RU2435575C2 - Deanol aceglumate demonstrating antiulcerogenic, gastroprotective and enteroprotective activity, combination possessing antiulcerogenic, gastroprotective and enteroprotective activity (versions), pharmaceutical composition - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, in particular, to medication, representing deanol aceglumate and possessing antiulcerogenic, gastro- and enteroprotective activity, and its combinations with anti-inflammatory, or anti-ulcer medications, or with anti-inflammatory and anti-ulcer medications.

EFFECT: medication possesses high antiulcerogenic, gastro- and enteroprotective activity, reduces side NSAID-induced ulcerative lesions of stomach and intestine.

6 cl, 2 tbl, 17 ex

Description

The invention relates to the field of medicine, specifically to a medicinal product having anti-ulcerogenic, gastro-and enteroprotective properties, which is proposed

deanol aceglumate: 2- (dimethylamino) ethanol N-acetyl-L-glutamate and its combination with anti-inflammatory or anti-ulcer drugs, or with anti-inflammatory and anti-ulcer drugs.

Deanol aceglumate is known as a low-toxic nootropic drug [Mashkovsky MD, Medicines, M., 14th ed., 2000, v. 1, p. 110]. In its chemical structure, it is close to the natural metabolites of the brain (GABA, glutamic acid).

The drug has neuroprotective properties with a distinct nootropic, psychostimulating and psycho-harmonizing effect [RF patent No. 2331414 (2006)]. The drug increases physical and mental performance [RF patent No. 2331413 (2006)]. In addition, it was found that deanol aceglumate has hepatoprotective properties [Radkevich L.A., Dissertation of the Doctor of Biological Sciences, M. 1998, RF patent No. 2068408 (1992), RF patent No. 2 US 747 (1996)].

During preclinical and clinical trials, the drug is known under the names Demanol, Nookler, Glutabianz, Nooklerin.

Clinical studies of the drug nooclerin (aceanolumate deanol) made it possible to recommend it as an effective antiasthenic agent [Yu.A. Aleksandrovsky, A.S. Avedisova et al., “Use of the drug Nooclerin as an antiasthenic agent in patients with functional asthenia” J. Psychotherapy and psychopharmacotherapy, 2003, v.5, No. 4, p.3-6].

Known dosage forms of Aceglumate deanol: a solid dosage form that enhances physical performance [RF patent No. 2331413 (2006)] and an injectable dosage form having neuroprotective properties [RF patent No. 2331414 (2006)].

It is known that for the treatment of various types of pain, mainly with neuralgic, muscle, joint pain, with headache and toothache, the so-called non-steroidal anti-inflammatory drugs (NSAIDs) are widely used. Their feature is the antipyretic effect, which manifests itself in febrile conditions, and anti-inflammatory effect, expressed to varying degrees in different compounds of this group; the absence of a depressing effect on the respiratory and cough centers; the absence of euphoria and phenomena of mental and physical dependence when using them [M.D. Mashkovsky, Medicines, M., New Wave LLC, 2002, vol. I, pp. 146-147, 159-174]. Therefore, these drugs are widely used in medical practice, including in the independent uncontrolled use of their patients.

However, it is also known that NSAID therapy is accompanied by a wide range of adverse reactions, the most common of which are NSAID-induced ulcerative lesions of the stomach and intestines [Nasonov E.L. Nonsteroidal anti-inflammatory drugs (Prospects for use in medicine). Moscow. Anko. - p.142, 2000].

This leads to the relevance of the search for the most optimal methods of protecting the gastrointestinal tract while taking NSAIDs (Nasonov E.L. Nonsteroidal anti-inflammatory drugs (Prospects for use in medicine). Moscow. “Anko.” - p.142, 2.000; Karateev A. E. Pathology of the upper gastrointestinal tract in patients with rheumatic diseases receiving anti-inflammatory therapy. Diss. MD, Moscow, 2006].

The use of antiulcer drugs of a different mechanism of action (ranitidine and omeprazole) does not always ensure high treatment efficiency and is accompanied by adverse side reactions.

The aim of the invention is to establish the anti-ulcerogenic, gastrointestinal and enteroprotective effects of deanol atseglumat, the preparation of combinations of deanol atseglumat and anti-inflammatory, or anti-ulcer, or anti-inflammatory and anti-ulcer drugs that have an antulcerogenic, gastro and enteroprotective effect, as well as their combined drugs.

There are no data in the literature on the anti-ulcerogenic properties of Aceglumate deanol, its combinations with antiulcer drugs and NSAIDs and its combined dosage forms.

The creation of combined drugs containing several pharmaceutical substances is a difficult task, because in the manufacture of dosage forms, technological processes can be accompanied by increased temperature, humidity and other factors affecting the drug.

In this regard, it was necessary to study the possible chemical interaction of pharmaceutical substances belonging to different chemical classes and containing active fragments of molecules.

RANITIDINE

N- [2 - [[[5 - [(Dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-etendiamine (as hydrochloride)

Omeprazole

5-Methoxy-2 - [[(4-methoxy-3,5, -dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole

DICLOFENAC

2 - [(2,6-Dichlorophenyl) amino] benzeneacetic acid (and as sodium salt)

INDOMETACIN

1- (4-Chlorobenzoyl) -5-methoxy-2-methyl-1H-indole-3-acetic acid

Phenylbutazone

4-butyl-1,2-diphenyl-3,5-pyrazolidinedione

ACETYLSALICYLIC ACID

2- (Acetyloxy) benzoic acid

Ibuprofen

α-Methyl-4- (2-methylpropyl) benzoylacetic acid

KETOPROFEN

2- (3-Benzoylphenyl) propionic acid = 3-Benzoyl-α-methylbenzeneacetic acid

A study was made of the possible chemical interaction of aceanolumate deanol and the listed substances at various temperature conditions

(+30 - +90) ° С and relative humidity from 50% to 90%, - manufacturing conditions for combined dosage forms.

