RU2448702C2 - Pharmaceutical composition for gastric and/or duodenal ulcer - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is offered a pharmaceutical composition for treating and/or preventing gastric and duodenal ulcer containing a proton pump inhibitor (PPI) and N-acetyl-5-methoxytriptamine (melatonin) in the following proportions: PPI - 10 mg - 30 mg; N-acetyl-5-methoxytriptamine (melatonin) - 2 mg - 8 mg; excipients - up to 100 mg with the PPI being presented by the compounds specified in a group: lansoprazole, rabeprazole, esomeprazole, pantoprazole The composition has been found to provide the efficacy equal or exceeding such ensured by common doses of the PPI with prolonged therapeutic action (i.e. specified PPI doses are single and daily).

EFFECT: pharmaceutical composition may be presented by a solid dosage form - tablets, film-coated tablets, softgel capsules, solid gel capsules, by a soft dosage form - rectal suppositories.

3 cl, 21 tbl

Description

The invention relates to medicine and relates to a new pharmaceutical composition for the treatment of gastric ulcer (UB) and duodenal ulcer (UBD).

Of the large number of diseases of the gastrointestinal tract, peptic ulcer of the stomach and duodenum is of particular social and medical importance, since in frequency it exceeds all other pathologies of this group. According to world statistics, peptic ulcer disease is common in approximately 10% of the adult population [8, 14].

Proton pump inhibitors (PPIs) are by far the clinically most effective drugs for the treatment of UBI and UBDK, as well as the treatment of stressful gastrointestinal ulcers.

IPPs have an antisecretory effect due to the inhibition of H +, K + -ATPase (proton pump) of the parietal cells of the gastric mucosa, reduce basal and stimulated gastric secretion, regardless of the nature of the stimulus.

Lansoprazole, like other PPIs, has an independent anti-Helicobacter pylori activity, which is characteristic of them as a class of drugs, and also increases the oxygenation of the gastric mucosa, stimulates the production of bicarbonates, which, in combination with inhibition of pepsin synthesis, has a pronounced gastroprotective effect, increasing the potential of protective factors of the gastric mucosa , especially with prolonged maintenance therapy [16, 17].

Despite the current advances in therapy, ulcer is characterized by exacerbations and cannot be completely cured. In recent years, the use of anti-Helicobacter therapy has significantly increased the effectiveness of anti-ulcer treatment and reduced the incidence of relapses, however, Helicobacter reinfection, and consequently the need for repeated sanitization therapy with a change in antibiotic and the formation of antibiotic-resistant forms of infection in this regard, necessitates the search for new pathogenetically substantiated ways treatment of peptic ulcer.

Another problem is the seasonality of exacerbations in patients with ulcer, which to some extent is due to a violation of the level and rhythm (daily and seasonal) of melatonin production.

Melatonin is the neuropeptide of the pineal gland, is N-acetyl-5-methoxytryptamine and is the biochemical key of the biological clock located in the suprachiasmatic nuclei of the hypothalamus [10, 11].

It has a wide range of biological activity:

antioxidant, antistress, sedative, immunomodulatory, vasodilator functions.

The presence of melatonin was found throughout the gastrointestinal tract, moreover, in some cells this hormone is synthesized. Melatonin affects the motility of the digestive system, the microcirculation and proliferation of mucosal cells. In patients with peptic ulcer, gross violations of the daily rhythm of melatonin production were revealed [1, 3]. The degree of violations of melatonin production directly correlates with the severity of the clinical course of the disease, and the ulcer-protective effects of melatonin on the model of ulcers caused by light inversion are clearly demonstrated in the experiment. It is no coincidence that peptic ulcer exacerbation is most often observed in the spring season. This period is characterized not only by possible vitamin deficiency, but also by the restructuring of the light regime, which inevitably affects the activity of the pineal gland.

