RU2463052C1 - Pharmaceutical composition with anticonvulsant activity for parenteral introduction - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition showing anticonvulsant activity on the basis of phenobarbital and a non-steroidal anti-inflammatory agent (fenamate) taken in molar ratio 23:5. The pharmaceutical composition is presented in the form of a dosage form for parenteral introduction and contains sodium phenobarbital 233 mg, sodium mefenamate 31.0 mg or sodium tolfenamate 33.5 mg, 1,2-propylene glycol 400 mg and ethanol 100 mg as stabilisers and hydroxypropyl-β-cyclodextrin 200 mg as an agent for prolonged release and reduced irritation, and distilled water for injections.

EFFECT: anticonvulsant composition possess high protective anticonvulsant efficacy in emergency management of convulsant poisoning, storage stability, low toxicity, high therapeutic range, prolonged action and minimally manifested local irritant action in parenteral introduction.

3 dwg, 7 tbl, 8 ex

Description

The invention relates to medicine, namely to the treatment of convulsive syndrome, and can be used in emergency medical care as an anticonvulsant for the treatment of a convulsive attack.

The problem of creating effective forms of anticonvulsants is currently quite acute. A number of promising compounds that differ from traditional anticonvulsants in greater efficacy cannot be used in emergency care due to insufficient stability of solutions or a small amount of active principle due to its low solubility. Of particular relevance to this problem is the need for relief of epileptic status and convulsive syndrome of toxic origin.

As a rule, at the time of emergency care for the epistatus, its etiological cause is not known, and symptomatic treatment involves the use of the most powerful anticonvulsants from the benzodiazepine group (diazepam, lorazepam, midazolam, clonazepam). In severe poisoning with organochlorine and fluorine insecticides, a convulsive seizure refractoriness to benzodiazepine therapy often develops [1], which necessitates the use of second-line drugs - phenytoin and barbiturates (thiopental, hexenal, phenobarbital) [2]. At the same time, dosage forms of lorazepam, clonazepam, phenytoin, phenobarbital and phenosphenitoin for parenteral administration in Russia have not yet been registered. On the one hand, the insolubility of these compounds in water determines the relevance of creating forms for parenteral administration. On the other hand, the inadequate effectiveness of regular anticonvulsants in some cases raises the question of increasing their activity by combined use with adjuvanted drugs.

Existing foreign samples of the dosage forms of most anticonvulsants are prepared using organic solvents and in some cases have pronounced local toxic effects. The possibilities of this approach to dissolution are limited by low indicators of the maximum concentration of the active substance in the dosage form, as well as the toxic effects of the solvents used.

In addition to using traditional approaches (derivatization of the starting compounds, the use of organic solvents, emulsifiers and surfactants), nanosized polymer carriers and inclusion complexes with cyclodextrins can be used to obtain stable dosage forms of anticonvulsants [3]. Dosage forms created using these approaches may possess controlled release properties of the active substance.

Highly active anticonvulsants include derivatives of barbituric acid, and in particular phenobarbital. The advantages of phenobarbital are its high anticonvulsant efficacy in case of poisoning by gamma-aminobutyric acid receptor antagonists (GABA). The drug has a long-term effect and is widely used in neurological practice, especially in the debut of epilepsy in children. This barbiturate is highly effective in case of intoxication with pentylenetetrazole, picrotoxin and bicucullin [2, 4-7].

However, the following disadvantages are characteristic of phenobarbital and other barbiturates:

- a pronounced inhibitory effect on the structure of the brain, a high likelihood of developing respiratory and circulatory disorders;

- high toxicity;

- a small breadth of therapeutic effect.

The results of radioligand studies of the interaction of toxicants with their biological targets, an analysis of the clinical cases of poisoning, and data from an experimental study of the effectiveness of anticonvulsants indicate that in case of poisoning with convulsive agents, only parenteral administration of anticonvulsants can provide acceptable levels of protection [4, 8, 9]. Phenobarbital is used abroad in clinical practice for emergency treatment of convulsive syndrome, since a dosage form for parenteral administration has been developed and registered for it. Its basis is the soluble sodium salt of phenobarbital, which is characterized by relative speed and high metabolic rate.