It is shown that under the studied conditions there is no chemical interaction. According to the chromatographic study (TLC, HPLC), no degradation products were found under close contact of the studied molecules.

These data served as the basis for the development of combined medicines of deanol aceglumate with ranitidine, omeprazole, diclofenac, indomethacin, phenylbutazone, acetylsalicylic acid, ibuprofen and ketoprofen.

The most widely used dosage forms of antiulcer and NSAIDs are oral dosage forms in the form of tablets, capsules, powders, injection forms. Rectal suppositories are also effective, similar in speed and effectiveness to intramuscular and subcutaneous injections.

We developed precisely these combined dosage forms. The ratio of active substances (active substance) and auxiliary substances (target additives) was, wt.%:

active substance 0.05-60.0 targeted supplements 40.0-99.5

Cellulose derivatives, starches, various sugars, organic acids (succinic, citric, malic, benzoic, N-acetyl-6-aminohexanoic), polyvinylpyrrolidone, polysorbates, polyethylene oxides, glycerin, alcohols, sodium benzoate, alkali carbonates and bicarbonates were used as auxiliary substances. and alkaline earth metals, salts of stearic acid, silicon dioxide (aerosil), as well as corrective substances and flavorings, in the following ratio of components, wt.%:

crash are small 0-25 Sahara 0-20 cellulose derivatives 0-30 stearic acid salts 0-1.0 silicon dioxide (aerosil) 0-1.0 polyvinylpyrrolidones 0-4.5 polysorbates 0-1.0 polyethylene oxides 0-98.0 succinic acid 0-3.0 citric acid 0-5.0 malic acid 0-2.0 benzoic acid or sodium benzoate 0-2.0 N-acetyl-6-aminohexanoic acid 0-10 carbonates and bicarbonates of sodium, magnesium 0-3.0 corrective substances 0-1.0 flavorings 0-0.5

The proposed amounts of starch, cellulose derivatives, aerosil contained in solid dosage oral formulations increase the disintegration and dissolution of leforms, provide an increase in the rate of release and absorption of active substances. Salts of stearic acid provide the sliding effect necessary when pressing the tablet mass. Organic acids, sodium and magnesium carbonates and bicarbonates provide the necessary buffer balance.

We found that, as a suppository base for the preparation of rectal suppositories, it is preferable to use polyethylene oxides with the addition of polysorbates, which provide the maximum release of active substances from suppositories.

Combined dosage forms can be made in the form of injection solutions, tablets with and without a film coating, rectal suppositories, powders (in capsules), powders (in laminated bags for preparing solutions and suspensions for oral administration).

In the manufacture of powders, it is advisable to use sorbitol, xylitol, aspartame, sodium cyclamate, fruit and berry flavorings as flavoring agents (corrective substances).

The claimed ratios of the components are found experimentally and are optimal, which allows to obtain a technical result corresponding to the task. All combined dosage forms met the requirements of the State Pharmacopoeia of the 11th and 12th editions, had a shelf life of at least 2 years and provided a high therapeutic effect of active substances.

One way to obtain solid dosage forms is to obtain homogenized bulk powders or granules containing the necessary ingredients. These powders can be used for encapsulation, preparation of solutions or suspensions for oral administration or for the preparation of tablets by compression.

Rectal suppositories were prepared according to generally accepted technology by the method of pouring.

Clivico-pharmacological studies of the anti-ulcerogenic, gastrointestinal and enteroprotective effects of deanol aceglumate

The anti-ulcerogenic properties of Aceglumate deanol, its combined use with anti-inflammatory and anti-ulcer drugs have been established for the first time. Evaluation of anti-ulcerogenic activity was carried out on two models of ulcerogenic lesions of the gastrointestinal tract.

In the first model, ulcerative lesions of the gastric mucosa were reproduced by a single intraperitoneal administration of phenylbutazone at a dose of 200 mg / kg after a 24-hour hunger. Results were evaluated one day after drug administration. The experiments were performed on 66 white non-linear male rats.

Table 1 Experiment structure No. p / p Experiment Conditions Number of animals one 2 3 Model 1. Phenylbutazone. 200 mg / kg iv once (control) 12 2 Deanol Aceglumate 50 mg / kg 6 3 Deanol Aceglumate 100 mg / kg 6 four Deanol Aceglumate 250 mg / kg 6 5 Omeprazole 37 mg / kg (2% of LD ₅₀ ) 6 6 Omeprazole 37 mg / kg + Deanol Aceglumate 100 mg / kg 6 7 Ranitidine 25 mg / kg (2% of LD ₅₀ ) 6 8 Ranitidine 25 mg / kg + Deanol Aceglumate 100 mg / kg 6

Conducted 8 series of experiments. The control series consisted of 12 animals. In the first 2-4 hours after the administration of phenylbutazone, mortality in the control group was 25% (4 of 16 animals). In the experimental series, mortality of animals was not observed.