Taking into account the properties of melatonin both at the body level (biorhythmological, antioxidant and immunomodulating effects), and at the level of the digestive tract (participation in the mechanisms of motility, microcirculation, proliferation, cytoprotection), as well as the results of numerous experimental studies that demonstrate the ulcer-protective effects of melatonin in various models ulcers [13, 15], at the present stage there is no doubt the role of violations of melatonin production in the pathogenetic mechanisms of the onset and exacerbation of ulcer.

The above dictates the need for a further search for methods of optimizing the treatment of patients with gastric ulcer and duodenal ulcer, relief of seasonal exacerbations.

An object of the present invention is to provide a new pharmaceutical composition for the treatment of gastric ulcer and duodenal ulcer.

This goal is achieved by creating a pharmaceutical composition containing a proton pump inhibitor (PPI), characterized in that it further comprises N-acetyl-5-methoxytryptamine (melatonin) in the following ratio of components:

proton pump inhibitor (PPI) - 10 mg - 30 mg

N-acetyl-5-methoxytryptamine (melatonin) - 2 mg - 8 mg

Excipients - up to 100 mg.

As a proton pump inhibitor, there may be lansoprazole, omeprazole, rabeprazole, esomeprazole, pantoprazole.

The pharmaceutical composition can be made in the form of a solid dosage form - tablets, coated tablets, soft gelatin capsules, hard gelatin capsules, in the form of a soft dosage form - rectal suppository.

An example of obtaining a solid dosage form of a pharmaceutical composition: a solid dosage form is prepared by mixing therapeutically effective amounts of active active ingredients — melatonin and a proton pump inhibitor (PPI), for example lansoprozole, omeprazole, rabeprazole, esomeprazole, pantoprazole with pharmaceutically acceptable excipients (excipients), with subsequent wet granulation of the mixture, drying of the granulate, dry granulation, dusting of the granulate and pelletizing of the granulate. Possibly, after pelletizing the granulate, tablets are coated with a film of a mixture of methyl cellulose, titanium dioxide and tropeolin.

Perhaps, after dry granulation, the granulate is encapsulated in soft or hard gelatin capsules.

An example of obtaining a soft dosage form - a rectal suppository: a soft rectal dosage form is obtained by preparing the base, which consists in mixing in a reactor with a stirrer and with heating components, for example paraffin, hydro fat, cocoa butter. The heated hydro-fat is pumped into the reactor with pre-melted paraffin and the mixture is heated to a temperature of 60-70 ° C. Then cocoa butter is added, but it is ensured that the heating does not exceed 70 ° C and is not prolonged, in order to avoid changing the modification of cocoa butter and increasing its melting temperature by 2-3 °. The finished fat base is filtered through a Druk filter, as a filtering material - belting fabric or brass mesh. And with the help of compressed air they transfer it to the reactor, where the active medicinal substances are introduced.

Introduction to the basis of medicinal substances is carried out by preparing a concentrate of a solution of the active drug substance. In this case, the physicochemical properties of the components are taken into account. The drug concentrate solution selected from the group of substances of lansoprazole, omeprazole, rabeprazole, esomeprazole, pantoprazole is filtered and fed to the reactor.

Then carry out the formation and packaging of candles. It is possible to pour suppositories on machines with separate casting and packaging operations or on automated lines.

The present invention has found that the use of a proton pump blocker, for example lansoprazole with melatonin in the form of a combined preparation for the treatment of gastric ulcer and duodenal ulcer, increases the effectiveness of treatment, including seasonal exacerbations.

A powerful stimulation of the secretion of duodenal bicarbonate was revealed, due to which the antisecretory effect of this pharmaceutical composition was increased in comparison with single preparations of IPP.