In Russia, at present, the dosage form of phenobarbital for parenteral administration is not registered. This circumstance indicates the presence of the anticonvulsant in question another significant drawback, limiting its use in cases of poisoning with convulsive agents and with epileptic status, which consists in the impossibility of parenteral administration of it in the provision of emergency medical care for health reasons.

However, it is known that in the case of phenobarbital monotherapy, on the one hand, the necessary protection is not guaranteed in case of poisoning with some organochlorine insecticides [2], and on the other hand, the likelihood of developing negative side effects characteristic of barbiturates remains. To enhance the therapeutic effect of the anticonvulsant and increase the breadth of the therapeutic effect (STD), it is recommended to use it in combination with non-steroidal anti-inflammatory drugs (NSAIDs) [10]. The combined use of barbiturates and official NSAIDs can increase the anticonvulsant effectiveness of barbituric acid derivatives and significantly reduce their effective dose, which, in turn, helps to increase the breadth of the therapeutic effect of the drugs.

So, to overcome the disadvantages characteristic of monotherapy with barbiturates, in the treatment of convulsive syndrome, it is proposed to use a tool that provides for the combined use of an anticonvulsant of the class of barbiturates (phenobarbital, hexobarbital, thiopental sodium, ethinal, barbamil) and NSAIDs (pelecoxib, nimesulide, therapeutic ketolac) [10].

The practical use of this drug in cases of poisoning by convulsive agents is hindered by the fact that, in the case of combined use of phenobarbital and NSAIDs, their administration is provided for separately, since there are no combined preparations containing both of these components in a single dosage form. The route of administration of the components of this drug is also not regulated and, apparently, it is determined as oral, since currently in Russia anticonvulsants of the class of barbiturates and NSAIDs (celecoxib, nimesulide) are available only in tablet form.

These significant drawbacks indicate the impossibility of using the drug in question in the emergency treatment of poisoning with convulsive agents and epileptic status.

Sodium phenobarbital in the dosage form of an injection solution was adopted as a prototype, since in this form it is widely used in clinical practice and is closest to the claimed invention in composition, method of administration, indications for use and achieved anticonvulsant effect.

The prototype tool in composition is an aqueous solution of phenobarbital sodium salt (at a concentration of 130 mg / ml) containing ethanol (10%), benzyl alcohol (1.5%) and propylene glycol (67.8%) as stabilizers.

The aim of the invention was to find a comprehensive anticonvulsant based on phenobarbital and a non-steroidal anti-inflammatory drug, characterized by high protective anticonvulsant efficacy in emergency treatment of poisoning with convulsive agents, storage stability, low toxicity, large therapeutic breadth, long-term effect and minimally pronounced local irritant effect with parenteral administration .

This goal is achieved by creating a pharmaceutical composition intended for parenteral administration, in which, unlike the prototype, in addition to phenobarbital, stabilizers and a solvent, NSAIDs and an agent that provide a prolonged release of active substances and reduce irritation at the injection site are additionally included.

Recommended NSAIDs are derivatives of anthranilic acid - phenamates.

Phenobarbital and phenamates are used in the form of sodium salts.

Compounds from the group of sodium mefenamate (MFNa) or sodium tolfenamate (TFNa) are used as phenamates.

As stabilizers, which are incorporated into the inventive pharmaceutical composition to ensure its high storage stability, 1,2-propylene glycol and ethanol are used.

Hydroxypropyl-β-cyclodextrin is used as an agent providing a prolonged release of active substances and a decrease in irritating effects at the injection site.

Distilled water for injection is used as a solvent.

The inventive pharmaceutical composition is made in parenteral dosage form and includes components in the following amounts:

phenobarbital sodium 233 mg fenamate in the form of: mefenamate sodium 31.0 mg or tolfenamate sodium 33.5 mg 1,2-propylene glycol 400 mg ethanol 100 mg hydroxypropyl-β-cyclodextrin 200 mg distilled water for injection up to 1 ml

In this case, the active substances (sodium phenobarbital and phenamate) are prescribed in a strictly defined molar ratio, namely: 23: 5.