The studied drugs were administered 60 minutes before the injection of phenylbutazone intragastrically once. In the study of the combined anti-ulcerogenic effect, omeprazole and ranitidine were administered 60 minutes, deanol aceglumate 30 minutes before phenylbutazone.

In the second model, which includes 8 series, the induction of ulcerative defects in the mucous membrane of the stomach and intestines was carried out by 5-day course administration of indomethacin at a dose of 5 mg / kg or diclofenac at a dose of 1 mg / kg per os after two hours without food and water. The experiments were performed on 97 white non-linear rats of both sexes weighing 200-250 g.

table 2 Experiment structure No. p / p Model 2 The number of animals in the group one 2 3 one Indomethacin 5 mg / kg or Diclofenac at a dose of 1 mg / kg intragastrically 5 days - (control) 13 2 Deanol Aceglumate 50 mg / kg 10 3 Deanol Aceglumate 100 mg / kg 12 four Deanol Aceglumate 250 mg / kg 10 5 Omeprazole 37 mg / kg (2% of LD ₅₀ ) 10 6 Omeprazole 37 mg / kg + Deanol Aceglumate 100 mg / kg 12 7 Ranitidine 25 mg / kg (2% of LD ₅₀ ) 6 8 Ranitidine 25 mg / kg + Deanol Aceglumate 100 mg / kg 12

The control group consisted of 13 animals. Mortality in the control group was 7% (1 animal out of 14). In the experimental groups, mortality was absent. The studied drugs were administered intragastrically by the probe method 60 minutes before the administration of indomethacin or diclofenac once a day for 5 days. In the study of the anti-ulcerogenic effect of the combined administration of drugs, omeprazole and ranitidine were administered 60 minutes, and deanol atseglumat 30 minutes before the administration of indomethacin or diclofenac.

The intact group consisted of 10 animals. The animals were slaughtered by the guillotine method after preliminary administration of sodium thiopental at a dose of 50 mg / kg ip. After decapitation, blood was taken for biochemical research methods. At autopsy, the picture of the mucous membrane of the stomach and intestines (the number and area of ulcerative defects, the presence of signs of bleeding, perforations) was evaluated. When assessing ulcerative lesions of the gastric mucosa, a clinical endoscopic characteristic was used [Chernekhovskaya N.E. et al., 2006].

The introduction of phenylbutazone at a dose of 200 mg / kg led after 24 hours to severe ulcerative lesions of the gastric mucosa in all experimental animals. Moreover, the total area of ulcers was 28.0 ± 1.97 mm ² , and the number was 20.33 ± 1.35 per animal on average. All experimental animals showed signs of bleeding. The area of deep ulcers with signs of bleeding was 9.67 ± 1.59 mm ² , and their number was 5.50 ± 0.83. The proportion of deep ulcers was 39.80 ± 6.63% by area and 27.69 ± 5.45% by number.

A light-optical study revealed a pattern of multiple erosion within 2/3 of the thickness of the mucous membrane. Single erosion reached its own plate. The blood vessels of the submucosal layer were dilated and full-blooded. There was a sharp edema of the submucosa in the projection of erosion with polymorphic cell infiltration.

The use of Aceglumate deanol at a dose of 50 mg / kg against the background of modeling gastric ulcer by the administration of phenylbutazone did not have a significant anti-carcinogenic effect. An additional administration of 100 mg / kg deanol atseglumate had a significant anti-ulcerogenic effect on the gastric mucosa: the total number of ulcers decreased by 35%, the number of deep ulcers by 46%. At the same time, the proportion of deep ulcers in area and in quantity did not change compared to the control. Ulcerative lesions of the gastric mucosa and signs of bleeding were recorded in all experimental animals from this series.

Histologically, diffuse and focal large-cell infiltration (lymphocytes, plasmocytes, monocytes) of the gastric mucosa was observed, especially in the basal sections of the own muscle plate, submucosa. In some parts of the serous membrane of the stomach, edema and large cell infiltration were noted. The muscularis was intact.

With an increase in the administered dose of the drug to 250 mg / kg, there was no further significant decrease in the number of ulcers, but a decrease in the total area of the ulcer surface by 32% was observed. In addition, the area of deep ulcers was significantly reduced compared with the control group (by 31%) and the surface ulcer area (by 39%).

When modeling gastric ulcer by the administration of phenylbutazone, the use of aceanolum deanol at a dose of 50 and 100 mg / kg did not affect the value of the studied biochemical parameters. However, when using the largest of the studied doses of the drug, a decrease in ALT and LDH activity was observed compared to the control. A significant effect on some indicators of lipid peroxidation was also recorded against the background of the use of large of the studied doses as a means of correction. Moreover, in comparison with the control, the activity of catalase in the blood plasma, the content of MDA and FEMDA decreased. In erythrocytes, a decrease in the content of secondary LPO products was also observed. In the stomach tissue compared with the control, the content of MDA increased and a decrease in RLPO was observed. And in the liver, small and large intestine, the content of secondary LPO products decreased.

Thus, the obtained results testify to the gastroprotective effect of deanol aceglumate under conditions of induction of gastric ulcer by phenylbutazone, to the absence of growth of markers of the cytolytic syndrome, to some decrease in LPO activity in plasma, erythrocytes, intestines, liver and its growth in stomach tissues.

