Gastro-resistant omeprazol microgranules and process for production thereof

The present invention relates to the pharmaceutical microgranules of omeprazole, protected by the action of gastric juice, which possess stability within a time frame, which corresponds to the pharmacological requirements, and to the process of obtaining these granules.

Omeprazole or 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -IH-benzimidazole, an anti-ulcer substance that reduces gastrointestinal acid secretion, is well known [1].

Omeprazole has a very low solubility in water, but in the basic solutions, on the contrary, it is well soluble and in the acidic environment it rapidly disintegrates. Its half-aggregation period is 10 minutes in aqueous solutions with a pH lower than 4.18 hours at a pH equal to 6.5, and approximately 300 days at a pH equal to 11.

Therefore, upon oral reception of omeprazole it is necessary to protect о such a pharmaceutical form of the active substance from the gastric juice by the form of gelatin capsules, pills or powders, to prevent any contact of the active substance with the acid medium until it is completely dissolved in intestine, where omeprazole will be absorbed; alias, until the pH of the environment exceeds 6.8.

The dissolution characteristic of omeprazole oral prescriptions in vitro, as well as the biological effect results obtained for humans with these oral prescriptions, consisting of protected granules, have been described [2].

However, it has been observed that ordinary intestinal granules do not possess sufficient stability over time to be used in a pharmaceutically effective form (gelatin capsules or pills in microgranules), because rapid disintegration of the active base has been observed, if they are deposited under the usual conditions of use. (room temperature 25 ° C, humidity between 40 and 75%) with the formation of harmful products of disintegration, as described, for example, in Acta Chemica Scandinavia, 43, 1989, 536-548 (Ame Brandstrom et al.).

In order to overcome these disadvantages, a process for obtaining omeprazole microgranules with a polymer coating, resistant to the action of gastric juice by mixing omeprazole and mannitol in the presence of the polymeric colloidal binder, was applied and the mixture was applied to the neutral granules and granules. then apply the polymeric protective layer with the subsequent application of the polymer layer, resistant to the action of the gastric juice, the flakes are extracted, dry and calibrate [3].

Then the microgranules, thus obtained, are usually protected by the action of the gastric juice, so that they correspond to the standards of dissolution and resistance to the action of the gastric juice, determined for the optimal oral reception of the product, ie the dissolution - more than 75% over 30 minutes in aqueous medium with pH 6.8 and resistance to the action of gastric juice - more than 85% over 2 hours in medium with pH 1.2. The microgranules described and the process for their preparation are the closest, in essence, to the present invention.

However, this process of obtaining possesses a series of serious shortcomings, both from the technical point of view and from the economic point of view. The first of these shortcomings is the need to prepare the composition, products and mixtures with the risk of general intoxication and instability in the manufacturing process. In addition it is necessary to use the specialized and expensive equipment, which increases the preface of the active base and leads to the cost of the extremely high end product for wide use worldwide, at the same time the cost of the daily treatment with the use of this product is much higher than the cost of the treatment with the use of the salt. bismuth and metronidazole or macrolide, which act as antacid agents and agents, which destroy Helicobacter pylori (agents responsible for most gastrointestinal ulcers).

The problem of the present invention is to develop a more economical process for obtaining omeprazole microgranules, and to obtain microgranules with a uniform omeprazole content.

To solve this problem, a process was obtained for obtaining omeprazole microgranules with polymeric coating, resistant to the action of gastric juice by mixing omeprazole and mannitol, in the presence of a polymeric colloidal binder, and then applied to the neutral granules of sugar, then starch. apply the protective layer of polymer, resistant to the action of gastric juice, the flakes are extracted, dried and calibrated, at the same time, the application of omeprazole and mannitol is carried out in the dry state by means of a binder solution of the hydroxypropylmethyl cellulose type with a high viscosity о 80% mass. of ethanol and 20% by mass. of water.

The invention also relates to omeprazole microgranules with polymer coating, resistant to the action of gastric juice, which confines a neutral core consisting of sugar and starch with a colloidal polymer layer and the active layer of omeprazole in combination with mannitol and polymer coating , the ratio of omeprazole to mannitol constitutes 1: 1.

The technical result consists in improving the uniformity of the omeprazole content in microgranules.

