RU2531092C1 - Method for preparing antiulcer gastroretentive agent - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the pharmaceutical industry, particularly to a method for preparing an antiulcer gastroretentive agent. A method for preparing the antiulcer gastroretentive agent by extracting asp bark in the certain environment, adding guar gum (guar) and carboxymethyl cellulose sodium salt (Na-CMC) in the certain environment to the dry asp bark extract; the prepared mixture is agitated until smooth and subject to dry granulation by pre-moulding; the mould bars are ground, and the prepared granulate is tabletted.

EFFECT: method for preparing the antiulcer gastroretentive agent provides higher antiulcer action ensured by using the more advanced dosage form having a higher dose of the dry asp bark extract able to be retained in the stomach for a long time and regulating the release of the active substance.

19 dwg

Description

The invention relates to the field of pharmacy and relates to a method for producing anti-ulcer gastroretive agent.

The search and study of new highly effective treatments for diseases of the gastrointestinal tract, including in the form of modern dosage forms with controlled release of drugs, is one of the urgent problems of modern gastroenterology. Despite the significant successes achieved in the field of synthetic antiulcer drugs, plants continue to be one of the promising sources of new biologically active compounds. For example, herbal preparations such as Vikair, Vicalin, Befungin, etc., which have anti-ulcer action (Mashkovsky M.D. Medicines. 15th ed., Revised., Revised and widely used) are widely used. . M.: LLC "Publishing House New Wave", 2005. 1200 p., Ill.).

Among the plant raw materials containing biologically active substances (BAS) with antiulcer action, the bark of the common aspen (Populus tremula L.), willow family (Salicaceae), and the poplar genus (Populus), which contains significant amounts of various phenolic compounds (phenological glycosides, phenolic acids, flavonoids) (Turetskova V.F. Theoretical and experimental substantiation of the rational use of the bark and shoots of sea buckthorn and buckthorn buckthorn bark and aspen bark: abstract of diss. ... Dr. Pharm. Sciences. Perm, 2001. 49 p.).

There is a method of producing an anti-ulcer agent from willow leaves in the form of an infusion, which is an aqueous extract from dried ground willow leaves, obtained by extracting raw materials with boiling water at a ratio of 1: 9, infusion time 30 minutes, cooling 45 minutes (Patent No. 2187322).

The disadvantages of this method are:

- the inability to use in an industrial environment, due to the chemical and microbiological instability of water extracts during storage (shelf life of not more than 1 day);

- the use of boiling water in the manufacturing process, which can lead to the destruction of the main biologically active substances (phenological glycosides) of this type of raw material.

A known method of obtaining funds with anti-ulcer action from dry aspen bark in the form of an extract obtained by multistage countercurrent extraction with 40% ethyl alcohol, followed by purification, thickening under vacuum at a temperature of 40-50 ° C and drying in a vacuum cabinet brand СШВ-45 at temperature 40-50 ° C (Patent No. 2086251).

The disadvantages of this method are:

- the inability to ensure high accuracy of dosing, since it is not a metered drug;

- the presence of a bitter taste and dampness during storage. The closest to the achieved technical result, the prototype is a method of obtaining funds with anti-ulcer action from the extract of dry aspen bark in the form of a tablet dosage form (Patent No. 2144899).

The disadvantages of this method are:

- a low dosage of the active component, in connection with which there is a need for three times the use of the drug per day, which creates certain inconveniences in the treatment of such a chronic disease as peptic ulcer;

- the difficulty of obtaining a stable product, due to the high dampness;

- an insignificant period of the active substance in the stomach, which reduces the effectiveness of the treatment of peptic ulcer of this section of the gastrointestinal tract.

The technical result of the claimed invention is the expansion of the range of antiulcer preparations of plant origin, through the use of a more advanced gastroretensive dosage form, capable of staying for a long time within the stomach and regulate the release of the active substance.