A single administration of ranitidine at a dose of 2% of LD ₅₀ reduced the total number of ulcers induced by phenylbutazone by 28% and the total area of gastric ulcer by 39%, but did not significantly affect the number and area of deep ulcers. The combined use of ranitidine and deanol aceglumate in the studied doses led to a significant decrease in the number of deep ulcers compared with ranitidine monotherapy (by 70%). In 50% of the animals in the group, there were no signs of intragastric bleeding (p <0.05).

Histologically, focal atrophy of the mucous membrane was observed, in some areas large-cell infiltration of the mucous membrane, submucosal membrane, and own muscle plate was observed, and single dilated lymphatic vessels with intravascular leukocyte stasis were found. Compared to the control series, deep glands were lined with an epithelium with a hyperchromic nucleus (regenerative epithelium) almost throughout its length. A slight swelling was noted.

In the combined use of drugs against the background of the induction of gastric ulcer by the administration of phenylbutazone compared with the control, there was no increase in the activity of aminotransferases and LDH, regarded as markers of the cytolytic syndrome. With the combination of omeprazole and deanol aceglumate, an increase in the content of MDA in the liver and small intestine and an increase in MDA and FEMDA in the stomach tissue were observed. With the combined use of ranitidine and aceglumate deanol, the content of MDA in the liver, stomach and intestinal tissue was lower than with ranitidine monotherapy.

It was noted that the combined use of deanol aceglumate and omeprazole can significantly reduce the total number of ulcers (by 61%), the number of deep ulcers (by 71%) and the area of deep ulcers (by 54%) compared with the series with the administration of omeprazole as monotherapy . The total number of surface ulcers decreased by 53%. In 42% of animals, no intragastric bleeding was observed (p <0.05).

An increase in the content of LPO secondary products in the tissues of the stomach with the combined use of omeprazole and deanol aceglumate was not observed.

Given that the administration of phenylbutazone does not reproduce intestinal damage, for a more adequate assessment of the anti-carcinogenic activity of the studied drugs, we used the administration of indomethacin or diclofenac for 5 days to simulate ulcerative lesions of the gastrointestinal tract.

Moreover, ulceration in the stomach, including with the presence of bleeding, was observed in all experimental animals. The area of deep ulcers averaged 92% of the total lesion area. Histologically, a picture of ulceration with penetration was observed in the stomach, marked diffuse polymorphic cell infiltration was noted.

The introduction of deanol. Aceglumate at a dose of 50 mg / kg led to a significant reduction in the total number of ulcers by 65%, and the number of deep ulcers by 87%. The area of deep ulcers was reduced by 70%. The revealed changes led to a reduction in the proportion of deep ulcers in terms of number and area.

With an increase in the dose of Aceglumate deanol, compared with the smaller of the studied doses, to 100 mg / kg, a decrease in the area of deep ulcers by 51% and the total area of the ulcer lesion by 52% was observed. Histologically revealed surface erosion.

With an increase in the dose of Aceglumate deanol to 250 mg / kg, there was no further significant increase in the anti-ulcerogenic effect. Thus, the number and area of deep ulcers did not differ from the series with the use of Aceglumate deanol at a dose of 100 mg / kg, and the area and number of surface ulcers increased. At the same time, however, the proportion of deep ulcers in terms of number and area decreased almost twice as compared with the data of the series with the introduction of deanol aceglumate at a dose of 100 mg / kg. It should be noted that the development of ulcers was not completely prevented, but in 3 animals from the series, no deep ulcers were observed (p <0.05).

The additional use of Aceglumate deanol in the doses studied in the ulcer model induced by indomethacin or diclofenac led to a decrease in ALT (by 62%, 38% and 77%) and ACT (by 59%, 29% and 79%, respectively). The bilirubin content did not change, and LDH activity decreased by 18% and 80% when the drug was administered at a dose of 100 and 250 mg / kg.

In addition, an increase in the content of MDA (by 29%) and a decrease in FEMDA (by 19%) were observed in the blood plasma, which led to a decrease in AOA and RLPO of the plasma when using deanol atseglumat at a dose of 50 mg / kg. With an increase in the administered dose to 250 mg / kg, on the contrary, the content of MDA decreased by 44%, and FEMDA by 55% compared with the control. Plasma catalase activity decreased by 29% when the drug was administered at a dose of 250 mg / kg. In erythrocytes with the use of Aceglumate deanol at a dose of 50 mg / kg, the content of MDA and FEMDA was 51% and 28% more than the control, respectively. When the dose was increased to 100 mg / kg, it did not differ, and when using 250 mg / kg, it was again below the control by 47% and 39%, respectively. At the same time, catalase activation was 2.3 times and RLPO growth by 65%.

In the tissues of the stomach, an increase in the content of secondary LPO products by 2-2.3 times was observed. In the tissues of the small intestine, the content of MDA decreased by 41% with the introduction of Aceglumate deanol at a dose of 250 mg / kg, and in the colon - by 41% and 79% when using the drug at a dose of 100 and 250 mg / kg.

Thus, the results obtained indicate that deanol aceglumate exhibits a gastroprotective effect in conditions of modeling gastric ulcer with indomethacin or diclofenac, does not increase the activity of aminotransferases. The drug leads to an increase in the activity of lipid peroxidation in plasma and red blood cells when using the lower of the studied doses and to its decrease when administered at a dose of 250 mg / kg. Histologically, moderate focal hyperplasia of the mucous membrane was observed, mild focal, mainly large-cell (lymphocytes, monocytes) infiltration, edema of the submucous membrane and internal muscular membrane were recorded.

