RU2303450C2 - Nonsteroid anti-inflammatory analgesic drug - Google Patents

Abstract

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to medicinal agents in forms of solutions, tablets, capsules, ointments, suppositories and other formulations used in treatment of joint inflammation of different etiology, soft tissue contusions and thrombophlebitis. The proposed medicinal agent comprises the active mixture of two medicinal substance indometacin with thiotriazoline in the ratio 1:(1-3). Using the proposed medicinal agent provides significant enhancing the effectiveness of treatment as compared with indometacin only based on significant reducing toxicity. In using the proposed medicinal agent the therapeutic effect is attained in less dose of indometacin that allow prevention of development of toxic damages of stomach mucosa.

EFFECT: improved and valuable medicinal properties of drug.

4 tbl, 4 ex

Description

The invention relates to medicine, in particular to medicines in the form of solutions, tablets, capsules, ointments, suppositories and other forms used to treat inflammation of the joints of various etiologies, soft tissue injuries, thrombophlebitis.

Known drug "Indomethacin" (Reference Vidal Medicines in Russia. - M .: AstraFarmService. - 1995. - S.475-476).

Indomethacin is one of the most effective non-steroidal anti-inflammatory drugs (NSAIDs) and for its pharmacological purpose, as well as for the achieved anti-inflammatory and analgesic effect, we take it as a prototype.

The disadvantage of indomethacin is its toxicity, which causes headaches, dizziness, dyspeptic symptoms, drowsiness, the development of ulcerative lesions of the gastrointestinal mucosa and bleeding (Khattab MM, Gad MZ, Abdallah D. Protective role of nitric oxide in indomethacin-induced gastric ulceration by a mechanism independent of gastric acid secretion // Pharmacol. Res. - 2001. - Vol. 43. - No. 5. - P.463-467).

The basis of the invention is the task of developing a drug with a wide range of pharmacological effects that are superior in anti-inflammatory, analgesic efficacy to a prototype with a less pronounced toxic effect.

The solution to this problem provides a non-steroidal anti-inflammatory, analgesic agent containing indomethacin and thiotriazoline as an active base in a ratio of 1: (1-3).

This ratio of drugs for all forms of drugs according to the invention is maintained within the above ranges, and the concentration of active components in drugs is determined by the conditions for the introduction of a particular dosage form to the patient and is due to the maximum bioavailability of the drug in the body.

The pharmacological effect of the use of the invention.

The use of the proposed drug in a therapeutic dose in accordance with the invention allows to increase anti-inflammatory activity in comparison with indomethacin in the acute period of inflammation (in the alteration phase) by 7% and in the edema phase by 12.3%, which is due to an increase in anticyclooxygenic activity of the combination of drugs and the ability of thiotriazolin to stabilize the cytoplasmic membranes of tissue cells, blood vessels and reduce vascular permeability.

The use of a combination of drugs in a therapeutic dose, in accordance with the invention, potentiates the analgesic properties of indomethacin, lowering the threshold of pain sensitivity by 2.1-3.6 times compared with indomethacin.

In addition, the drug according to the invention is more than two times less likely to cause damage to the gastric mucosa (ulcers and erosion) compared with indomethacin due to the wide spectrum of action of thiotriazoline, which blocks the toxicity of indomethacin.

The invention is illustrated below by the description and examples of studies of the medicinal product according to the invention and the prototype.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used symptomatic drugs in medicine. However, drugs of this group are not safe, since even their short-term use can lead to the development of adverse reactions that occur in 25% of cases, and in 5% of patients, especially the elderly, can be life-threatening. The leading mechanism determining the effectiveness of NSAIDs is associated with the suppression of cyclooxygenase (COX) activity, which plays a leading role in the development of the inflammatory response.

Improving the quality of anti-inflammatory therapy of NSAIDs can be achieved by creating a rational combination with drugs that limit their toxic effect, for example, ulcerogenicity.

Accordingly, to identify the most effective combination of NSAIDs with other drugs, a wide range of doses were studied: indomethacin (prototype) and a combination of indomethacin with thiotriazoline in various ratios. In the course of the study, anti-inflammatory, analgesic activity of the drugs and their damaging effect on the gastric mucosa were established.

The study of anti-inflammatory activity of drugs

The study was conducted on 132 white mice weighing 18-22 g.

The activity of the test substances was determined by their ability to reduce the development of edema in comparison with the control and was expressed as a percentage that shows how much the drug inhibits the development of edema in relation to the control, where the magnitude of the edema is taken as 100%.