Example 1:

On the basis of GOU VPO Nizhny State Medical Academy of Roszdrav in 2009, a preclinical study of the specific antiulcer activity of the combination of drugs "Melatonin" + "Lansoprazole" was conducted. The study of drugs was carried out with the aim of studying the specific pharmacological effect of the composition of the drugs during intragastric administration under the conditions of modeling stress immobilization stomach ulcers in rats in comparison with the drug lansoprazole, omeprazole, rabeprazole, esomeprazole, pantoprazole.

In the experiments, 150 sexually mature male rats that passed 14-day quarantine were used. Animals were randomly assigned to groups using body weight as a criterion so that the individual animal weight did not differ by more than 20% from the average weight. The basic care and maintenance rules are in accordance with the guidelines given in the GLP manual.

The distribution of the groups:

Preventive action:

1. Control (distilled water), n = 10;

1a. Lansoprazole + Melatonin, n = 10;

1b. Lansoprazole, n = 10;

2. Control (distilled water), n = 10;

2a. Omeprazole + Melatonin, n = 10;

2b. Omeprazole, n = 10;

3. Control (distilled water), n = 10;

3a. Rabeprazole + Melatonin, n = 10;

3b. Rabeprazole, n = 10;

4. Control (distilled water), n = 10;

4a. Esomeprazole + Melatonin, n = 10;

4b. Esomeprazole, n = 10;

5. Control (distilled water), n = 10;

5a. Pantoprazole + Melatonin, n = 10;

5 B. Pantoprazole, n = 10;

Therapeutic effect:

1. Control (distilled water), n = 10;

1a. Lansoprozole + Melatonin, n = 10;

1b. Lansoprazole, n = 10;

2. Control (distilled water), n = 10;

2a. Omeprazole + Melatonin, n = 10;

2b. Omeprazole, n = 10;

3. Control (distilled water), n = 10;

3a. Rabeprozole + Melatonin, n = 10;

3b. Rabeprozole, n = 10;

4. Control (distilled water), n = 10;

4a. Esomeprazole + Melatonin, n = 10;

4b. Esomeprazole, n = 10;

5. Control (distilled water), n = 10;

5a. Pantoprazole + Melatonin, n = 10;

5 B. Pantoprazole, n = 10;

Based on the treatment regimen recommended by the applicant for treatment with melatonin (3 mg per day), lansoprazole (30 mg per day), the equitherapeutic dose of melatonin for rats was 0.25 mg / kg / day, the equitherapeutic dose of lansoprazole, omeprazole, rabeprazole, esomeprazole, pantoprazole was 2 5 mg / kg / day. Control animals were also intragastrically injected with a similar amount of distilled water.

The specific pharmacological effect of the drug was studied in the modeling of stress immobilization stomach ulcers in rats.

The prophylactic effect of the combination of drugs was studied prophylactically at a 7-day administration in an equi-therapeutic dose until the rats underwent stress immobilization stomach ulcers.

It was revealed that the drug had a prophylactic anti-ulcer effect, more pronounced when used in combination with melatonin at a dosage, equitherapeutic dosages of 3 and 6 mg for a person (Table 1). Addition to the lansoprazole, omeprazole, rabeprazole, esomeprazole, pantoprazole of melatonin at a dosage, equitherapeutic 1 mg for humans, did not have an additional effect (the preventive effect of this combination is comparable to the effect of a single drug lansoprazole, omeprazole, rabeprazole, esomeprazole, pant oprazole). The use in combination of a dosage of melatonin, an equitherapeutic 9 mg for humans, was accompanied by the occurrence of adverse events (transient tachycardia was observed within 1 hour after using the combination in 10% of experimental animals).