The introduction of omeprazole in the form of monotherapy at a dose of 2% of LD ₅₀ significantly reduced the total number of ulcers by 57%. At the same time, the area of ulcerative lesions decreased by 79%, the area of deep ulcers - by 81%. Histologically revealed a picture of surface erosion. Zones of necrosis were noted within the mucous membrane with preservation of the basal layer of cells, necrotic detritus with the addition of hemoglobin pigment and cell infiltration was detected at the bottom of erosion.

The combination of omeprazole with deanol aceglumate in a dose of 100 mg / kg significantly reduced the number of deep ulcers by 90% compared with omeprazole monotherapy. The area of deep ulcers did not change, but at the same time in 3 of their 6 animals the development of deep ulcers was not observed (p <0.05).

The use of ranitidine at a dose of 2% of LD ₅₀ did not lead to a significant limitation of the ulceration processes induced by the administration of indomethacin or diclofenac. According to the combination of ranitidine with deanol aceglumate at a dose of 100 mg / kg, a significant decrease in the total number of ulcers by 32%, the total area of ulcers by 31%, and the number of deep ulcers by 73% was noted. In addition, in comparison with ranitidine monotherapy data, the area of deep ulcers was also reduced by 44%. In 2 animals, ulcers were absent. At the same time, a moderate polymorphic-cell inflammatory infiltration was observed histologically in the mucous membrane.

An experimental model with the introduction of indomethacin or diclofenac allowed reproducing ulcerative lesions not only of the stomach, but also of the intestine. In the small intestine in the control group of animals, against the background of the administration of indomethacin or diclofenac, the number of ulcers reached 161.1 ± 23.8, and the area of the ulcer lesion was 831.1 ± 76.5 mm ² per animal.

The use of deanol aceglumate had a significant anti-ulcerogenic effect on the mucous membrane of the small intestine. With the introduction of acetanolumate deanol at a dose of 50 mg / kg, the total number of ulcers decreased to 2.8 ± 0.73, and the area to 5.4 ± 1.44 mm ² . No ulceration was observed in 3 out of 10 animals. With an increase in the dose of the drug to 100 mg / kg, the total number of ulcers decreased to 1.27 ± 0.47, and the area decreased to 2.64 ± 0.94 mm ² (p <0.001). Moreover, in 50% of the animals there was no ulcerative lesion of the small intestine. With an increase in the dose of Aceglumate deanol to 250 mg / kg, ulceration in the small intestine was completely prevented.

In the colon, after administration of indomethacin or diclofenac, the total number of ulcers after 5 days of observation was 28.2 ± 2.6, and their average area reached 92.9 ± 9.8 mm ² . With the introduction of 50 mg / kg deanol aceglumate, the total number of ulcers and their area did not change significantly. With the use of a dose of 100 mg / kg, the total number of ulcers decreased by 61%, and their area per animal, on average, by 65%. Against the background of the introduction of the largest of the studied doses of aceanolumate deanol (250 mg / kg), a further decrease in the number of ulcers in the colon to 9.1 ± 0.88, and their area to 20.72 ± 1.96 mm ^2, was observed compared with the control .

Thus, the obtained results demonstrate the gastroprotective and enteroprotective effect of Aceglumate deanol in modeling ulcerative lesions of the gastrointestinal tract with indomethacin or diclofenac.

The effect of aceanolumate deanol on the enteroprotective efficacy of representatives of standard anti-ulcerogenic groups of drugs: omeprazole and ranitidine was studied.

With the combined use of omeprazole with deanol aceglumate at a dose of 100 mg / kg, the number of ulcers in the small intestine decreased by 69% compared with omeprazole monotherapy, and their area - by 74%.

In the colon, with the introduction of omeprazole, the number of ulcers decreased by 68% compared with the control group, the average area - by 89%. With the combined use of omeprazole with deanol aceglumate, a positive dynamics was also observed in the colon mucosa: the number of ulcers decreased by 93%, and their area - by 94%. In 50% of the animals, ulceration was prevented.

Ranitidine in the studied dose reduced the area of ulcerative lesions of the small intestine to a lesser extent than omeprazole. However, with the combination of ranitidine with deanol aceglumate, the indicators were already comparable with the antiulcerogenic effect of the comparison drugs. So, the number of ulcers decreased to 2.50 ± 0.65 (p <0.001), and the area to 5.01 ± 1.35 mm ² . In the colon, the administration of ranitidine did not affect the processes of ulceration, but when combined with deanol aceglumate, a significant reduction in the total area of ulcers was observed.

Against the background of the combined use of deanol atseglumat and ranitidine under conditions of induction of ulceration with indomethacin or diclofenac, the content of LPO secondary products in the blood, tissues of the stomach, liver, small and large intestine did not exceed the performance of the series with the administration of ranitidine as monotherapy.

With the combined use of omeprazole, ranitidine, and aceanolum deanol, no increase in the activity of ALT, ACT, and LDH in the blood plasma of experimental animals was also observed.

Thus, the results obtained indicate that deanol aceglumate has an anti-carcinogenic, gastroprotective and enteroprotective effect and increases the anti-carcinogenic efficacy of omeprazole and ranitidine under experimental conditions for modeling gastrointestinal ulcer associated with non-steroidal anti-inflammatory drugs. In addition, it was shown that the combined use of deanol aceglumate with antiulcer drugs or NSAIDs, or both at the same time, leads to a sharp decrease (in some cases, complete disappearance) of adverse NSAID-induced ulcerative lesions of the stomach and intestines.