One hour after the creation of dextran edema, the animals were removed from the experiment by decapitation and inflamed and non-inflammatory hind legs were amputated at the level of the hip joint. After using the drugs inside, it maximally reduces the volume of edema in the first hour of inflammation by 62.9-66.4% of the proposed drug, in which the dose of indomethacin is 2.5 mg less compared to the maximum decongestant effect (56.95%) of the pure drug in dose of 7.5 mg / kg. Since in the interval of 30-90 minutes histamine and serotonin take an active part in the pathogenesis of inflammation, the penetration of which into the focus of inflammation is facilitated by dextran, we can conclude that the proposed drug most effectively inhibits the release of tissue alteration factors - serotonin and histamine.

After 3 hours, on the model of carrageenin edema after using the studied drugs inside, the high efficiency of the mixture of indomethacin and thiotriazolin was established, which in the ratio of 1: 3 (at a dose of indomethacin 5 mg / kg and thiotriazolin 15 mg / kg) eliminated paw edema by 71.1%, whereas indomethacin at a dose of 7.5 mg / kg reduced edema by only 65.1%. Since prostaglandins, which play an important role in the development of carrageenin inflammation, take an active part in the pathogenesis of inflammation in the range of 2.5-5.5 hours, the use of the proposed drug can most effectively suppress the release of prostaglandins and thus limit the development of edema.

Thus, we can conclude that the studied drugs (with oral administration) have a pronounced anti-inflammatory effect, especially the proposed drug. The results are shown in tables No. 1 and No. 2.

The study of the analgesic activity of drugs

To study the analgesic activity of the preparations, two standard models were used: a) electric pain stimulation of the root of the tail of the rat and b) tail withdrawal (thermal immersion). Studies were conducted on 144 white Wistar rats weighing 180-200 g, in 24 groups of animals. Each group contained 6 individuals - males. Rats received indomethacin preparations, and a mixture of indomethacin with thiotriazolinum inside, in different doses.

The assessment of pain sensitivity was determined after 2-3 minutes and 90 minutes by the appearance of a vocal reaction (squeak, vocalization) and tail movement in response to a gradually increasing electrical irritation from the ESL-1 electric stimulator. The duration of each irritation did not exceed 1 second. The results are shown in table No. 3. The data obtained show a decrease in the threshold of pain sensitivity in all groups of animals that received both pure indomethacin and thiotriazolin. Indomethacin maximally reduced the pain sensitivity threshold of 50.3% -62.7% by tail response and vocalization after 90 minutes of observation after applying it at a dose of 10 mg / kg. At the same time, the proposed drug at a dose (indomethacin 5 mg / kg and thiotriazoline 15 mg / kg) increased the threshold of resistance to pain irritation by 80.0% -85.6% by tail reaction and vocalization. In this case, the dose of indomethacin is reduced by half. In the proposed drug, thiotriazoline potentiates the analgesic properties of indomethacin.

Thus, we can conclude that the studied drugs (when taken orally) have a pronounced analgesic effect, especially the proposed drug. The results are shown in table No. 3.

The study of ulcerogenicity of drugs

It is known that one of the adverse effects of the use of indomethacin inside is its toxic effect on the gastric mucosa with the appearance of hyperemia, ulcerations and ulcers. A study of the ulcerogenicity of the preparations was carried out on 30 white Wistar rats weighing 160-200 g. Groups of animals (in each group of 6 animals) received preparations: indomethacin and a mixture of indomethacin with thiotriazoline in effective doses orally for four days. Animals were decapitated on the fourth day, the stomach was removed, they were dissected along the lesser curvature, and washed in saline to remove the contents. Evaluation of the ulcerogenic effect was carried out visually by the number of ulcerative defects, which was reflected in the scores and ulcer index (NI). The results are shown in table No. 4. The results of the study showed that the proposed drug in a dose (indomethacin 5 mg / kg and thiotriazolin 15 mg / kg) is 2.5-3 times less likely to cause ulceration of the gastric mucosa compared to indomethacin in doses of 5-10 mg / kg. In this case, the ulcer index after using the proposed drug compared with indomethacin is reduced by half (table. No. 4), i.e. the proposed drug has advantages over indomethacin, as it is less ulcerogenic and toxic. The toxicity of the proposed drug LD ₅₀ is 750 mg / kg of mass, which is five times lower compared with indomethacin, LD _{50 of} which is 150 mg / kg.