The technical result is achieved by the fact that guar gum (guar) and carboxymethyl cellulose sodium salt (Na-CMC) are added to the dry aspen bark extract in a mass ratio of 35: 17.5: 17.5, respectively, the resulting mixture is mixed until a homogeneous mass is exposed to dry granulation by pressing briquettes at a pressure of 120 MPa, which are ground and the resulting granulate is tabletted at a pressure of 40 MPa.

The authors propose a method for producing an antiulcer gastroretive agent, which allows to increase the gastroprotective activity of dry aspen bark extract due to its long retention time within the stomach and regulation of the release of active substances.

The method is as follows.

The method is illustrated in figures 1-19.

Figure 1 presents a comparative assessment of the viscosities of 0.1% polymer solutions and their compositions.

Figure 2 presents the dependence of the viscosity of 0.1% solutions of the studied polymer compositions on the ratio of components.

- среднее значение; $${\Delta }^{\overline{x}}$$

- доверительный интервал.Figure 3 presents data on the study of the technological properties of synergistically interacting compositions, where $$\overline{X}$$

- average value; $${\Delta }^{\overline{x}}$$

- confidence interval.

In figure 4, four prescriptions with dry aspen bark extract are proposed, the composition of which included various amounts of the studied pairs of polymer compounds.

- среднее значение; $${\Delta }^{\overline{x}}$$

- доверительный интервал.Figure 5 presents data on the study of the technological properties of the studied formulations with dry aspen bark extract, where $$\overline{X}$$

- average value; $${\Delta }^{\overline{x}}$$

- confidence interval.

Figure 6 shows the change in the ratio of height to diameter of model tablets (mm) obtained by direct compression after aging in various environments.

7 shows the volume (mm ² ) of model tablets obtained by direct compression at various pressures.

On figa presents a diagram of the increase in volume S (%) of model tablets obtained by direct compression after exposure to water purified for 1 hour.

On figb presents a diagram of the increase in volume S (%) of model tablets obtained by direct compression, after keeping in a hydrochloric acid solution of 0.1 and for 1 hour.

Figure 9 presents the dissolution profile of model tablets with dry aspen bark extract in various environments.

Figure 10 presents a diagram of the diameter change of model tablets with dry aspen bark extract when swelling in various environments.

- среднее значение; $${\Delta }^{\overline{x}}$$

- доверительный интервал.Figure 11 shows the particle size distribution of tableted masses obtained by dry granulation, where $$\overline{X}$$

- average value; $${\Delta }^{\overline{x}}$$

- confidence interval.

On Fig presents the dependence of the flowability of the combined fractions of tableted masses on the used pressing pressure.

On Fig presents data on the change in the ratio of height to diameter and volume of developed gastroreactive tablets with aspen bark extract dry for 24 hours (in this table, the sign “-” means a decrease in volume, “+” means an increase in volume).

On Fig presents the dissolution profile of the developed gastroreactive tablets with extract of aspen bark dry for 24 hours.

On Fig given a table of analysis of the obtained tablets according to the indicators "Description", "Average weight" and "Microbiological frequency" for one and a half years of storage.

- среднее значение; $${\Delta }^{\overline{x}}$$

- доверительный интервал.On Fig translated data on the quantitative content of the main groups of biologically active substances during one and a half years of storage, where $$\overline{X}$$

- average value; $${\Delta }^{\overline{x}}$$

- confidence interval.

- среднее значение; $${\Delta }^{\overline{x}}$$

- доверительный интервал.On Fig presents the main indicators of gastroretensive dosage forms, such as "swelling" and the dissolution profile during one and a half years of storage, where $$\overline{X}$$

- average value; $${\Delta }^{\overline{x}}$$

- confidence interval.

On Fig presents the effect of course administration of the extract of aspen bark pelletized “GR” and tablet mixtures on the development of indomethacin ulceration in the gastric mucosa in female mice CD-1 (X ± m) (in this table, the numbers of the compared groups are indicated before the significance level p) .