This result is obtained due to the fact that the application of omeprazole and mannitol is carried out in the dry state by means of the high viscosity polymer binder solution.

In accordance with the invention, omeprazole is used in powder form, diluted with о practically equal amount of mannitol until a stable homogeneous suspension is obtained, and ensuring uniformity of the omeprazole confinement when applied to the neutral core, consisting of a mixture of sugar and ami don.

Thus, the present invention relates to the stable microgranules of omeprazole, characterized in that they contain a neutral core, consisting of sugar and ami don, coated with an active layer, which confines omeprazole diluted with mannitol m practically equal amount, and the outer layer which protects against the action of gastric juice.

Diluted powder according to the invention represents a mixture of omeprazole, mannitol powder, sodium lauryl sodium sulfate and carboxymethyl starch.

Preferably, the blended powders have a relatively equal particle size, this size being less than 100 μ.

The practically equal size means that the omeprazole / mannitol powder mass ratio is 1, ie between 0.9 and 1.2.

Neutral kernels, consisting of sugar and starch in mass ratio: 4 wafers per 1 part of omeprazole powder, have an average diameter between 0.7 mm and 0.9 mm.

The active base layer or the active layer, applied to the neutral cores, will preferably have a thickness of approximately 100 to 300 pm (0.1 to 0.3 mm).

In order to ensure the active base during the preservation of the microgranules according to the invention, the humidity of the active layer is 1%, preferably less than 0.5%.

According to the invention, the outer layer confines the layer consisting of mannitol and binder, which isolates the core on which omeprazole is applied, and the outer layer, designed to protect the active layer from the action of gastric juice.

Preferably, hydroxypropylmethylcellulose (HPMC) is used as a binder when the layer, which is opposed to the gastric juice, includes hydroxypropylmethylcellulose phthalate (FHPMC) or anionic copolymers of methacrylic acid and talc.

In order to meet the criteria for dissolving omeprazole microgranules in vitro, according to which, at least, 75% omeprazole should be dissolved over 30 min, if the microgranules are introduced into a water medium with pH = 6.3 at 37 ° C, the initial mixture of omeprazole and mannitol is processed with approximately 10% carboxymethyl starch (EXPLOTAB® marketed by MENDELL) for the complete disintegration of the granules at pH = 6.8 and about 5% of surface-active substance, such as sodium lauryl sulfate, which improves dissolution of omeprazole m the intestine.

Moreover, the hydroxypropylmethylcellulose solutions (PHARMACOAT®, marketed by the company CHEN-ETSU), which have a high viscosity, of the order of 15 centipuas (15xl0 '³Ps) and used as a solution for mixing at least 80% ethanol and not more than 20% water, for example, mixing 10 water pipes to 90 ° 95 ° ethanol, and using small quantities with in order to limit that it is possible to contain the solvents and the water granules when obtaining the active granules, they are used as binder solutions for applying the active layer to the neutral core and then additional protection of mannitol.

When obtaining the omeprazole granules after the preliminary processing of the active omeprazole and mannitol granules by depositing sucrose syrup of 33% m mixture 44/56 mass of water and ethanol with the formation of the intermediate layer, the stable coating is applied to the action of the gastric juice consisting of hydroxypropylmethyl cellulose phthalate (HP 50R brand, marketed by SHIN-ETSU) in the form of a 7.5% solution, 80/20 mixture of acetone mass and 95 ° ethanol, at the same time, the overall mass of sucrose in the sugar syrup is 25% of the mass of the final coating, which protects against the action of gastric juice. This external layer can confine talc as a slip means.

During all the stages of application of the coatings the temperature of the granules is reduced between 32 and 38 ° C; between all the stages, the drying is carried out so that the soil content comes to be minimal and the final water content is less than 1% and ethanol - less than 2000 ppm.

Other features and advantages of this invention will become clearer in the light of the following examples.

Example 1. Process for obtaining microgranules containing 8.41% by mass of omeprazole. All indicated quantities are expressed in kg of dry mass of the final quantity equal to 237.80 kg of microgranules with omeprazole content of 84.1 mg / g of microgranules.