The composition and methods of manufacturing the inventive combined dosage forms are given in the following examples.

Example 1. In an apparatus with a stirrer, load 105 g of aceglumate deanol, 150 ml of purified water. To the resulting solution, add 20 g of hydroxypropyl cellulose, mix thoroughly and add 50 g of diclofenac, 200 g of microcrystalline cellulose, mix thoroughly until a homogeneous mass is formed. 20 g of N-acetyl-6-aminohexanoic acid, 15 g of silicon, dioxide, 25 g of starch, 52 g of magnesium carbonate are gradually added to the mass. The mixture is thoroughly mixed and wiped through a sieve to obtain granules of not more than 2 mm. The resulting granules are dried to a residual moisture content of not more than 1.0%. Dry granules, representing a powder, are mixed with 30 g of magnesium carbonate, 6.0 g of silicon dioxide and 5 g of stearic acid. Mix thoroughly until smooth and tablet. Get 1000 tablets containing in one tablet 100 mg of deanol aceglumate and 50 mg of diclofenac. The resulting tablets meet the requirements of the State Pharmacopoeia XI and XII ed.

Example 2. Analogously to example 1, tablets are obtained which are coated with an enteric-soluble polymer film coating. The resulting film-coated tablets contain in one tablet 100 mg of acetolumate deanol and 50 mg of diclofenac and meet the requirements of the State Pharmacopoeia XI and XII ed.

Example 3. Analogously to example 1, 2, but instead of diclofenac add 50 g of ketoprofen. Get tablets that are coated with an enteric-soluble polymer film coating.

The resulting film-coated tablets contain 100 mg of acetolumate deanol and 50 mg of ketoprofen in one tablet and meet the requirements of the State Pharmacopoeia XI and XII ed.

Example 4. In an apparatus with a stirrer, 200 ml of water for injection, 27 g of diclofenac, 50 ml of 1M sodium hydroxide solution, 15 g of N-acetyl-6-aminohexanoic acid, 35 g of ethanol aceglumate deanol, 1 g of ethylenediaminetetraacetic acid disodium salt and 2 g sodium metabisulfite. The mass is thoroughly mixed. The volume is adjusted to 1 liter with water for injection. The solution is filtered, poured into ampoules, sterilized. Get 1000 ampoules containing in 1 ml of a solution of 33.3 mg of deanol aceglumate and 25 mg of diclofenac. The resulting solution meets the requirements of the State Pharmacopoeia XI and XII ed.

Example 5. Analogously to example 4, 200 ml of water for injection, 53 g of ketoprofen, 50 ml of 1M sodium hydroxide solution, 35 g of ethanol diethanol tetraacetic acid disodium salt and 2 g of metabisulfite sodium are loaded into a stirrer. The mass is thoroughly mixed. The volume is adjusted to 1 liter with water for injection. The solution is filtered, poured into ampoules, sterilized. Get 1000 ampoules containing in 1 ml of a solution of 33.3 mg of deanol. Aceglumate and 50 mg of ketoprofen, which meet the requirements of the State Pharmacopoeia XI and XII ed.

Example 6. In the apparatus with a stirrer load 105 g of aceglumate deanol, 260 g of microcrystalline cellulose, 32 g of starch, 380 g of sorbitol. The mass is thoroughly mixed. To the obtained homogeneous mass, the previously obtained dried powder of 105 g of acetylsalicylic acid, 32 g of citric acid, 10 g of succinic acid, 90 g of sorbitol, 170 g of sodium bicarbonate, 10 g of sodium benzoate is gradually added with stirring. The mass is thoroughly homogenized and scattered in capsules. 1000 capsules are obtained containing in one capsule 100 mg of aceglumate deanol and 100 mg of acetylsalicylic acid. The resulting preparation in capsules meets the requirements of the State Pharmacopoeia XI and XII ed.

Example 7. In an apparatus with a stirrer, 105 g of aceglumate deanol, 260 g of microcrystalline cellulose, 32 g of starch, 380 g of sorbitol are loaded. The mass is thoroughly mixed. To the obtained homogeneous mass, the previously obtained dried powder of 105 g of acetylsalicylic acid, 23 g of omeprazole, 32 g of citric acid, 10 g of succinic acid, 90 g of sorbitol, 170 g of sodium bicarbonate, 10 g of sodium benzoate is gradually added with stirring. The mass is thoroughly homogenized and scattered in capsules. 1000 capsules are obtained containing in one capsule 100 mg of aceglumate deanol, 100 mg of acetylsalicylic acid and 20 mg of omeprazole. The resulting preparation in capsules meets the requirements of the State Pharmacopoeia XI and XII ed.

Example 8. In a apparatus with a stirrer, load 105 g of acetanolumate deanol, 110 g of acetylsalicylic acid, 250 g of citric acid, 80 g of succinic acid, 95 g of sorbitol, 50 g of N-acetyl-6-aminohexanoic acid, 80 g of potassium bicarbonate, 460 g sodium bicarbonate, 20 g of sodium benzoate, 100 g of milk sugar, 2 g of aspartame, 0.2 g of flavoring and 4 g of polyvinylpyrrolidone (collidone 25). With the addition of each ingredient, the mass is thoroughly mixed. Sifted through a sieve and fall asleep in laminated bags of 1.0 g and sealed them. The resulting powder contains in one packet 100 mg of aceglumate deanol and 100 mg of acetylsalicylic acid and is suitable for receiving a solution or suspension for oral administration. The resulting preparation in laminated bags meets the requirements of the State Pharmacopoeia XI and XII ed.