Fig. 19 shows the effect of the course administration of an aspen bark extract of tabletted “GR” and tablet mixtures on the development of indomethacin ulceration in the gastric mucosa in female mice CD-1 (X ± m) (in this table, the numbers of the compared groups are indicated before the significance level p) .

An example of the method

350 g of crushed extract of dried aspen bark, obtained using multistage countercurrent extraction with 40% ethyl alcohol, followed by purification, concentration under vacuum at a temperature of 40-50 ° C and drying in a vacuum oven at a temperature of 40-50 ° C, are thoroughly mixed with 175 g guar (GOST 5860-75) and 175 g of Na-CMC (ND 42-11281-00). The resulting mixture is stirred until a homogeneous mass. Briquettes with a diameter of 15 mm are obtained from this mixture in a P-10 hydraulic press at a pressure of 120 MPa, which are grinded using a centrifugal grinder. The tabletted mixture is dosed at 0.70 g, and tablets with a diameter of 12 mm are obtained on a P-10 hydraulic press at a pressure of 40 MPa.

The resulting tablets have an average weight of 0.696 g, a deviation from the average weight of 0.14-3.30%; the content of phenolic acids is 0.0186 ± 0.0006 g; the content of phenological glycosides is 0.0670 ± 0.0020 g; the indicator "swelling" is more than 15 mm; dissolution profile - after 1 hour 21.15 ± 2.15%, 4 hours - 36.64 ± 2.12% and 8 hours - 56.32 ± 2.21%; according to microbiological purity correspond to category 3B.

The inventive method for producing an antiulcer gastroretive agent with aspen bark extract dry has the following advantages over the well-known: increasing the antiulcer effect due to the use of a more advanced dosage form with an increased dose of dry aspen bark extract, which can stay for a long time within the stomach and regulate the release of the active substance.

To study the synergistic effect, we compared the viscosity of aqueous 0.1% polymer solutions and compositions of individual polymers in a 1: 1 ratio, providing a similar solution concentration (Hoikhman D., Gromova L.I., Sala Y. Study of synergistic gelation of the guar gellan composition in water solutions // Chemical and Pharmaceutical Journal. 2004. T.41. No. 5. S.42-45).

An analysis of the data presented in the table (Fig. 1) indicates that only four pairs of polymer compounds (No. 1, 2, 7, and 13) exhibit synergistic properties, with the most significant increase in viscosity observed in the joint presence of PVP with Na-CMC and guar with Na-CMC (pairs of polymers No. 7 and No. 13).

A study of the dependence of the viscosity of aqueous solutions of 0.1% on the mass ratios of polymers suggests that in the first pair of polymers, with an increase in the number of PVPs, the viscosity increases, the maximum value of the viscosity of the polymers appears when the ratio of the components is 1: 4. In contrast, the maximum viscosity in the second pair of polymers is provided when the ratio of components 1: 1 (figure 2).

An analysis of the technological properties of the studied pairs of polymers allowed us to conclude that the first pair has poor flowability (3.37 ± 0.07 g / s), the second pair has very poor flowability (2.38 ± 0.01 g / s). The first pair has a twice lower indicator of "bulk density" than the second (316.61 ± 3.55 kg / m ³ and 673.74 ± 5.23 kg / m ^3, respectively); high mass loss upon drying (11.63 ± 0.24% and 8.40 ± 0.40%, respectively), high hygroscopicity (21.59 ± 0.08% and 22.32 ± 0.89%, respectively). It should be noted that the first pair of polymers has a compressibility higher than “very good” (189.47 ± 1.81 N), and the second pair is only satisfactory (33.60 ± 1.42 N) (Fig. 3).

Due to the fact that both pairs of polymer compounds can be used to obtain tablets with gastro-regenerative effect, four formulations were developed and obtained, which included a therapeutic dose of dry aspen bark extract 0.35 g and various amounts of the studied pairs of polymer compounds (Fig. .four).