The inventive pharmaceutical composition is therapeutic and is intended for administration after the entry of the toxicant into the body.

The ability to achieve the objectives of the invention is confirmed by the results of the studies presented in the following examples.

Example 1. Obtaining the claimed pharmaceutical composition in a dosage form for parenteral administration

To obtain the dosage form of the claimed pharmaceutical composition with a volume of 10 ml, the following algorithm of actions is performed: a sample of sodium phenobarbital (2.33 g) and the phenamate used in the form of sodium mefenamate (0.310 g) or sodium tolfenamate (0.335 g) are placed in a 10 ml volumetric flask, 1.2-propylene glycol (4.0 g), ethanol (1.0 g), hydroxypropyl-β-cyclodextrin (2.0 g) are added, then the volume of the solution in the flask is adjusted to 10 ml by adding distilled water for injection.

In this case, sodium phenobarbital and sodium salts of phenamates are used in the form of substances manufactured by Sigma (USA).

As you can see, the process of obtaining the dosage form of the claimed pharmaceutical composition for parenteral administration is simple, and when it is used, substances of known chemicals are used, the release of which can be easily mastered by the domestic industry.

Further in the examples, the results of an experimental study of the following anticonvulsants are shown:

- prototype agent (sodium phenobarbital in the form of an official dosage form for parenteral administration of Luminal Sodium® Injection 130 mg / ml, Baxter Healthcare);

- the claimed pharmaceutical composition comprising sodium mefenamate (MFNa) as a phenamate;

- the claimed pharmaceutical composition comprising sodium tolfenamate (TFNa) as a phenamate.

Example 2. Evaluation of the stability of the dosage form of the claimed pharmaceutical composition

When developing the dosage form of the claimed pharmaceutical composition, they focused on achieving the maximum concentration of the active substances included in its composition, as well as its high storage stability.

The stability of the developed dosage form of the claimed pharmaceutical composition during storage was evaluated by determining the experimental shelf life based on the method of “accelerated aging” at elevated temperature [11].

The calculation of the experimental shelf life was carried out according to the formula:

where C is the experimental shelf life, years;

With _ex - experimental shelf life, days;

A is a coefficient taken equal to 2;

t _xp is the storage temperature, 20 ° C;

t _ex - experimental storage temperature, 70 ° C.

To obtain the data necessary for the calculation, the prepared solutions for research of the claimed pharmaceutical composition were filled into ampoules and sealed, then placed in a thermostat and kept at a temperature of 70 ° C until flakes, turbidity, crystal precipitation or a color change of the solution appeared. The frequency of monitoring the state of the solution was 6 days.

When the ampoules in the thermostat have visually visible signs of unsuitability for further use (flakes, turbidity, the appearance of crystals or a change in the color of the solution), these ampoules were removed and their experimental shelf life was recorded. Then, the average experimental shelf life of batches of dosage forms of the claimed pharmaceutical composition containing MFNa or TFNa was determined, which was 46.8 ± 1.3 days or 50.7 ± 1.2 days, respectively.

The experimentally established shelf life of the dosage forms of the claimed pharmaceutical composition containing MFNa or TFNa was 4.1 ± 0.1 years or 4.4 ± 0.1 years, respectively.

When studying the stability of the developed dosage forms of the claimed pharmaceutical composition, we also measured the concentrations of the active substances included in its composition (sodium phenobarbital, sodium mefenamate, sodium tolfenamate) and evaluated their dynamics under storage conditions at elevated temperatures.

The research results presented in figure 1, allowed to conclude that during the entire observation period, the concentrations of all active substances remained practically unchanged, which also indicates the stability of the obtained dosage forms of the claimed pharmaceutical composition.

In addition, to demonstrate the stability of the dosage forms of the claimed pharmaceutical composition, the anticonvulsant efficacy of solutions prepared ex tempore or taken after storage for 2 years according to the “accelerated aging” method was compared in experiments on rats after intramuscular administration 5 minutes after pentylenetetrazole poisoning in dose of 1 LD ₉₉ .