Example 9, 135 g of polyethylene oxide 1500, 15 g of polyethylene oxide 400, 2 g of glycerol are loaded into a stirrer. The mass is heated to 50-55 ° C while stirring, then 10.5 g of aceglumate deanol are added. 5.5 g of diclofenac and 3 g of N-acetyl-6-aminohexanoic acid. The mass is thoroughly mixed and poured into suppository forms. 1.5 g of the suppository contains 100 mg of Aceglumate deanol and 50 mg of diclofenac.

Example 10. In the apparatus with a stirrer load 135 g of polyethylene oxide 1500, 15 g of polyethylene oxide 400, 2 g of glycerol. The mass is heated to 50-55 ° C with stirring, then 10.5 g of aceglumate deanol, 5.5 g of indomethacin and 3 g of N-acetyl-6-aminohexanoic acid are added. The mass is thoroughly mixed and poured into suppository forms. In 1.5 g of the suppository contains 100 mg of Aceglumate deanol and 50 mg of indomethacin.

Example 11. In the apparatus with a stirrer load 105 g of deanol aceglumate, 150 ml of purified water. To the resulting solution, add 20 g of hydroxypropyl cellulose, mix thoroughly and add 23 g of omeprazole, 52 g of starch, 400 g of microcrystalline cellulose, mix thoroughly until a homogeneous mass is formed. 20 g of N-acetyl-6-amimogsanoic acid, 15 g of silicon dioxide, 25 g of polyvinylpyrrolidone (collidone 25), 80 g of milk sugar, 52 g of magnesium carbonate are gradually added to the mass. The mixture is thoroughly mixed and wiped through a sieve to obtain granules of not more than 2 mm. The resulting granules are dried to a residual moisture content of not more than 1.0%. Dry granules, representing a powder, are mixed with 30 g of magnesium carbonate, 6 g of silicon dioxide and 5 g of stearic acid. Mix thoroughly until smooth and tablet. 1000 tablets are obtained containing in one tablet 100 mg of Aceglumate deanol and 20 mg of omeprazole. The resulting tablets meet the requirements of the State Pharmacopoeia XI and XII ed.

Example 12. Analogously to example 11 in a apparatus with a stirrer load 105 g of deanol aceglumate, 150 ml of purified water. To the resulting solution, add 20 g of hydroxypropyl cellulose, mix thoroughly and add 13 g of omeprazole, 52 g of starch, 400 g of microcrystalline cellulose, mix thoroughly until a homogeneous mass is formed. 15 g of silicon dioxide, 25 g of polyvinylpyrrolidone (collidone 25), 80 g of sugar, milk, 52 g of magnesium carbonate are gradually added to the mass. The mixture is thoroughly mixed and wiped through a sieve to obtain granules of not more than 2 mm. The resulting granules are dried to a residual moisture content of not more than 1.0%. Dry granules, representing a powder, are mixed with 30 g of magnesium carbonate, 6 g of silicon dioxide and 5 g of stearic acid. Mix thoroughly until smooth and tablet. 1000 tablets are obtained containing in one tablet 100 mg of Aceglumate deanol and 10 mg of omeprazole. The resulting tablets meet the requirements of the State Pharmacopoeia XI and XII ed.

Example 13. In the apparatus with a stirrer, load 105 g of aceanolumate deanol, 150 ml of purified water. To the resulting solution, add 20 g of hydroxypropyl cellulose, mix thoroughly and add 310 g of ranitidine, 52 g of starch, 250 g of microcrystalline cellulose, mix thoroughly until a homogeneous mass is formed. 20 g of N-acetyl-6-aminohexanoic acid, 15 g of silicon dioxide, 25 g of polyvinylpyrrolidone (collidone 25), 80 g of sugar, milk, 52 g of magnesium carbonate are gradually added to the mass. The mixture is thoroughly mixed and wiped through a sieve to obtain granules of not more than 2 mm. The resulting granules are dried to a residual moisture content of not more than 1.0%. Dry granules, which are a powder, are mixed with 30.0 g of magnesium carbonate, 6.0 g of silicon dioxide and 5.0 g of stearic acid. Mix thoroughly until smooth and tablet. Get 1000 tablets containing in one tablet 100 mg of deanol aceglumate and 300 mg of ranitidine. The resulting tablets meet the requirements of the State Pharmacopoeia XI and XII ed.

Example 14. Analogously to example 13, in a apparatus with a stirrer load 105 g of aceanolumate deanol, 150 ml of purified water. To the resulting solution, add 20 g of hydroxypropyl cellulose, mix thoroughly and add 155 g of ranitidine, 52 g of starch, 300 g of microcrystalline cellulose, mix thoroughly until a homogeneous mass is formed. 15 g of silicon dioxide, 25 g of polyvinylpyrrolidone (collidone 25), 80 g of milk sugar, 52 g of magnesium carbonate are gradually added to the mass. The mixture is thoroughly mixed and wiped through a sieve to obtain granules of not more than 2 mm. The resulting granules are dried to a residual moisture content of not more than 1.0%. Dry granules, representing a powder, are mixed with 30 g of magnesium carbonate, 6 g of silicon dioxide and 5 g of stearic acid. Mix thoroughly until smooth and tablet. Get 1000 tablets containing in one tablet 100 mg of deanol aceglumate and 150 mg of ranitidine. The resulting tablets meet the requirements of the State Pharmacopoeia XI and XII ed.