Compozifia

<td>Neutral granules of sugar and starch</td><td> 80.00</td>

<td>Active layer:</td><td></td>

<td>omeprazole</td><td> 20.00</td>

<td>Manita</td><td> 20.00</td>

<td>Carboxymethyl starch (CMA)</td><td> 4.00</td>

<td>Sodium Laurylsulfate</td><td> 2.00</td>

<td>Additional protective layer:</td><td></td>

<td>Manita</td><td> 50.00</td>

<td>sucrose</td><td> 8.00</td>

<td>HPMC 15 cents</td><td> 3.20</td>

<td>The layer that is resistant to gastric juice</td><td></td>

<td>FHPMC '</td><td> 32.00</td>

<td>talcum</td><td> 18.60</td>

237.80

The process according to the invention consists in that 20 kg of omeprazole is diluted with 20 kg of mannite in the presence of CMA and 2 kg of sodium lauryl sulphate and the obtained dry mixture is linked with 80 kg of neutral sugars and starch with a diameter between 0.7 and 0.9 mm, the 4% HPMC solution (1.6 kg) mixed with water (20 wafers) and 95 ° ethanol (80 wafers) in a rotary turbine with a slant bottom is applied to the active granules thus obtained with the help of 50 kg of sawdust, with the subsequent processing of the granules thus obtained with 33% sugar syrup (8 kg sucrose), which consists of 44 ponds of water to 56 pips of 95 ° ethanol, and finally, the coating is applied, protecting against the action of the juice. gastric, by loading 32 kg of FHPMC in the form of 7% solution in a mixture of 80 95 ° ethanol wafers to 20 acetone wafers.

The granules thus obtained resist the gastric juice action more than 85% in the environment with a pH equal to 1.2, because over 2 h at 37 ° C the amount of omeprazole not released in this medium is 91.7%. In aqueous medium with pH = 6.8 the dissolution of the granules over 30 minutes has the omeprazole content of 92%, ie the quantity greater than 72%, which represents the minimum allowable standard.

At the end of 12 and 24 months the corresponding values ​​of the resistance to gastric juice acfion is 92.1% and 92.8%, and the dissolution at pH equal to 6.8 is achieved at 91.4% and 93.8% in the same working conditions.

Moreover, the very light beige color of the granules, which are kept in gelatin capsules at room temperature and the humidity of the environment (60%) in glass bottles, covered with a protective stopper and containing a drying agent, remains unchanged in within at least 24 months.

Example 2. Stability research

The stability of omeprazole was investigated in 4 groups of gelatin capsules, including microgranules according to the invention, and in the о microgranule group. Below are the data related to the research of the sample groups, the storage conditions, the methods of analysis and the results.

THE RESEARCH OF THE TRIAL GROUPS

Gelatin capsules with omeprazole

C458-1-2, C458-1-6, C458-2-3 and C458-2-4

Omeprazole microgranules

UQM 001-3

Date of manufacture | Storage time

<td></td><td></td><td>(months)</td>

<td>C458-1-2,</td><td>June 1983</td><td> 36</td>

<td>C458-1-6,</td><td>February 1984</td><td> 36</td>

<td>C458-2-3</td><td>September 1984</td><td> 24</td>

<td>C458-2-4</td><td>October 1984</td><td> 24</td>

<td>UQM 001-3</td><td>October 1990</td><td> 3</td>

2. CONDITIONS OF KEEPING

-25 ° C - relative humidity 60%

-30 ° C - relative humidity 30-40%, 60%

-37 ° C - relative humidity 20-30%, 90%

-50 ° C - relative humidity 80%

- refrigerator.

3. PROBLEM ANALYSIS

a. Gelatin capsules

Solution test

A. - For the numerical determination of omeprazole the contents of 5 gelatin capsules were deposited in a graduated retort with the volume of 250 ml, then 200 ml of methanol-water ammonia solution (95/5) were deposited and they were kneaded in a magnetic stirrer for 30 min. With the help of the solvent the volume was brought up to the marking. 10 ml of dichloromethane were filtered and diluted in the 100 ml retort and the volume was brought up to the mark with the methanol-ammonia-dichloromethane solution (24/1/75).

В - for the determination of the disintegration products the contents of two gelatin capsules were dissolved in 8 ml of methanol-ammonia solution (95/5) and mixed with the magnetic stirrer for 30 min. 2.5 ml of filtrate from 100 ml of dichloromethane was immediately injected into the chromatograph.