Summing up the data of studies on the technological properties of tablet mixtures for further study, two prescriptions were selected - No. 1 and No. 4. These prescriptions have higher values of the indicator of "bulk density" (593.7 ± 13.15 kg / m ³ and 741.93 ± 6.42 kg / m ^3, respectively) and a lower value of the indicator of mass loss upon drying (5.59 ± 0.22% and 5.62 ± 0.13%, respectively) compared with other prescriptions (figure 5).

Since gastroretentive tablets should simultaneously increase in size to 15 mm or more within 1 hour, and also provide a gradual release of active substances, studies were conducted to study the “swelling” rate and dissolution profiles of model tablets with a diameter of 12 mm, made on the basis of tabletting mixtures according to the prescriptions No. 1 and No. 4 in the pressure range from 40 MPa to 120 MPa.

The determination of the “swelling” indicator of the studied tablets was carried out on a device for determining the solubility of tablets AK-7 M-00-00 PS (“Rotating basket”) in two environments (hydrochloric acid solution 0.1 pi purified water), the volume of the medium is 900 ml, temperature - 37 ± 0.5 ° С, basket rotation speed - 100 rpm. The experiment time was one hour (corresponds to the residence time of the tablet in the stomach).

The “swelling” indicator was considered from two positions: the ratio of the height to the diameter of the tablet after contact with the liquid medium for one hour of exposure in the dissolution medium (mm) and as the increase in tablet volume S (%), which was calculated as the ratio of tablet volume (V ₁ ) after one hour of incubation in the dissolution medium to the initial volume (V ₀ ) (Hoikhman D., Gromova LI, Sela J. Investigation of the synergistic gelation of the guar-gellan composition in aqueous solutions // Chemical-Pharmaceutical Journal. 2004. T.41 . No. 5. S. 42-45).

It was revealed that the maximum increase in tablets within one hour provides prescription No. 4. The diameter of tablets made by this recipe in purified water exceeds 15 mm, regardless of the pressing pressure. In an acidic medium of size 15 mm, only tablets obtained according to prescription No. 4 are reached at a compression pressure of 40 MPa (Fig. 6).

The maximum increase in not only the diameter, but also the volume of the tablet is achieved by obtaining model tablets with aspen bark extract dry according to the prescription No. 4 at a compression pressure of 40 MPa (volume increase over 1 hour varies from 190 to 263% in purified water and from 180 to 221 % in hydrochloric acid, a solution of 0.1 n) (Fig.7, 8A, 8B).

Given the above, to study the dissolution profiles, model tablets were made only at a pressure of 40 MPa.

The determination of the dissolution profiles of model tablets obtained according to the prescriptions No. 1 and No. 4 was carried out according to the requirements of the General Pharmacopoeia Monograph 42-0003-00 “Dissolution” on the device for determining the solubility of tablets AK-7 M-00-00 PS (“Rotating basket”). Purified water and 0.1 N hydrochloric acid solution were used as the dissolution medium, the volume of the medium was 900 ml, the temperature was 37 ± 0.5 ° C, and the basket rotation speed was 100 rpm. Sampling was carried out after 1 hour for 8 hours. After selection, the dissolution medium was replenished in the same volume. The selected samples were cooled at room temperature, in which the concentration of phenolic acids was determined by the direct SPS method, as the most difficult soluble group of the biologically active substances in the extract.

The analysis of the dissolution profiles of model tablets (Fig. 9), made according to the formulation No. 1, at a pressure of 40 MPa, indicates that the test substances are completely released within 4 hours in purified water and 6.5 hours in an acidic environment. The release of the active ingredient from tablets obtained by prescription No. 4, at a pressure of 40 MPa, is slower over 8 hours.

Of fundamental importance in the development of gastroretentive tablets is the preservation of the size of the swollen tablet for a long time necessary for its retention within the stomach. Therefore, in parallel with studying the dissolution profile, the diameter of model tablets was measured for 8 hours.