Table 1 The effect of the preventive use of the drug Lansoprazole and combinations of drugs Melatonin + Lansoprazole on the number of ulcerative destruction of the gastric mucosa in rats after stress immobilization (number of ulcers / cm ² ) (M ± m) The control Lansoprazole Melatonin 1 mg + lansoprazole Melatonin 3 mg + Lansoprazole Melatonin 6 mg + Lansoprazole Melatonin 9 mg + Lansoprazole 4.37 ± 1.06 Severe hyperemia 0.82 ± 0.52
Moderate hyperemia 0.83 ± 0.64
Moderate hyperemia 0.21 ± 0.32
Mostly only mild hyperemia 0.22 ± 0.78
Mostly only mild hyperemia 0.21 ± 0.15
Mostly only mild hyperemia

table 2 The effect of the preventive use of the drug Omeprazole and combinations of drugs Melatonin + Omeprazole on the number of ulcerative destruction of the gastric mucosa in rats after stress immobilization (number of ulcers / cm ² ) (M ± m) The control Omeprazole Melatonin 1 mg + Omeprazole Melatonin 3 mg + Omeprazole Melatonin 6 mg + Omeprazole Melatonin 9 mg + Omeprazole 4.35 ± 1.08 Severe hyperemia 0.79 ± 0.55 Moderate hyperemia 0.80 ± 0.57
Moderate hyperemia 0.20 ± 0.35
Mostly only mild hyperemia 0.20 ± 0.76
Mostly only mild hyperemia 0.20 ± 0.15
Mostly only mild hyperemia

Table 3 The effect of the preventive use of the drug Rabeprazole and combination of drugs Melatonin + Rabeprazole on the number of ulcerative destruction of the gastric mucosa in rats after stress immobilization (the number of ulcers / cm ² ) (M ± m) The control Rabeprozole Rabeprazole + Melatonin 1 mg Rabeprazole + Melatonin 3 mg Rabeprazole + Melatonin 6 mg Rabeprozole + Melatonin 9 mg 4.37 ± 1.06 Severe hyperemia 0.82 ± 0.52
Moderate hyperemia 0.83 ± 0.64
Moderate hyperemia 0.21 ± 0.32
Mostly only mild hyperemia 0.22 ± 0.78
Mostly only mild hyperemia 0.21 ± 0.15
Mostly only mild hyperemia

Table 4 The effect of the preventive use of the drug Esomeprazole and combinations of the drugs Melatonin + Esomeprazole on the number of ulcerative destruction of the gastric mucosa in rats after stress immobilization (number of ulcers / cm ² ) (M ± m) The control Esomeprazole Esomeprazole + Melatonin 1 mg Esomeprazole + Melatonin 3 mg Esomeprazole + Melatonin 6 mg Esomeprazole + Melatonin 9 mg 4.20 ± 1.16 Severe hyperemia 0.88 ± 0.54
Moderate hyperemia 0.86 ± 0.54
Moderate hyperemia 0.33 ± 0.34
Mostly only mild hyperemia 0.29 ± 0.62
Mostly only mild hyperemia 0.27 ± 0.09
Mostly only mild hyperemia

Table 5 The effect of the preventive use of Pantoprazole and combinations of Melatonin + Pantoprazole on the number of ulcerative destruction of the gastric mucosa in rats after stress immobilization (ulcers / cm ² ) (M ± m) The control Pantopra angry Pantoprazole + Melatonin 1 mg Pantoprazole + Melatonin 3 mg Pantoprazole + Melatonin 6 mg Pantoprazole + Melatonin 9 mg 3.97 ± 0.74
Severe hyperemia 0.91 ± 0.52 Moderate hyperemia 0.89 ± 0.66
Moderate hyperemia 0.40 ± 0.30
Mostly only mild hyperemia 0.37 ± 0.78
Mostly only mild hyperemia 0.35 ± 0.12
Mostly only mild hyperemia

Thus, the preventive use of the combination of drugs “Lansoprozole + Melatonin” “Omeprazole Melatonin”, “Rabeprazole + Melatonin”, “Esomeprazole + Melatonin”, “Pantoprazole + Melatonin” with the use of melatonin in dosages of 3–9 mg, equitherapeutic for humans, significantly improved the effectiveness indicator of the drug is lansoprazole, omeprazole, rabeprazole, esomeprazole, pantoprazole (Table 6-10), but an acceptable safety profile has been established for the dosage range of 3-6 mg of Melatonin.