Equipment and conditions

- High efficiency liquid chromatography apparatus CLHP equipped with a UV detector

- Silica precolonette, 7 pm, 15 mm long and 3.2 mm internal diameter (Brownlee or equivalent).

- Colonel Lichrosorb Si 60, with 5 pm with length 124 mm and internal diameter 4 mm (Hibar Merk or equivalent).

- Flow speed: Iml / min

- The indications are written at 280 nm

- Injection: 40 pm.

System control

After the stability of the baseline has been achieved, the system is controlled as follows:

Standard omeprazole is dissolved in 5 ml and 5 ml of the corresponding sulfur H 168/66 (formula shown below) in 100 ml mobile phase. The injection of 40 ml takes place several times, until a constant refining time is obtained (the difference between two injections &lt;1%).

The refining time of omeprazole is 10 min and the refining time of the H 168/66 sulfone - 8 min.

b. Microgranule

Determination of the percentage content of omeprazole in microgranules

The content of omeprazole in microgranules is determined using ultraviolet spectrometry after separation by high-efficiency liquid chromatography.

Live reactions

- Acetonitrile for CLHP (for example, CARLO ERBA no. 412409)

- Phosphate of dibasic sodium (Na₂HPO4)

- Monobasic sodium phosphate (Na₂HPO4, H₂A)

- Distilled water

- Reference substances: omeprazole.

Instruments

Liquid chromatography apparatus equipped with a UV detector (280 nm):

* 2 stainless steel columns in set:

- pre-colon: length 1.5cm -0 internal 3.2 mm - grain size 7pm

- colon: length 12.5 cm - 0 internal 4 mm - grain size 5 pm * Staging phase: Lichrosorb RP18 * Injection system: for the quantity of 20 ml (eg WISP 712 automatic injector).

* Integrator: LCI 100 PERKIN ELMER or WATERS 645 DATA MODULE

Testing the resistance to the action of gastric juice and dissolution

The microgranules were mixed for 2 h 30 min under favorable conditions at constant temperature (37 ° C ± 0.5 ° C) in a dissolution apparatus.

apparatus

The dissolving device used is a pallet machine, described in the European Pharmacopoeia.

Turning speed: 100 rpm

Volume used: 500 ml of medium with pH 1.2

Add 500ml of medium with pH 7.6.

averages

Environment I: Acidic environment

2 g of sodium chloride and 7 ml of concentrated hydrochloric acid (37%) are introduced into a retort with volume of IL. Make up the volume until marked with purified water. Stir until dissolved. The pH of this solution should be 1.2 ± 0.05.

IL-Medium pH 7.6 (for addition).

Dibasic sodium phosphate solution (Na₂HPO₄) 0.235 M.

1 L of solution for 2 vessels is prepared.

4. RESULTS AND CONCLUSIONS

The results are summarized in the following tables.

In determining the confinement of impurities in all sample groups, two main impurities were found. In the tables with the obtained results they are marked by I and I '.

A: Retention period (in months)

В: Storage conditions - ° C. Relative humidity

C: Appearance

Gelatine capsules with omeprazole, group C 458-1-2

Table 1

<td rowspan="2">A</td><td colspan="2" rowspan="2">В</td><td rowspan="2">c</td><td rowspan="2">D</td><td rowspan="2">E</td><td rowspan="2">I %</td><td colspan="2">F</td>

<td>I ' %</td><td>Alfie %</td>

<td> 0</td><td></td><td></td><td>of</td><td> 6</td><td> 20.3</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td> 6</td><td> 25</td><td> 60</td><td>of</td><td> 5</td><td> 20.6</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td></td><td> 30</td><td> 60</td><td>of</td><td> 7</td><td> 20.1</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td></td><td> 50</td><td> 80</td><td>c</td><td> 7</td><td> 19.4</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.3</td>