A comparative assessment of the diameter of tablets made according to prescriptions No. 1 and No. 4, after swelling in various media, indicates that only model tablets obtained according to 8 hours are reached and retained for 8 hours by the model tablets obtained by recipe number 4 (figure 10).

Given the fact that the selected tablet mixture (recipe No. 4) has poor flowability and compressibility above the “very good” indicator, the possibility of using the dry granulation method to increase flowability was studied.

The tablettable mixture obtained according to recipe No. 4 was pressed under various pressures (from 40 MPa to 120 MPa) in a 15 mm diameter matrix on a P-10 hydraulic press into briquettes. Briquettes were ground on a centrifugal grinder, grade LU-2601, to obtain a large powder. The study of the fractional composition was carried out according to the methodology GF XI ed. General Pharmacopoeia Monograph “Determination of fineness of powders and sieves” using a standard set of sieves, followed by weighing each fraction.

Studies have shown that the masses obtained by dry granulation have a polydisperse composition with a predominance of a coarse fraction (from 17.95% to 24.86%), as well as the smallest fraction (from 20.15% to 33.75%) (Fig. eleven).

The flowability of the combined fractions obtained at compression pressures from 40 MPa to 120 MPa was evaluated by a standard method.

A comparison of the obtained data indicates that the granular masses obtained under pressure from 40 MPa to 120 MPa have satisfactory flowability (from 3.96 g / s to 5.76 g / s) (Fig. 12).

The granulate obtained was dosed with a TK-3 dispensing spoon of 0.70 g each and tablets 12 mm in diameter were obtained on a P-10 laboratory hydraulic press at a pressure of 40 MPa.

The in vitro justification of the gastroretentive and prolonged action of the tablets was carried out on the basis of studying dissolution profiles for 24 hours while measuring the diameter of the swollen tablets.

The study was carried out on a device for determining the solubility of tablets of the type "Rotating basket".

The analysis of the data on the study of the indicator "swelling" shows that in an acidic environment there is a gradual increase in the volume of tablets, the maximum volume is reached after 14 hours - 2833.85 mm ³ , while the increase in the volume of tablets is + 417.82%. After which there is a gradual decrease in this indicator (Fig.13).

The results of the simultaneously measured diameter of the tablets show that the required 15 mm necessary for their retention within the stomach is achieved after 1 hour in an acidic environment and stored for 22 hours. The maximum diameter of the tablets is provided after 14 hours (Fig. 13).

A study of the dissolution profile of the obtained tablets shows that almost complete release of phenolic acids is observed 24 hours after being in an acidic medium of 99.12 ± 1.21%, while within the first hour 20.13 ± 0.15% is released, 4 hours - 36 , 64 ± 2.12% and 8 hours - 56.32 ± 2.21% (Fig. 14).

The stability of the obtained drug was studied according to indicators regulated by the requirements of the Global Fund of XIth ed., General Pharmacopoeia Monograph “Tablets” and OSTU 91500.05.001-00 “Quality standards of medicines. Basic Provisions, ”and such important indicators of gastroretensive dosage forms as“ swelling ”and the dissolution profile during natural storage at a relative humidity of 40% and a temperature of 15-25 ° C for a year and a half.

From the data presented on Fig it follows that the indicators, the average weight of the tablets and microbiological purity, meet the requirements and do not change for a year and a half.

A study of the stability of a tabletted preparation according to the content of two groups of biologically active substances (phenolic acids and phenological glycosides by the SPS method) showed that the content of active substances practically does not change during a year and a half of storage (Fig. 16).

The study of the indicator "swelling" and the dissolution profile of the tablets showed that by increasing their volume in the medium corresponding to the pH of the stomach, they can have a targeted gastroprotective effect with the gradual release of active substances (Fig. 17).