Table 6 The effectiveness of the antiulcer effect of the preventive use of the drug Lansoprazole and a combination of drugs Melatonin + Lansoprazole in comparison with the control Therapy Lansopraz ol Melatonin 1 mg + lansoprazole Melatonin 3 mg + Lansoprazole Melatonin 6 mg + Lansoprazole Melatonin 9 mg + Lansoprazole Effect 82% 82% 94.9% 95% 95%

Table 7 The effectiveness of the antiulcer effect of the preventive use of the drug Omeprazole and the combination of drugs Melatonin + Omeprazole in comparison with the control Therapy Rabeprozole Omeprazole + Melatonin 1 mg Omeprazole + Melatonin 3 mg Omeprazole + Melatonin 6 mg Omeprazole + Melatonin 9 mg Effect 79% 80% 92.4% 94.8% 95.3%

Table 8 The effectiveness of the antiulcer effect of the preventive use of the drug Rabeprazole and the combination of drugs Melatonin + Rabeprazole in comparison with the control Therapy Rabeprozole Rabeprazole + Melatonin 1 mg Rabeprazole + Melatonin 3 mg Rabeprazole + Melatonin 6 mg Rabeprazole + Melatonin 9 mg Effect 78% 81% 93.4% 96% 96.3%

Table 9 The effectiveness of the antiulcer effect of the preventive use of the drug Esomeprazole and the combination of the drugs Melatonin + Esomeprazole in comparison with the control Therapy Esomeprazole Esomeprazole + Melatonin 1 mg Esomeprazole + Melatonin 3 mg Esomeprazole + Melatonin 6 mg Esomeprazole + Melatonin 9 mg Effect 77% 80% 92.9% 96% 95%

Table 10 The effectiveness of the antiulcer effect of the preventive use of Pantoprazole and the combination of Melatonin + Pantoprazole in comparison with the control Therapy Pantoprazole Pantoprazole + Melatonin 1 mg Pantoprazole + Melatonin 3 mg Pantoprazole + Melatonin 6 mg Pantoprazole + Melatonin 9 mg Effect 80% 81% 93.7% 95.3% 95.8%

The therapeutic effect of the combination of drugs “Lansoprozole + Melatonin” “Omeprazole + Melatonin,“ Rabeprazole + Melatonin ”,“ Esomeprazole + Melatonin ”,“ Pantoprazole + Melatonin ”on the reparative regeneration of the gastric mucosa was also studied in the simulation of stressful immobilization rats. After their reproduction (see above), the next day they started to treat with drugs with intragastric administration for 7 days. It was revealed that the drug has a therapeutic antiulcer effect (Table 11-15).

Table 11 The effect of the therapeutic use of the drug Lansoprazole and combination of drugs Melatonin + Lansoprazole on the number of ulcerative destruction in rats after stress immobilization (M ± m) Effects The control Lansopra
angry Melatonin 1 mg + lansoprazole Melatonin 3 mg + Lansoprazole Melatonin 6 mg + Lansoprazole Melatonin 9 mg + Lansoprazole The number of ulcers / cm ² 4.18 ± 1.10 2.3 ± 1.12 2.2 ± 1.10 0.5 ± 0.01 0.34 ± 0.02 0.33 ± 0.02 Mucosal condition oh Hyperemia Hyperemia Hyperemia Slight hyperemia Normal color Normal color

Table 12 The effect of the therapeutic use of Omeprazole and combinations of Omeprazole + Melatonin on the number of ulcerative destruction in rats after stress immobilization (M ± m) Effects The control Omeprazole Melatonin 1 mg + Omeprazole Melatonin 3 mg + Omeprazole Melatonin 6 mg + Omeprazole Melatonin 9 mg + Omeprazole The number of ulcers / cm ² 4.28 ± 1.02 2.5 ± 1.03 2.34 ± 1.10 0.49 ± 0.01 0.37 ± 0.02 0.33 ± 0.01 Mucosal condition Hyperemia Hyperemia Hyperemia Slight hyperemia Normal color Normal color