<td> 12</td><td> 25</td><td> 60</td><td>of</td><td> 5</td><td> 20.5</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td></td><td> 30</td><td> 60</td><td>b</td><td> 6</td><td> 20.5</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td> 18</td><td> 25</td><td> 60</td><td>of</td><td> 6</td><td> 19.8</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td></td><td> 30</td><td> 60</td><td>b</td><td> 6</td><td> 20.1</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td> 24</td><td> 25</td><td> 60</td><td>of</td><td> 6</td><td> 20.7</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td></td><td> 30</td><td> 60</td><td>c</td><td> 7</td><td> 20.2</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.3</td>

<td> 30</td><td> 25</td><td> 60</td><td>of</td><td> 6</td><td> 20.3</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.3</td>

<td> 36</td><td> 25</td><td> 60</td><td>b</td><td> 6</td><td> 19.9</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.3</td>

<td></td><td></td><td> 60</td><td>of</td><td> 6</td><td> 20.8</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

a = white. b = colored. corresponds, c = colored. does not match.

Gelatin capsules with omeprazole, sample group C458-1-6

Table 2

<td rowspan="2">A</td><td colspan="2" rowspan="2">В</td><td rowspan="2">c</td><td rowspan="2">D</td><td rowspan="2">E</td><td colspan="3">F</td>

<td>I %</td><td>I ' %</td><td>Alfie %</td>

<td> 0</td><td></td><td></td><td>of</td><td> 5</td><td> 19.4</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td> 6</td><td> 25</td><td> 60</td><td>of</td><td> 5</td><td> 19.6</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td></td><td> 30</td><td> 60</td><td>of</td><td> 6</td><td> 19.5</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td></td><td> 50</td><td> 80</td><td>c</td><td> 7</td><td> 18.7</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.4</td>

<td> 12</td><td> 25</td><td> 60</td><td>of</td><td> 5</td><td> 19.2</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td></td><td> 30</td><td> 60</td><td>b</td><td> 6</td><td> 19.3</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td> 18</td><td> 25</td><td> 60</td><td>of</td><td> 5</td><td> 19.7</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td></td><td> 30</td><td> 60</td><td>b</td><td> 5</td><td> 19.1</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.3</td>

<td> 24</td><td> 25</td><td> 60</td><td>of</td><td> 6</td><td> 19.0</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td></td><td> 30</td><td> 60</td><td>c</td><td> 6</td><td> 19.2</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.3</td>

<td> 30</td><td></td><td></td><td>of</td><td> 6</td><td> 19.8</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td></td><td> 25</td><td> 60</td><td>of</td><td> 5</td><td> 19.3</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td> 36</td><td></td><td></td><td>of</td><td> 6</td><td> 19.8</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td></td><td> 25</td><td> 60</td><td>b</td><td> 5</td><td> 19.2</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

a = white. b = colored. corresponds, c = colored. does not match.

Gelatin capsules with omeprazole, sample group C458-2-3

<td colspan="8">Table 3</td>

<td>A</td><td>В</td><td>C</td><td>D</td><td>E</td><td></td><td>F</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>I</td><td>I '</td><td>Alfie</td>

<td></td><td></td><td></td><td></td><td></td><td> %</td><td> %</td><td> %</td>

<td> 0</td><td></td><td>of</td><td> &lt;5</td><td> 21.2</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td> 6</td><td>refrigerator</td><td>of</td><td> &lt;5</td><td> 20.9</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td></td><td> 25 60</td><td>of</td><td> 5</td><td> 21.1</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td> 12</td><td>refrigerator</td><td>of</td><td> 5</td><td> 20.8</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td></td><td> 25 60</td><td>of</td><td> &lt;0.5</td><td> 20.7</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td> 18</td><td>refrigerator</td><td>of</td><td> &lt;0.5</td><td> 20.6</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td></td><td> 25 60</td><td>of</td><td> 5</td><td> 20.4</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td> 24</td><td> 25 60</td><td>of</td><td> 6</td><td> 20.7</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

a = white;

Gelatin capsules with omeprazole, group C458-2-4

<td colspan="8">Table 4</td>

<td>A</td><td>В</td><td>C</td><td>D</td><td>E</td><td></td><td>F</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>I</td><td>I '</td><td>Alfie</td>

