 2% solution of the hydrochloride of the specified diaminododecane in ampoules of 5 ml of the following composition: 3,5-diamino-1,2,4-thiadiazole hydrochloride 20 g of Tris(hydroxymethyl)aminomethane 17 g, water for injection up to 1 L. Despite the fact that clinical trials according to the letter of FC USSR Ministry of health, from 1.08.1984 mostly completed successfully, antizol still not implemented the practice of medicine, as specified dosage form was-low-tech. During the repeated playback of making the dosage form, especially in the semiindustrial scale, it was found that it does not satisfy pharmacopeial requirements. It doesn't withstand conventional sterilization, because the conditions of sterilization amisola was carried out by the method tindalizatsii by heating at 60oC for 1 hour 5 times every 24 hours, maintaining the temperature intervals 25-37oC. However, the method tindalizatsii unacceptable for industrial production. Moreover, the solution for prolonged storage unstable, we observed appearance of opalescence.

Thus, as the prototype of the first object of the invention is selected known antihypoxic agent antizol /1/. For the second object "method" is selected the same prototype, because it indicates the stage of preparation of a 2% aqueous solution of active compound. Known substance, i.e. the composition of the medicinal product, and a method of obtaining medicines prototype unsuitable because they do not allow to obtain a stable aqueous solutions of the specified diaminododecane required concentration. Up to the present time injectable dosage form of diaminododecane suitable for medical use and to meet the production and pharmacopeial requirements is missing.

The purpose of the invention is the expansion of the range of medicines antihypoxic action and increase therapeutic efficacy in their application due to castaneamollissima and pharmacopeial requirements with improved properties: sufficient solubility in water, stability during storage, the possibility of sterilization, neutral and high antihypoxic activity.

This goal is achieved by the claimed antihypoxic agent on the basis of 3,5-diamino-1,2,4-thiadiazole and a method thereof. The inventive tool is the fact that as a derivative of 1,2,4-thiadiazole it contains 3,5-diamino-1,2,4-thiadiazole and additionally contains succinic acid, poliglyukin and sodium hydroxide in the following ratio, wt. h

3,5-diamino-1,2,4-thiadiazole 1

Succinic acid 0.1 to 0.6

Poliglyukin 0,7-1,3

The sodium hydroxide To a pH of 5.5oC-8,5

The purpose of the invention is also achieved by a method of obtaining the specified antihypoxic tools.

Developed a way to get antihypoxic funds by preparing an aqueous solution derived 1,2,4-thiadiazole, characterized in that dissolve in water at a temperature of 50 to 75oC 3,5-diamino-1,2,4-thiadiazole with polyglycine, then the solution is injected succinic acid, the resulting mixture is titrated with a solution of sodium hydroxide to a pH of 5.5oC8,5, maintained at a temperature a solution is cooled, then the solution is subjected to sterile filtration and t in the above ratio.

The instability of aqueous solutions of 3,5-diamino-1,2,4-thiadiazole with long-term storage led to the development of its pharmaceutical form sterile lyophilized powder. To ensure necessary for medical use dosage of the active substance in the vial (300 mg) solubility of diaminododecane in water at 20oC was insufficient, and in a wide range of pH (from 4.7 to 11) it does not depend on pH. In a physiologically acceptable range of pH from 5.5 to 8.5 solubility of diaminododecane not exceed 40 mg/ml however, the required concentration of active substance in the manufacture of the dosage form should be 60 mg/ml, based on the fact that therapeutic dosage vial equal to 300 mg, and the volume of solution in the vial used for drying should be no more than 5 ml. Thus, to increase the solubility of diaminododecane requires the introduction of additional ingredients. Because antihypoxic activity diaminododecane increases in the presence of succinic acid, the study of mixtures of diaminododecane and succinic acid of different composition, including the addition of solubilization and reason to achieve F. free succinic acid and not the succinate of diaminododecane. Potentiometric titration proved the absence of the latter in the claimed medicinal product, due to the low basicity of diaminododecane. The addition of sodium hydroxide necessary to ensure that received the drug were consistent with physiological pH and to reduce the irritant effect. This is experimentally established optimum interval pH from 5.5 to 8.5.

The optimal ratio of succinate sodium to the current matter is the fact that when it is understating the lack of antihypoxic activity, and when it overestimation decreases the solubility of diaminododecane in water and increases unwanted irritant effect. According to the experimental data, the optimal ratio of succinic acid to diaminododecane is in significant part from 0.3 to 0.6 for 1 h thiadiazole derivative.

To achieve solubility of the drug in water and as a solubilizer proposed poliglyukin in a ratio of from 0.7 to 1.3 hours 1 hour diaminododecane. When using fewer poliglyukina not reach the required solubility and aggregate stability of the dosage form, while Pharma same increase.

The criterion for the stability of the claimed medicinal product and the prototype was no sediment or signs of sludge (snake, opalescence) within 24 hours. This time interval determined by the duration of the process in the manufacture legform in a production environment. The results of the experiments are given in table. 1.

The research antihypoxic activity of the claimed medicinal product and the prototype was carried out on a model of acute hypoxic hypoxia (hypobaric hypoxia) 140 white rats weighing 150-180 g Modeling of acute hypoxia was performed in a flow chamber with an ambient temperature of 20-22oC. Animals raised on height of 12,000 feet, the lifting Speed of 35 m / second to 2-minute area at an altitude of 5000 m, the Maximum length of stay of animals at the maximum elevation was 20 minutes Recorded the following parameters: 1) the lifetime limit on the height, which is counted from the moment to the height before the onset of death; 2) survival of animals. Survivors believed rats that survived a 20-minute hypoxic episode.

The inventive tool and a prototype was administered intraperitoneally at a dose of 25 ml/astories (physiological solution). The results are presented in table.2.