Table 13 The effect of therapeutic use of rabeprazole and combinations of rabeprazole + Melatonin on the number of ulcerative destruction in rats after stress immobilization (M ± m) Effects The control Rabeprazole Melatonin 1 mg + Rabeprazole Melatonin 3 mg + Rabeprazole Melatonin 6 mg + Rabeprazole Melatonin 9 mg + Rabepra
angry The number of ulcers / cm ² 4.18 ± 1.10 2.7 ± 0.87 2.5 ± 1.10 0.66 ± 0.01 0.54 ± 0.02 0.53 ± 0.02 Mucosal condition Hyperemia Hyperemia Hyperemia Slight hyperemia Normal color Normal color

Table 14 The effect of the therapeutic use of the drug Esomeprazole and the combination of Esomeprazole + Melatonin on the number of ulcerative destruction in rats after stress immobilization (M ± m) Effects The control Esomeprazole Melatonin 1 mg + Esomeprazole Melatonin 3 mg + Esomeprazole Melatonin
6 mg + esomeprazole Melatonin
9 mg + esomeprazole The number of ulcers / cm ² 4.18 ± 1.10 2.4 ± 1.09 2.38 ± 1.10 0.52 ± 0.01 0.36 ± 0.02 0.35 ± 0.01 Mucus condition
that Hyperemia Hyperemia Hyperemia Slight hyperemia Normal color Normal color

Table 15 The effect of the therapeutic use of Pantoprazole and combinations of Pantoprazole + Melatonin on the number of ulcerative destruction in rats after stress immobilization (M ± m) Effects The control Pantopra
angry Melatonin 1 mg + Pantoprazole Melatonin 3 mg + Pantoprazole Melatonin 6 mg + Pantoprazole Melatonin 9 mg + Pantoprazole The number of ulcers / cm 4.18 ± 1.10 1.93 ± 1.06 1.99 ± 1.10 0.53 ± 0.01 0.38 ± 0.03 0.37 ± 0.02 Mucosal condition Hyperemia Hyperemia Hyperemia Slight hyperemia Normal color Normal color

With the introduction of drugs within 7 days after the formation of immobilization stress on the mucous membrane in the group of drugs lansoprazole, omeprazole, rabeprazole, esomeprazole, pantoprazole, the decrease in the number of ulcerative defects decreased by almost 50% compared with the control group of animals.

In the group of animals treated with Lansoprozole + Melatonin 1 mg, Omeprazole + Melatonin 1 mg, Rabeprazole + Melatonin 1 mg, Esomeprazole + Melatonin 1 mg, Pantoprazole + Melatonin 1 mg, a decrease in the number of ulcerative defects was also noted mucosa by 50% compared with the control group, but there were no statistically significant differences from the group of monopreparations lansoprazole, omeprazole, rabeprazole, esomeprazole, pantoprazole. Thus, at this dosage, Melatonin does not increase the effectiveness of the drugs lansoprazole, omeprazole, rabeprazole, esomeprazole, pantoprazole.

In a series using a combination of drugs “Lansoprozole + Melatonin” “Omeprazole + Melatonin”, “Rabeprazole + Melatonin”, “Esomeprazole + Melatonin”, “Pantoprazole + Melatonin” with the use of melatonin in dosages equivalent to 3–9 mg for humans, it was not noted even hyperemia (examples in tables 16-21).