It was experimentally established that in cases of using solutions, both prepared ex tempore and taken after storage, no significant differences in anticonvulsant efficacy were observed. The data shown in table 1 indicate a slight decrease in the effectiveness of the claimed pharmaceutical composition if used after storage.

Thus, it has been experimentally established that the claimed pharmaceutical composition in a dosage form for parenteral administration is characterized by storage stability, sufficient for its practical use as a medicine [12, 13].

Example 3. The study of the toxicity of sodium phenobarbital during monotherapy or its introduction in the composition of the claimed pharmaceutical composition

The toxicity of sodium phenobarbital during monotherapy or when administered as part of the claimed pharmaceutical composition was evaluated by determining the average toxic (by the effect of the development of lateral position) and average lethal doses.

The average effective doses of the drugs were determined by the probit analysis method (according to Finney) using a personal computer and the STATISTICA + 2005 application package for Windows. At least 6 points (doses) of 6 animals per point were used to determine the average effective doses of drugs. In each group, mean values and mean error were calculated. The significance of differences in the average values of the controlled parameters in the experimental groups was evaluated by the Student t-test.

The experiments were performed on white male rats weighing 180-220 g. In the experiment, 3 groups of animals were formed, 36 animals each.

The animals of the first group were injected intramuscularly with sodium phenobarbital (prototype agent).

The animals of the second and third experimental groups were injected intramuscularly with the inventive pharmaceutical composition containing MFNa or TFNa.

From the results presented in figure 2 it follows that with the introduction of sodium phenobarbital in the composition of the claimed pharmaceutical composition, the average toxic doses of barbiturate were the highest and exceeded this indicator of the prototype, respectively, 1.7 and 2.0 times (the differences were significant at p <0.05 )

Also, the claimed pharmaceutical composition, including MFNa or TFNa, was characterized by higher mean lethal doses, which were significantly different from the level of the prototype means (p <0.05).

The reduction in toxicity of the claimed pharmaceutical composition is due to the effect on GABA _A receptors of its phenamates (sodium mefenamate or sodium tolfenamate).

Example 4. Determination of the breadth of the therapeutic effect, safety factor and average effective doses (to prevent death in case of poisoning with corazole) of the prototype and the claimed pharmaceutical composition in experiments on rats

The following indicators were used as criteria for the safe use of anticonvulsants: the breadth of the therapeutic effect (SHD, the ratio of the average lethal dose to the average effective) and the safety factor (FB, the ratio of the average lethal dose to the average toxic).

In experiments performed on white male rats weighing 180-220 g, the conditions for which are described in example 3, the determination of the average lethal, moderate toxic and average effective doses of the investigated anticonvulsants was carried out.

Experimentally established performance characteristics (average effective doses for the prevention of death during rat poisoning with corazole at a dose of 1 LD ₉₉ (ED ₅₀ )) and toxicity (medium toxic (TD ₅₀ ) and average lethal (LD ₅₀ ) doses), as well as calculated safety indicators (STD and FB ) means of the prototype and the claimed pharmaceutical composition for intramuscular administration to rats are shown in table 2.

It was found that the claimed pharmaceutical composition has higher safe use (STD and FB) in comparison with the prototype.

The breadth of the therapeutic effect of the claimed pharmaceutical composition containing MFNa or TFNa exceeds the specified indicator of the prototype in 1.8 and 2.3 times, respectively.

According to the value of the safety factor indicator, the claimed pharmaceutical composition with MFNa or TFNa exceeds the prototype agent by 2.6 and 3.4 times, respectively.

Example 5. The study of the depriving effect of sodium phenobarbital during monotherapy or its introduction as part of the claimed pharmaceutical composition

It is known that the use of phenobarbital in high doses can be accompanied by adverse reactions that are associated with its pronounced sedative-hypnotic effect, inhibition of the respiratory and cardiovascular systems. The earliest sign of the development of the deprimative effect of barbiturate may be a violation of the reproduction of conditioned reflexes in animals.

When studying the depriving effect of sodium phenobarbital on the conditionally motivating activity of animals, the method of motor food reflex was used, which allows us to evaluate the effect of neurotropic agents on the reproduction of the food-producing skill formed as a result of training.