Example 15. In the apparatus with a stirrer load 105 g of deanol aceglumate, 150 ml of purified water. To the resulting solution, add 20 g of hydroxypropyl cellulose, mix thoroughly and add 23 g of omeprazole, 52 g of starch, 400 g of microcrystalline cellulose, mix thoroughly until a homogeneous mass is formed. 20 g of N-acetyl-6-aminohexanoic acid, 250 g of ibuprofen, 15 g of silicon dioxide, 25 g of polyvinylpyrrolidone (collidone 25), 80 g of milk sugar, 52 g of magnesium carbonate are gradually added to the mass. The mixture is thoroughly mixed and wiped through a sieve to obtain granules of not more than 2 mm. The resulting granules are dried to a residual moisture content of not more than 1.0%. Dry granules, representing a powder, are mixed with 30 g of magnesium carbonate, 6 g of silicon dioxide and 5 g of stearic acid. Mix thoroughly until smooth and tablet. 1000 tablets are obtained containing in one tablet 100 mg of Aceglumate deanol, 20 mg of omeprazole and 200 mg of ibuprofen. The resulting tablets meet the requirements of the State Pharmacopoeia XI and XII ed.

Example 16. In the apparatus with a stirrer load 1.05 g of aceanolumate deanol, 150 ml of purified water. To the resulting solution, add 20 g of hydroxypropyl cellulose, mix thoroughly and add 23 g of omeprazole, 52 g of starch, 400 g of microcrystalline cellulose, mix thoroughly until a homogeneous mass is formed. 105 g of phenylbutazone, 20 g of N-acetyl-6-aminohexanoic acid, 15 g of silicon dioxide, 25 g of polyvinylpyrrolidone (collidone 25), 80 g of milk sugar, 52 g of magnesium carbonate are gradually added to the mass. The mixture is thoroughly mixed and wiped through a sieve to obtain granules of not more than 2 mm. The resulting granules are dried to a residual moisture content of not more than 1.0%. Dry granules, representing a powder, are mixed with 30 g of magnesium carbonate, 6 g of silicon dioxide and 5 g of stearic acid. Mix thoroughly until smooth and tablet. 1000 tablets are obtained containing in one tablet 100 mg of acetanolum deanol, 100 mg of phenylbutazone and 20 mg of omeprazole. The resulting tablets meet the requirements of the State Pharmacopoeia XI and XII ed.

Example 17. Analogously to example 16, 105 g of deanol aceglumate, 150 ml of purified water are loaded into an apparatus with a stirrer. To the resulting solution, add 20 g of hydroxypropyl cellulose, mix thoroughly and add 155 g of ranitidine, 53 g of ketoprofen, 52 g of starch, 300 g of microcrystalline cellulose, mix thoroughly until a homogeneous mass is formed. 15 g of silicon dioxide, 25 g of polyvinylpyrrolidone (collidone 25), 80 g of milk sugar, 52 g of magnesium carbonate are gradually added to the mass. The mixture is thoroughly mixed and wiped through a sieve to obtain granules of not more than 2 mm. The resulting granules are dried to a residual moisture content of not more than 1.0%. Dry granules, representing a powder, are mixed with 30 g of magnesium carbonate, 6 g of silicon dioxide and 5 g of stearic acid. Mix thoroughly until smooth and tablet. 1000 tablets are obtained containing 100 mg of ranitidine and 50 mg of ketoprofen in a single tablet of 100 mg of Aceglumate deanol. The resulting tablets meet the requirements of the State Pharmacopoeia XI and XII ed.

The shelf life of all developed dosage forms given in examples 1-17, at least 2 years.

All the claimed combined dosage forms have anti-inflammatory, anti-ulcerogenic, gastro- and enteroprotective effects.

Thus, the positive effect and industrial applicability of the invention lies in the possibility of obtaining new highly effective, combined drugs with anti-inflammatory, anti-ulcerogenic, gastro- and enteroprotective effects by affordable methods.

Claims (6)

1. A drug with anti-ulcerogenic, gastroprotective and enteroprotective effects, which is a deanol aceglumate. 2. The combination of deanol atseglumat and anti-inflammatory drug or deanol atseglumat and anti-inflammatory and anti-ulcer drugs that has anti-inflammatory, anti-ulcerogenic, gastroprotective and enteroprotective effects or anti-inflammatory, antiulcer, anti-ulcerogenic, gastroprotective and enteroprotective. 3. The combination according to claim 2, characterized in that it is made in the form of a solid dosage form, or in the form of capsules, or in the form of a powder for the preparation of a solution or suspension for drinking, or in the form of an injection solution, or in the form of a soft dosage form. 4. The combination according to claim 3, characterized in that the solid dosage form is made in the form of tablets or powder or in the form of a powder for the preparation of a solution or suspension for drinking. 5. The combination according to claim 3, characterized in that the soft dosage form is made in the form of candles. 6. The combination according to claims 2-5 for the production of drugs for the treatment of acute rheumatism, acute, subacute and chronic rheumatoid polyarthritis, non-specific infectious polyarthritis, ankylosing spondylitis, gout, psoriatic arthritis, erythema nodosum, minor chorea and other diseases associated with pain and inflammation.