Table 16 The effectiveness of the therapeutic use of the drug Lansoprazole and combinations of drugs Melatonin + Lansoprazole in comparison with the control Therapy Lansoprazole Melatonin + Lansoprazole 1 mg 3 mg 6 mg 9 mg Efficiency% 44.97 47.36 88.04 ^* 91.87 ^* 92.11 ^* * - differences are significant at p <0.05 compared with the lansoprazole group

Table 17 The effectiveness of the therapeutic use of the drug Omeprazole and combinations of drugs Melatonin + Omeprazole in comparison with the control Therapy Omeprazole Melatonin + Omeprazole 1 mg 3 mg 6 mg 9 mg Efficiency% 42.57 43.19 85.02 ^* 93.87 ^* 93.18 ^* * - differences are significant at p <0.05 compared with the omeprazole group

Table 18 The effectiveness of the therapeutic use of the drug Rabeprazole and combination of drugs Melatonin + Rabeprazole in comparison with the control Therapy Rabeprazole Melatonin + Rabeprazole 1 mg 3 mg 6 mg 9 mg Efficiency% 45.86 46.26 90.12 * 95.17 * 94.81 * * - differences are significant at p <0.05 compared with the rabeprazole group

Table 19 The effectiveness of the therapeutic use of the drug Esomeprazole and a combination of drugs Melatonin + Esomeprazole in comparison with the control Therapy Esomeprazole Melatonin + Esomeprazole 1 mg 3 mg 6 mg 9 mg Efficiency% 48.17 47.16 87.33 ^* 92.87 ^* 92.31 ^* * - the differences are significant at p <0.05 compared with the esomeprazole group

Table 20 The effectiveness of the therapeutic use of the drug Esomeprazole and a combination of drugs Melatonin + Esomeprazole in comparison with the control Therapy Esomeprazole Melatonin + Esomeprazole 1 mg 3 mg 6 mg 9 mg Efficiency% 41.37 42.66 88.32 ^* 92.67 ^* 92.19 ^* * - the differences are significant at p <0.05 compared with the esomeprazole group

Table 21 The effectiveness of the therapeutic use of the drug Pantoprazole and a combination of drugs Melatonin + Pantoprazole in comparison with the control Therapy Pantoprazole Melatonin + Pantoprazole 1 mg 3 mg 6 mg 9 mg Efficiency% 50.12 49.36 83.56 ^* 92.87 ^* 91.67 ^* * - the differences are significant at p <0.05 compared with the Pantoprazole group

There were no statistically significant differences between the groups Lansoprazole and Lansoprozole + Melatonin 1 mg, Omeprazole and Omeprazole + Melatonin 1 mg, Rabeprozole and Rabeprazole + Melatonin 1 mg, Esomeprazole and Esomeprazole + Melatonin 1 mg, Pantoprozole 1 mg and Pantoprozole + Panton. Efficiency in both groups was comparable. Thus, it was revealed that Melatonin in this dosage does not increase the effectiveness of the anti-ulcer action of lansoprazole.

Significant differences were obtained when studying the anti-ulcer effect of combinations of Melatonin 3 mg, 6 mg, 9 mg with Lansoprazole, Omeprazole, Rabeprazole, Esomeprazole, Pantoprozole. From the data of tables 16-20 it can be seen that in the indicated groups the effectiveness of the combination exceeded the effectiveness of pure Lansoprazole, Omeprazole, Rabeprazole, Esomeprazole, Pantoprozole 2 times or more.

However, the use of a combination of a dosage of melatonin, an equiterpatic dose of 9 mg for humans, was accompanied by the occurrence of tachycardia within 30 minutes - 1 hour after using the combination in 10% of experimental animals).

Thus, doses of Melatonin 3-6 mg in combination with Lansoprazole, Omeprazole, Rabeprazole, Esomeprazole, Pantoprazole have the optimal efficacy and safety profile.

INFORMATION SOURCES

1. Guidance on the experimental (preclinical) study of new pharmacological substances // M: Medicine, 2005. - 832 p.

2. Report on a preclinical study of the specific activity of the combination of drugs “Melatonin” + “Lansoprazole”, GOU VPO NizhGMA Roszdrav, 2009.