The results of studies of acute toxicity of the claimed medicinal product and for comparison with the prototype presented in table. 3. The toxicity study was conducted in accordance with the time guidelines of the Pharmacological Committee ("Requirements for pre-clinical study of the General toxic action of new pharmacological substances", M. 1985) on outbred white rats weighing 180-200, All samples were tested in a wide range of doses from the maximum transmitted to absolutely lethal in animals of both sexes (5 animals of each sex per dose). Investigational dose of the drug was dissolved in distilled water and was administered at 1 ml intraperitoneally. The animals were observed for 7 days. According to the results of the determinations was calculated LD50using the least squares method using probit analysis on a programmable calculator MK-52 standard program (Ivanov Y. I., Pogorelec O. N. "Statistical processing of the results of biomedical research on calculators, programs, M, Medicine, 1990, S. 156 to 160). The death of animals was noted in 1 and 2 days, but not earlier than 4-5 h after intraperitoneal administration. Behavior alive the spine and reflexes. Animals that survived this period, was not killed in appearance and behavior did not differ from intact animals. Underweight in surviving animals with the introduction of the claimed medicinal product and the prototype was on the first day of 1.9 to 4.9% in males, 1.1 to 5.3 per cent in females; in the second day 0.5 to 4.5% in males and 2.2 to 5.5% in females; on the third day the body weight deviated from the original -3,0% to +3.2% of males, females from 0.6% to -8% For the fourth day in almost all animal body weight was higher source.

As can be seen from the table. 2, the claimed drug activity somewhat superior to the prototype. From table. 3 it follows that for acute toxicity it has no significant differences from the prototype.

Mapping local irritating action was performed for two substances: the claimed medicinal product and prototype on 5 rabbits male weight 1.3 to 1.7 kg

The inventive tool containing vial 0.3 g diaminododecane, and is equivalent to the specified substance is the mass of the prototype was dissolved in 20 ml of isotonic sodium chloride and was slowly introduced in the marginal ear vein at a dose of 25 mg/kg (diaminododecane). The control animal was injected with equivalent volume of solvent. Suschevsky segment ear vein, located at a distance of 3 cm above and below the place of administration of drugs. Tissue samples were fixed in formalin and embedded in paraffin. The sections were stained with hematoxylin and eosin.

Intravenous prototype expansion of the lumen of the vein, perivascular edema and swelling of the connective tissue of the auricle, leukocyte-eosinophilic infiltration, perivascular hemorrhage. In contrast, intravenous proposed drug was noted the same changes as the control animal, which was characterized by a plethora of veins and slight oedema of the connective tissue, the absence of an inflammatory reaction.

Thus, the inventive method and antihypoxic agent compared with the prototype allows you to:

to get a highly effective drug exceeds the prototype in the sense that it has more high antihypoxic activity and less pronounced local irritant action parenteral;

-to obtain a drug with pH close to neutral;

to increase the solubility of the active substance and thereby to ensure that it is not the solutions of the active substance, meet pharmacopoeial requirements.

To obtain the claimed funds used glass reactor with a stirrer and a jacket for heating capacity of about 1 liter In water was dissolved by heating the estimated number of diaminododecane and poliglyukina, then succinic acid, the resulting solution was titrated with a solution of sodium hydroxide to a pH of 5.5 to 8.5, kept at a temperature of 50-75oC and cooled. The finished solution is sterile filtered, they dosaged vials, freeze-dried method and corked. The yield of the target product is 90-95%

Shows the temperature settings and the sequence of mixing of the reagents required for obtaining a transparent solution for injection. We offer the optimum temperature is due to the fact that according to experimental data at lower temperatures is not achieved the desired solubility, and during the process at higher temperatures, thermal decomposition of diaminododecane and the appearance of opalescence. Stable transparent solution is obtained under the following process parameters: temperature range 50-75oC, the interval of pH from 5.5 to 8.5. at temperatures below 40oC Ralitsa in the field, close to the neutral value.

Justification of the ratios of the ingredients of a medicinal product is presented in the table.1 and 4. Failure to comply with the proposed limits of ratios of the ingredients of the composition, namely when using succinic acid less than the specified number (0,3 h ) lack of antihypoxic activity funds, and with a larger number (approximately 0.6 hours) decreases the solubility of the active substance and increases the irritant action of the tool. When using poliglyukina in the amount of less than 0.7 hours are not attained sufficient solubility and aggregate stability funds. Increase poliglyukina more of the claimed amount (1,3 h) is impractical because it does not lead to further improvement of the properties of medicines.

1. Antihypoxic agent based on the derived 1,2,4-thiadiazole, wherein as derived 1,2,4-thiadiazole it contains 3,5-diamino-1,2,4-thiadiazole and additionally contains succinic acid, poliglyukin and sodium hydroxide in the following ratio, wt.h.

3,5-diamino-1,2,4-thiadiazole 1

Succinic acid 0,3 0,6

Poliglyukin 0,7 1,3

The sodium hydroxide To a pH of 5.5 to 8.5

2. The way poeysia fact, that dissolve in water at 50 to 75oWith 3,5-diamino-1,2,4-thiadiazole with polyglycine, then the solution is injected succinic acid, the resulting mixture is titrated with a solution of sodium hydroxide to a pH of 5.5 to 8.5, maintained at a temperature a solution is cooled, then the solution is sterile-filtered and freeze-dried method of obtaining a sterile lyophilized powder, the components are taken in the following ratio, wt.h.

3,5-diamino-1,2,4-thiadiazole 1

Succinic acid 0,3 0,6

Poliglyukin 0,7 1,3

A solution of sodium hydroxide To a pH of 5.5 to 8.5 b

 

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