As a training model based on food reinforcement, we used the conditioned reflex motor food-producing reaction (UPR), the development of which was carried out in an experimental chamber with a start, central, and target compartment. In the course of the experiment, a conditioned reflex reaction of running to the shelf located in the target chamber was formed in animals. The skill was considered developed if the animal for two consecutive days made 8 regular runs out of 10, the average duration of which was 2-5 seconds.

The experiments were performed on white male rats weighing 180-220 g with a developed food-producing skill. In the experiment, 3 groups of animals were formed, 6 animals each.

The animals of the first group were injected intramuscularly with the prototype agent at a dose of 70 mg / kg. Sodium phenobarbital at the indicated dose causes the initial signs of central nervous system (CNS) depression [10].

The animals of the second and third groups were injected intramuscularly with the claimed pharmaceutical composition containing sodium phenobarbital at a dose of 70 mg / kg, as well as MFNa or TFNa at a dose of 9.5 mg / kg or 10.0 mg / kg, respectively.

Testing of experimental animals was carried out immediately before the administration of anticonvulsants, as well as after their administration: after 15 and 30 minutes, and then after 1, 2, 3, 4 and 6 hours. The average time was determined by the results of three runs. Failure of animals to test after three attempts was considered as a failure of the task.

The research results presented in table 3, allowed to establish that the introduction of the prototype in experimental animals at a dose of 70 mg / kg led to a slowdown in their test. Nevertheless, despite ataxia and some retardation, the conditioned conditioned reflex of running to the target shelf was developed. Disruption of the conditioned reflex was recorded in 17-50% of animals depending on the observation period.

The time interval from the moment of administration of the prototype agent (sodium phenobarbital) to the registration of its maximum effect on the conditioned reflex activity of animals was 15-120 minutes. In the case of administration of sodium phenobarbital in the composition of the claimed pharmaceutical composition containing MFNa or TFNa, the maximum effect on conditioned reflex activity in rats was observed after 120-180 minutes.

Thus, it was found that during monotherapy with sodium phenobarbital, the deprimative effect was most pronounced. After the introduction of sodium phenobarbital in the composition of the claimed pharmaceutical composition, a decrease in severity and a slowdown in the development of a toxic effect were revealed, which manifested itself 90 minutes later than the prototype agent.

Example 6. The study of the specific anticonvulsant activity of the prototype and the claimed pharmaceutical composition on rat poisoning models with corazole, thiosemicarbazide, picrotoxin, phosphacol, aminostigmine and strychnine at a dose of 1 LD ₉₉

The experiments were performed on white male rats weighing 180-220 g. Modeling of intoxication with convulsive poisons was carried out by intramuscular injection of 1 LD ₉₉ into experimental animals. Anticonvulsants were administered 5 minutes after poisoning.

Six experimental groups of 6 individuals were formed to study the anticonvulsant activity of the prototype agent and 12 experimental groups of 6 individuals each to study the anticonvulsant activity of the claimed pharmaceutical composition with MFNa or TFNa. The toxicant was administered intramuscularly to animals of all groups, after which an anticonvulsant was also administered intramuscularly after 5 minutes. The prototype was administered at a dose of 52.5 mg / kg. In the composition of the claimed pharmaceutical composition, sodium phenobarbital was administered at a dose of 52.5 mg / kg, TFNa at a dose of 7.7 mg / kg, MFNa at a dose of 7.1 mg / kg.

The criteria for the specific anticonvulsant activity of the studied anticonvulsants were the time of development of seizures and death, as well as the frequency of death of experimental animals during the observation period. The significance of differences in the average values of the controlled parameters in the experimental groups was evaluated by the Student t-test.

Convulsive activity was evaluated by a method based on the assessment of seizures in points [14]. Since convulsive reactions after the administration of toxicants in animals were characterized by pronounced polymorphism, to facilitate the registration of indicators of manifestation of convulsive activity, 1 and 2 points were combined and designated as “seizures of 1-2 degrees”. This group of symptoms included myoclonic tremors of the head or body, trismus of the masticatory muscles, clonic cramps of the forelimbs, and small tremor. Convulsive activity of 3-4 points, the manifestations of which were considered as lifting to the hind limbs, large tremor and clonic convulsions involving the muscles of the whole body, was designated as “seizures of 3-4 degrees” or “severe convulsions” [14].