3. Voznesenskaya L.A. Melatonin production in patients with duodenal ulcer. - Abstract. diss. Cand. honey. sciences. - 1998. - M. - 27 p.

4. Ivashkin V.T., Lapina T.L. Treatment of peptic ulcer: a new century - new achievements - new issues // breast cancer. - 2002 - T.4. - C.1 - 4.

5. Malinovskaya N.K. Melatonin and peptic ulcer. - Abstract. diss. Dr. med. sciences. - 1998. - M. - 48 p.

6. Minushkin O.N. Peptic ulcer. - 1995. - M. - 152 p.

7. Osadchuk M.A., Kirichuk V.F., Kvetnoy I.M. Diffuse neuroendocrine system: general biological and gastroenterological aspects. - 1996. - Publishing house of the Saratov honey. un-that. - Saratov. - 128 p.

8. Chernyakevich S.A., Babkova I.V., Mikhalev A.I. The results of treatment with proton pump inhibitors of complicated duodenal ulcers before and after surgical interventions // Clinical Medicine, 2002, No. 9, p.52-54.

9. Voznesenskaya L.A., Lakshin A.A., Malinovskaya N.K., Rapoport S.I. New pathogenetic approaches to the treatment of duodenal ulcer. // breast cancer, 2005, volume 7, No. 1, 16.

10. Malinovskaya N.K., Anisimov V.N. Basic ideas about the role of melatonin in the human body. Melatonin is normal and pathological. M .: Publishing House Medpraktika, 2004, pp. 72-84.

11. Anisimov V. N. Melatonin: role in the body, use in the clinic // St. Petersburg: Sistema Publishing House, 2007.

12. Kato K., Murai I., Asai S., Takahashi Y., Nagata T., Komuro S., Mizuno S., Iwasaki A., Ishikawa K., Arakawa Y. Circadian rhythm of melatonin and prostaglandin in modulation of stress-induced gastric mucosal lesions in rats. // Aliment. Pharmacol Ther. - 2002. - V.16. - Suppl. 2. - P.29-34.

13. Bandyopadhyay D., Biswas K., Bandyopadhyay U., Reiter R.J., Banerjee R.K. Melatonin protects against stress-induced gastric lesions by scavenging the hydroxyl radical. // J. Pineal Res. - 2000. - V.29. - P.248-252.

14. Freston J.W., Rose P.A., Heller C. et al. Safety profile of lansoprazole. // Drug safety. - 1999. - N.20 (2). - P. 195-205.

15. Bubenik G.A. Localization, physiological significance and possible clinical implication of gastrointestinal melatonin. // Biol. Signals Recept. - 2001. - V.10. - P.350-366.

16. Axon A.T. Eradication of Helicobacter pylori. Scand. // J. Gastroenterol. - 1996 .-- 31: 47-53.

17. Megraud F., Bouchard S., Lamouliatte H. Proton pump inhibitors have an ant microbial activity against H. pylori infection. // Gastroenterology. - 1991. - V.100 Suppl. - A123.

Claims (3)

1. A pharmaceutical composition for the treatment of gastric ulcer and / or duodenal ulcer, containing a proton pump inhibitor (PPI), characterized in that it further comprises N-acetyl-5-methoxytryptamine (melatonin) in the following ratio, mg:
proton pump inhibitor (PPI) 10 - 30
N-acetyl-5-methoxytryptamine (melatonin) 2-8
excipients up to 100, and the following compounds selected from the group are used as a proton pump inhibitor (PPI): lansoprazole, rabeprazole, esomeprazole, pantoprazole. 2. The pharmaceutical composition according to claim 1, characterized in that it is made in solid dosage form - tablets, coated tablets, soft gelatin capsules, hard gelatin capsules. 3. The pharmaceutical composition according to claim 1, characterized in that it is made in soft dosage form - suppositories.