<td></td><td></td><td></td><td></td><td></td><td> %</td><td> %</td><td> %</td>

<td> 0</td><td></td><td>of</td><td> 6</td><td> 20.7</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td> 6</td><td> 25 60</td><td>of</td><td> &lt;5</td><td> 20.8</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td> 12</td><td> 25 60</td><td>of</td><td> 5</td><td> 20.3</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td> 18</td><td> 25 60</td><td>of</td><td> 6</td><td> 20.5</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td> 24</td><td>refrigerator</td><td>of</td><td> 5</td><td> 20.0</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.2</td>

<td></td><td> 25 60</td><td>b</td><td> 5</td><td> 20.4</td><td> &lt;0.5</td><td> &lt;0.5</td><td> &lt;0.5</td>

a = white; b = colored. corresponds;

Omeprazole microgranule UQM 001-3

A: Conservation period (in months)

B: Conservation conditions - ° C, Relative humidity

C: Appearance

D: Contained of omeprazole (mg / g)

E: Testing the resistance to gastric juice effusion

F: Dissolution test -%

<td>A</td><td></td><td>В</td><td>C</td><td>D</td><td>E</td><td>F</td>

<td> 0</td><td></td><td></td><td>of</td><td> 78.0</td><td> 95.9</td><td> 95.0</td>

<td> 1</td><td> 25</td><td> 55-65</td><td>of</td><td> 80.8</td><td> 93.9</td><td> 94.0</td>

<td></td><td> 30</td><td> 30-40</td><td>of</td><td> 81.2</td><td> 94.4</td><td> 95.0</td>

<td></td><td> 37</td><td> 20-40</td><td>of</td><td> 80.4</td><td> 97.0</td><td> 97.0</td>

<td></td><td> 37</td><td> 90</td><td>of</td><td> 77.6</td><td> 97.5</td><td> 100.0</td>

<td> 3</td><td> 25</td><td> 56-65</td><td>of</td><td> 81.4</td><td> 91.6</td><td> 92.0</td>

<td> 30</td><td> 30-40</td><td>of</td><td> 79.1</td><td> 95.7</td><td> 96.0</td>

<td> 37</td><td> 20-40</td><td>of</td><td> 80.2</td><td> 92.0</td><td> 93.0</td>

<td> 37</td><td> 90</td><td>c</td><td> 41.9</td><td> -</td><td> -</td>

a = white. b = colored. corresponds, c = colored. does not match

Gelatin capsules have high stability in the refrigerator and at 25 ° C, up to 36 months inclusive. All impurities have a concentration less than 0.50%.

The content of impurities increases relative to the rise in temperature and humidity and may be sufficient to cause the coloration of the granules.

The microgranules kept in high volume possess high stability within 3 months at room temperature and relative humidity 55-65%, at 30 ° C and relative humidity 3040%, at 37 ° C and relative humidity 20-30%; and within о month at 37 ° C and relative humidity 90%.

TERMENULDE VAL ABILITATE

In the light of the obtained results, the characteristic features are maintained within 36 months, provided that the temperature in this term will not exceed 25 ° C.

FEATURES

<td>1. Appearance</td><td>Solid gelatin capsules containing granules from not too white to more puffy or more beige without foreign particles.</td>

<td>2. Average mass</td><td>Approx. M v 23 5 mg ± 10%</td>

<td>3. The content of omeprazole</td><td>18.0-22.0 mg / gelatin capsule (90-110%)</td>

<td>4. Resistance to the action of the acid environment</td><td> &gt;85%</td>

<td>5. Release to pH 6.8</td><td>&gt; 75% Total content &lt;2.0%,</td>

<td>6. Disaggregation products</td><td>content of the individual product &lt;0.5%.</td>

Obviously, a skilled person in this field will be able to realize the invention in microgranules, in particular, using devices in the stage of formation of the coating, for example, using the false liquefied layer instead of the turbine with the flat bottom, described above, or using the methacrylic polymers, using as materials, which protect against the action of gastric juice (for example, Eudragit L 100-55 or L 30 D by Rohm &amp; Hass), or by using polymers, which shows resistance to the action of gastric juice, without evading from the context and scope of the present invention.

On the other hand, the invention is not intended to obtain microgranules by the usual method of extrusion, described in previous publications: these methods require the use of omeprazole in solution, in bulk with contained solvents and water, which are avoided in the given process, for the purpose. avoidance of the consequences of the instability of omeprazole under such conditions.