The research results presented in tables 4, 5, 6 showed that in case of poisoning with all the studied model toxicants, the claimed pharmaceutical composition with TFNa or MFNa exceeds the prototype agent in anticonvulsant activity.

It was shown that the prototype agent had a more pronounced protective effect in case of poisoning with GABA-negative compounds (corazole, thiosemicarbazide, strychnine), while when intoxicated with cholinergic agents (phosphacol, aminostigmine), the use of the prototype agent did not prevent the death of most animals in group.

The therapeutic use of the claimed pharmaceutical composition with MFNa led to the later development of seizures, a decrease in their intensity and frequency of development. Significant (p <0.05) differences from the prototype agent were recorded in terms of the development of seizures of 1-2 and 3-4 degrees and in the time of death of animals in all experimental groups. A decrease in the mortality rate during poisoning with both GABA-negative compounds (corazole, picrotoxin, thiosemicarbazide, strychnine) to 0-50% and cholinergic drugs (phosphacol, aminostigmine) to 50-67% was noted.

The greatest anticonvulsant and protective effect was achieved with the use of the claimed pharmaceutical composition with TFNa.

The therapeutic introduction of this anticonvulsant ensured the survival of all animals in the group in case of poisoning with corazole, picrotoxin or strychnine at a dose of 1 LD ₉₉ .

A significant decrease in the death rate was observed with thiosemicarbazide poisoning (from 50 ± 22% when using the prototype to 17 ± 17%). In all experimental groups, a significant increase in the time of development of signs of intoxication was recorded (p <0.05, compared with the prototype), and a decrease in the frequency of severe seizures was noted.

The effect of the anticonvulsant on the manifestations of intoxication with anticholinesterase drugs (phosphacol, aminostigmine) was not enough pronounced for the full protective effect. However, compared with the prototype tool, the death rate in these groups decreased from 67-83% to 17-33%.

Example 7. Evaluation of the duration of action of the prototype and the claimed pharmaceutical composition in experiments on rats

Modeling of intoxication was achieved by subcutaneous administration of pentylenetetrazole at a dose of 125 mg / kg (1 LD ₉₉ ) to experimental animals.

To assess the duration of the protective effect of the investigated anticonvulsants, their activity was determined with prophylactic administration at various times before pentylenetetrazole poisoning. Considering that the anticonvulsant activity of sodium phenobarbital under these conditions is significantly higher than during its therapeutic use, for this series of experiments, a dose of barbiturate was chosen at which the drug did not have a pronounced protective effect in the case of therapeutic use.

In experiments performed on white male rats weighing 180-220 g, 30 experimental groups of 6 animals each were formed.

The prototype agent (sodium phenobarbital at a dose of 5.25 mg / kg) was administered to animals of groups 1-10.

The animals of groups 11-20 were administered the claimed pharmaceutical composition (sodium phenobarbital at a dose of 5.25 mg / kg and sodium mefenamate at a dose of 0.71 mg / kg).

The animals of the 21-30 groups were administered the claimed pharmaceutical composition (sodium phenobarbital at a dose of 5.25 mg / kg and sodium tolfenamate at a dose of 0.77 mg / kg).

The toxicant was administered to animals of all experimental groups according to the scheme:

Experimental group of animals The term of administration of pentylenetetrazole 1, 11, 21 Concomitantly with an anticonvulsant 2, 12, 22 After 15 min 3, 13, 23 After 30 min 4, 14, 24 After 60 min 5, 15, 25 After 120 min 6, 16, 26 After 180 min 7, 17, 27 After 240 min 8, 18, 28 After 360 min 9, 19, 29 After 420 min 10, 20, 30 After 480 min

It was experimentally established (figure 3) that the claimed pharmaceutical composition has the greatest duration of effective anticonvulsant action. The maximum level of anticonvulsant effect, characterized by the survival of experimental animals depending on the phenamate used, 73% or 83%, is observed 2 hours after administration. Then, after 2 hours, anticonvulsant efficacy decreases to 50% of animal survival and remains at this sufficiently high level for 2 hours. Thus, the introduction of the claimed pharmaceutical composition provides effective protection for 6 hours.