Thus, the proposed drug according to the invention has a higher anti-inflammatory, analgesic activity in comparison with the known indomethacin preparations, while the toxicity of indomethacin is reduced, because in the proposed drug, the achievement of the therapeutic effect is observed with a lower dose of indomethacin.

To illustrate the following examples of preclinical studies of orally administered drugs according to the invention.

Example No. 1

A study of anti-inflammatory activity in a carrageenin dextran model of inflammation.

Studies were carried out on 132 white mice weighing 18-22 g, animals were divided into 22 groups of 6 animals. For the formation of acute aseptic inflammation in laboratory animals, phlogogens — carrageenin and dextran — were used. The choice of two phlogogens is due to the fact that inflammation caused by different agents is distinguished by the peculiarities of its development and factors involved in its genesis. So, dextran causes the release of biogenic amines - histamine and serotonin, and carrageenin promotes exudation due to the activation of prostaglandin synthesis.

The studied drugs (indomethacin and a combination of indomethacin with thiotriazolin) were administered orally 1 hour before subplanetary administration of 0.05 ml of a 1% solution of carrageenin or 6% solution of dextran.

After 3 hours on the model of carrageenin edema (since in the interval of 2.5-5.5 hours in the pathogenesis of inflammation, it is prostoglandins that play an important role in the pathogenesis of carrageenan inflammation) and after 1 hour on the model of dextran edema (since in the interval For 30-90 min, histamine and serotonin take an active part in the pathogenesis of inflammation, dextran facilitates the penetration of these into the inflammation site) animals are removed from the experiment by decapitation and amputated and not amputated at the level of the hip joint Alain hind legs.

After this, the masses of limbs are weighed. The activity of the test substances is determined by their ability to reduce the development of edema in comparison with the control and expressed as a percentage, which show how much the drug inhibits the development of edema in relation to the control, where the magnitude of the edema is taken as 100%.

The results are shown in tables No. 1 and No. 2.

Table No. 1
Anti-inflammatory activity in a dextran edema model A drug Dose,
mg / kg Paw mass, mg The change in mass of the paw,% compared with the control Indomethacin 4.0 38.83 ± 2.03 50.1 * Indomethacin 5,0 34.83 ± 3.13 55.24 * Indomethacin 7.5 33.5 ± 2.21 56.95 * Indomethacin 10.0 41.33 ± 2.21 46.9 * Indomethacin 15.0 43.33 ± 5.43 44.3 * The control water 77.83 ± 6.3 0 Indomethacin 4.0 34.83 ± 1.34 55.2 * Thiotriazoline 12.0 Indomethacin 5,0 28.83 ± 3.89 62.9 * Thiotriazoline 10.0 Indomethacin 5,0 31.33 ± 3.19 59.7 * Thiotriazoline 15.0 Indomethacin 7.5 26.16 ± 4.29 66.4 * Thiotriazoline 7.5 The control water 77.83 ± 6.3 0 Note: * - significantly with respect to the initial background (P <0.05).

Table number 2
Anti-inflammatory activity on a model of carrageenan edema A drug Dose,
mg / kg Paw mass, mg Change in paw mass,% compared to control Indomethacin 4.0 37.2 ± 2.9 56.8 * Indomethacin 5,0 34.2 ± 4.9 58.8 * Indomethacin 7.5 29.0 ± 3.4 65.1 * Indomethacin 10.0 31.2 ± 5.5 62.5 * Indomethacin 15.0 41.3 ± 4.6 50.2 * The control water 83.0 ± 7 0 Indomethacin
Thiotriazoline 4.0
12.0 27.7 ± 2.5 69.0 * Indomethacin
Thiotriazoline 5,0
15.0 24.8 ± 2.1 71.1 * Indomethacin
Thiotriazoline 4.0
5,0 35.8 ± 4.8 58.3 * Indomethacin
Thiotriazoline 4.0
7.5 29.2 ± 3.3 66.1 * Indomethacin
Thiotriazoline 7.5
7.5 26.5 ± 3.7 69.2 * The control water 86.0 ± 6.6 0 Note: * - significantly with respect to the initial background (P <0.05).

Example No. 2

The study of analgesic activity was carried out taking into account the involvement of central and peripheral mechanisms (electric pain irritation of the root of the tail of a rat).

The studies were performed on 72 white Wistar rats weighing 180-200 g, which were divided into 12 groups of animals, each group contained 6 males. The drugs were received in different doses, according to which the animals were divided into groups. The studied drugs were administered orally.