A comparative evaluation of the pharmacological activity of the tablet mixture of dry aspen bark extract and the tablet “GR” mixture used in the preparation of gastroretensive tablets was carried out on a model of indomethacin ulcerogenesis on 41 outbred CD-1 female mice.

Indomethacin ulcer. The ulcerogenic effect of non-steroidal anti-inflammatory drugs (NSAIDs), used according to vital indications as part of cardiac and antirheumatic therapy, determines the relevance of the development of preventive and therapeutic gastroenterological measures. Among non-steroidal anti-inflammatory drugs, indomethacin has the most pronounced ulcerogenic effect, which served as the basis for choosing this drug as a damaging agent.

Indomethacin damage to the gastric mucosa in mice was reproduced by twice intragastric administration of indomethacin at a dose of 20 mg / kg twice with an interval of 4 hours, the number and nature of destructive changes in the mucosa was determined after 18 hours. Prophylactic course administration (4 days) of the studied substances was carried out orally through the probe once daily .

The last injection of substances occurred 1 hour before the onset of the action of the ulcer-forming factor.

Performance criteria for antiulcer activity

At the end of the experiments, animals were euthanized by the craniocervical dislocation method, the stomachs were removed, opened according to the lesser curvature, washed with cold saline and macroscopically using a magnifier in bright light, the number and area of destruction were determined, which were differentiated into point (less than 1 mm) and large (more 1 mm). The average number of ulcerations per animal in the group was calculated, the percentage of animals with ulcers (Khadzhai Y.I. Pharmacological study of natural flavonoids, furochromes and coumarins: Abstract of thesis ... Dr. med. Sciences. Kharkov, 1969. 24 s).

The Pauls Index (PI) was determined as an integral indicator of the amount of destruction by the formula:

$$\mathrm{AND}P=\frac{\mathrm{FROM}Rednee\mathrm{to}\mathrm{about}l-\mathrm{at}\mathrm{about}\mathrm{I\; am}s\mathrm{at}\times \%\mathrm{well}\mathrm{and}\mathrm{at}\mathrm{about}tnsx\mathrm{from}\mathrm{I\; am}s\mathrm{at}\mathrm{but}m\mathrm{and}}{\mathrm{one\; hundred}\%}$$

Antiulcer activity (PA) of drugs was determined as the ratio of the Pauls index in the control group to the Pauls index in the experimental group. The test agent was considered active if the PA was 2 or more units (Pauls F., Wick AM, Mac. Key EM et al. An assau method for anti ulcer substances // Gastroenterology. 1947. No. 8. P.774-782 .; Dobryakov Yu.I. Screening method for evaluating the antistress effect of drugs // Stress and Adaptation: Abstracts of the All-Union Symposium. Chisinau, 1978. P.172-173).

Model of indomethacin neoplasm

The following groups were used on the model system of indomethacin damage to the gastric mucosa of outbred female mice CD-1:

1. Control group (n = 11) - mice received purified water in a volume of 0.4 ml intragastrically through a probe once daily for a prophylactic course for 4 days, the last injection occurred 1 hour before the use of indomethacin.

2. A tablet mixture of 100 mg / kg (n = 10) - mice received the drug in a volume of 0.4 ml of purified water by intragastric daily prophylactic course for 4 days, the last injection occurred 1 hour before the use of indomethacin.

3. The “GR” tablet mixture of 100 mg / kg (n = 9) - the mice received the drug in a volume of 0.4 ml of purified water by the intragastric daily prophylactic course for 4 days, the last injection occurred 1 hour before the use of indomethacin.

4. The “GR” tablet mixture of 200 mg / kg (n = 11) - the mice received the drug in a volume of 0.4 ml intragastrically daily with a prophylactic course for 4 days, the last injection occurred 1 hour before the use of indomethacin.

The double use of indomethacin contributed to the development of all types of ulcerative destruction in the gastric mucosa in 100% of the mice of the control group, while the average number of ulcers per animal was 18.09 ± 1.47. The data obtained indicate a complete reproduction of the model situation (Fig. 18, 19).