At the same time, the maximum anticonvulsant effect of sodium phenobarbital, which provides 50% animal survival, is observed 1 hour after administration. After 2 hours after administration, the effectiveness of the drug is reduced to 33% of animal survival and in the future, the prototype agent practically does not show protective activity.

The results obtained indicate the development of a longer therapeutic effect of sodium phenobarbital when it is administered in combination with hydroxypropyl-β-cyclodextrin.

Example 8. The study of the local irritating effect of the prototype and the claimed pharmaceutical composition

Experiments to study the severity of the local irritant effect of the prototype and the claimed pharmaceutical composition were carried out on non-linear male rats weighing 180-220 g.

In the experiment, 3 groups of animals were formed, 6 animals each.

The animals of the first group were injected intramuscularly (into the muscles of the leg) with a prototype agent (sodium phenobarbital) in a volume of 0.2 ml per animal.

The animals of the second and third experimental groups were intramuscularly administered the inventive pharmaceutical composition in a dosage form recommended for parenteral administration containing MFNa or TFNa in a volume of 0.2 ml per animal.

The criterion for assessing local irritant action was the circumference of the lower leg (as a sign of edema). The circumference was recorded before the start of the experiment (background indicators) and 3, 7, 14 days after the administration of anticonvulsants.

The dynamics of the shin circumference of experimental animals against the background of the administration of anticonvulsants is presented in Table 7. As can be seen, the introduction of anticonvulsants caused an increase in the shin circumference of rats. The least pronounced local irritant effect was possessed by the claimed pharmaceutical composition containing both MFNa and TFNa.

The claimed invention meets the criterion of "novelty", since for the first time in emergency treatment of poisoning with convulsive agents of various groups, it is proposed to use a pharmaceutical composition that provides for the combined effects of phenobarbital sodium, NSAIDs from among phenamates and hydroxypropyl-β-cyclodextrin, characterized by high specific protective effectiveness, storage stability , low toxicity, large therapeutic breadth, long-lasting effect and minimally expressed depriving and spot-irritant when administered parenterally.

The claimed invention meets the criterion of "inventive step", since it is not obvious from the available sources of information that the composition of the claimed pharmaceutical composition includes sodium phenobarbital, a non-steroidal anti-inflammatory drug from among phenamates and hydroxypropyl-β-cyclodextrin, their optimal content and ratio, as well as the possibility increasing the protective anticonvulsant efficacy of barbiturate and reducing its toxicity.

Compliance with the criterion of "suitability for use" is proved by the results of numerous studies, which show that the claimed pharmaceutical composition in a dosage form for parenteral administration is characterized by high specific protective efficacy, low toxicity, minimally expressed depriving and local irritating effect, as well as high storage stability sufficient for its practical use as a means of emergency therapy for poisoning with convulsive agents. The preparation of the dosage form of the proposed pharmaceutical composition is simple and involves the use of substances of known chemicals, the release of which can be easily mastered by domestic industry.

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Claims (1)

A pharmaceutical composition with anticonvulsant activity, made in parenteral dosage form, comprising an anticonvulsant of the barbiturate class in the form of an aqueous solution of sodium phenobarbital and stabilizers in the form of ethanol and 1,2-propylene glycol, characterized in that it further comprises a non-steroidal anti-inflammatory agent, which contains phenamate in the form of sodium mefenamate or sodium tolfenamate, as well as an agent that provides prolonged release of active substances and reduces s irritating effect at the site of injection, which comprises as hydroxypropyl-β-cyclodextrin and its constituent components includes the following amounts:
phenobarbital sodium 233 mg fenamate in the form of: mefenamate sodium 31.0 mg or sodium tolfenamate 33.5 mg 1,2-propylene glycol 400 mg ethanol 100 mg hydroxypropyl-β-cyclodextrin 200 mg distilled water for injection up to 1 ml
moreover, sodium phenobarbital and phenamate include in a strictly defined molar ratio of 23: 5, respectively.

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