To assess the analgesic activity of painkillers, we used the method of electrical irritation of the rat tail. Steel needle electrodes (0.5 mm in diameter) with a fixed interelectrode distance (10 mm) were inserted under the skin at a distance of 1 cm from the root of the tail. The assessment of pain sensitivity was determined after 2-3 minutes (the animal calms down) and 90 minutes by the appearance of a vocal reaction (squeak, vocalization) and tail movement in response to a gradually increasing electrical irritation from the ESL-1 electric stimulator. The duration of each irritation did not exceed 1 second. The results are shown in table No. 3.

Example No. 3

The study of the analgesic properties of drugs on the model of tail withdrawal (thermal immersion).

The experiments were carried out on 72 white Wistar rats weighing 180-200 g. Animals were divided into 12 groups depending on the preparation received and its dose (each group contained 6 males). The latency of the tail tail reaction, after 3 cm of which was placed in a water bath at a temperature of 50 ± 0.2 ° С, was measured before the administration of the preparations and 90 minutes after the administration.

The results are shown in table No. 3.

Table number 3
Indicators of change in the threshold of pain response to irritation Groups of animals Pain threshold, amplitude (V) Tail registration Registration by vocalization reaction Indomethacin 5 mg / kg 1.36 + 0.55 + 38.7% 2.7 ± 1.17 + 21.6% Indomethacin 7.5 mg / kg 2.02 ± 0.31 + 40.6% * 3.91 + 1.15 + 45.8% Indomethacin 10 mg / kg 1.92 ± 0.33 + 50.3% * 4.2 ± 1.12 + 62.7% Indomethacin 15 mg / kg 1.44 ± 0.29 + 26.0% 4.2 ± 1.12% + 62.7% Indomethacin 5 mg / kg + thiotriazolin 5 mg / kg 1.63 ± 0.59 + 20.4% 3.62 + 1.79 + 45.8% Indomethacin 5 mg / kg + thiotriazolin 10 mg / kg 1.68 ± 0.33 + 58.5% * 3.2 + 1.48 + 78.0% * Indomethacin 5 mg / kg + thiotriazolin 15 mg / kg 1.75 ± 0.59 + 80.0% * 3.03 + 1.25 + 85.6% * Indomethacin 7.5 mg / kg + thiotriazolin
5 mg / kg 2.52 ± 0.51
46.5% * 4.2 + 1.12 + 50.0% * Indomethacin 7.5 mg / kg + thiotriazolin 10 mg / kg 1.64 ± 0.39 + 51.8% * 4.1 + 1.11 + 65.3% * Indomethacin 7.5 mg / kg + thiotriazolin 15 mg / kg 1.37 ± 0.2 + 90.3% * 2.38 + 0.86
+ 72.5% Indomethacin 5 mg / kg + thiotriazolin 20 mg / kg 1.24 + 0.08 + 53.0% * 2.96 + 1.5 + 64.0% The control 1.13 ± 0.42 + 26.0% 2.2 + 1.4 + 10.0% Note: in percent, the change in the pain threshold relative to the initial background is expressed; * - significantly with respect to the initial background (P <0.05).

Example No. 4

The study of the ulcerogenicity of indomethacin and its combinations with thiotriazolin.

Animals: 30 white Wistar rats weighing 160-200 g. Groups of animals treated with drugs in different doses (in each group of 6 animals):

1 - indomethacin 10 mg / kg;

2 - indomethacin 5 mg / kg;

3 - indomethacin 5 mg / kg + thiotriazolin 15 mg / kg;

4 - solvent in an adequate volume;

5 - good nutrition, drugs were not administered.

The principle of the method is a macroscopic study of the gastric mucosa of rats that received the drug on the background of fasting. Animals were decapitated on the fourth day, the stomach was removed, they were dissected along the lesser curvature, and washed in saline to remove the contents. Evaluation of the ulcerogenic effect was carried out visually by the number of ulcerative defects, which was reflected in the scores and ulcer index (NI).

The results are shown in table No. 4.

Table number 4
The effect of drugs and the studied combination on the development of damage to the gastric mucosa Groups of animals one 2 3 four 5 Number of ulcers 21.38 ± 2.32 17.17 ± 1.47 7.33 ± 2.73 1.66 ± 1.21 0 ME AND 25.8 21,2 11.2 4.8 0

Claims (1)

A non-steroidal anti-inflammatory and analgesic agent containing indomethacin as an active base, characterized in that the active base additionally contains thiotriazoline in the ratio of indomethacin to thiotriazolin 1: (1-3).