The use of a tablet mixture at a dose of 100 mg / kg contributed to a significant reduction in the number of ulcerative destruction. It should be noted a statistically significant decrease in both the average number of ulcers per animal by 1.7 times, and the number of strip-like - by 3.7 times (p <0.05), large - 6.3 times and point ulcers - by 1.4 times (p <0.05). In addition, there was a decrease in the number of mice with large (p <0.01) and stripe-shaped (p <0.01) destructions but compared with the same parameters of the control group (Fig. 18, 19). At the same time, the number of animals with the presence of gastritis and the manifestation of edema decreased significantly (2.7 times). However, the use of the tablet mixture did not reveal the gastroprotective effect of the aspen bark extract in full: the antiulcer activity was 1.7 points on this model system.

When analyzing the rest of the results, it was found that the gastroretensive dosage form (“GR” tablet), administered as a prophylactic course at doses of 100 and 200 mg / kg intragastrically in a similar mode, limited the formation of both the number of animals with ulcers (p <0.01), so and all types of ulcerative destruction that arose after exposure to indomethacin. Thus, the use of the “GR” tablet mixture at a dose of 100 mg / kg led to a decrease in the number of animals with point ulcers by 22.2%, their number - by 3.6 times (p <0.01), the number of mice with strip ulcers - 79.8%, their number - 24.8 times (p <0.01) compared with those of untreated animals. The absence of large ulcers in the mucosa of animals of this group was revealed (Fig. 18). As a result, the average number of ulcerative destruction decreased 4.7 times (p <0.01) relative to the same indicator of control animals.

In addition, it is necessary to note statistically significant differences in the studied parameters of the “GR” tablet mixture at a dose of 100 mg / kg, such as the number of animals with ulcers, the number of large and spot ulcers, the average number of ulcers, the percentage of animals with strip ulcers compared to those application groups of the tablet mixture.

An analysis of the data obtained in the study of gastroretensive dosage form revealed an identical pattern: increasing the dose to 200 mg / kg contributed to an increase in antiulcer activity to 8.8 points. The revealed positive change in the effect was summarized from the aggregate of statistically significant results of all the studied indicators. So, there was a decrease in the average number of animals with ulcers (p <0.01) of those indicators of animals treated with the tablet (p <0.01) mixture. The gastroprotective effect was realized in a statistically significant decrease in the number of point destruction, the average number of ulcers per animal compared with similar indicators in the group of tablets tabletted at a dose of 100 mg / kg, while the suppression of the genesis of strip ulcers was recorded. As a result of the study, the antiulcer activity of the “GR” tablet mixture was revealed, which amounted to 6.0 points at a dose of 100 mg / kg; at a dose of 200 mg / kg - 8.8 points.

Thus, in the model of indomethacin damage to the gastric mucosa in mice, a pronounced antiulcer effect was revealed when using the tablet “GR” mixture of aspen bark extract in doses of 100 and 200 mg / kg, which exceeded the similar activity of the compared tablet mixture, which confirms the rationality of the choice of excipients and the feasibility the development of a gastroretensive dosage form of a prospective antiulcer drug under study.

Claims (1)

A method of obtaining an antiulcer gastroretensive agent containing aspen bark extract dry, obtained using multistage countercurrent extraction with 40% ethyl alcohol, followed by purification, thickening under vacuum at a temperature of 40-50 ° C and drying in a vacuum oven at a temperature of 40-50 ° C characterized in that guar gum (guar) and carboxymethyl cellulose sodium salt are added to the extract in a mass ratio of 35: 17.5: 17.5, respectively, the resulting mixture is stirred until a homogeneous mass s, are subjected to dry granulation by pressing briquettes at a pressure of 120 MPa, which are ground and the resulting granulate is tabletted at a pressure of 40 MPa.

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