Pharmaceutic agent consisting of omeprazole granules and method of obtaining same

The subject of the invention is a pharmaceutical composition consisting of omeprazole microgranules protected in the stomach environment, showing periodic stability, as well as a method for the preparation of this agent. The invention therefore relates to a new stable formulation of omeprazole in the form of microgranules.

Omeprazole or 5-mctoxy-2 - /// 4-methoxy-3,5-dimethyl-2-pyridinyl / methyl / sulfinyl / -1H-benzimidazole, an anti-ulcer substance that reduces gastrointestinal acid secretion, is well known. It is described in Swedish Patent No. 7804231 (Aktiebolaget Hassie Fack).

It is known that omeprazole has very low water solubility but is easily soluble in alkaline solutions and that it degrades very quickly in an acidic environment. Its half-life is ten minutes in aqueous solutions with a pH less than 4, eighteen hours at a pH of 6.5 and about 300 days at a pH of 11.

When omeprazole is used orally, it is necessary to protect the galenical form of the active substance (capsules, tablets or powder) in the stomach environment so as to avoid any contact of this substance with the acidic environment at stomach level, completely ensuring

172 706 rapid dissolution in the intestinal environment in which omeprazole should be absorbed, i.e. as soon as the ambient pH becomes higher than 6.8.

Charakteer / stvkk rozniuzccaaia nostaai dduutnei omenraaolu - in the neoplasm. and also jj * · ε xuxxj, the results of bioavailability obtained in humans using such an oral form prepared from protected granules are described in Journal de Gastroenterologie Scandinave / 1985: 20 / suppl. 1θ8 /: 113-120, Pilbran A. Cederberg C /.

However, it has been found that classic gastro-resistant granules do not show periodic stability sufficient to be used in a satisfactory pharmaceutical form (capsules or microgranule tablets), since a rapid degradation of the active ingredient is observed when placed under ordinary conditions of use (ambient temperature 25 ° C, degree humidity from 40 to 75%) with the appearance of harmful decomposition products such as those described e.g. in Acta Chemica Scandinavia 43/1989 / 536-548 / Ame Brandstrom & al./.

To alleviate these disadvantages, it has been proposed (EP-A-0247 983 Hassie AG) to mix cellulose derivatives and disintegrants into a mixture with the appropriate amount of omepaazul and an alkaline salt of sodium, potassium, magnesium, calcium or alkaline ammonium salts so that by extrusion maintain a core whose composition is buffered and has an alkaline pH of 7 to 12.

Thus prepared microgranules are classically protected in the stomach environment and meet the standards of solubility and immunity in the stomach environment determined for optimal use of the oral product, i.e. solubility higher than 75% after 30 minutes in an aqueous environment with a pH of 6.8 and resistance in the higher stomach than 85% after 2 hours in an environment with a pH of 1.2.

However, this method of preparation has several important drawbacks, both for technical and economic reasons. First of all, it forces the production of combinations of products and mixtures with the risk of general toxicity and instability during the manufacturing process. In addition, an expensive special type of equipment must be used, which adds up to the high cost of the active ingredient, which leads to an excessive increase in the price of the final product when used on a global scale. The cost of daily treatment associated with the use of such a product is then much higher than the cost incurred during treatment bismuth salt, as an acid shielding agent, and ridaidol-macolide or macrolide, used to destroy Helicobacter pylori (the factor responsible for most gastrointestinal ulcers.

EP 237 506 describes a method of producing a pharmaceutical preparation in the form of granules containing, among others omeprazole, but this description shows fast-dissolving granules, i.e. already disintegrating in the stomach.

EP 470 047 discloses a formulation with a longer release time for the active substance, but it relates to antibiotics that are released gradually, first in the stomach and then in the intestine. So, he presents gastrointestinal preparations.

The subject of the invention prevents the disadvantages described above. Unlike these solutions, it presents a form of the preparation which is stable in the acidic environment of the stomach, and thus releases active substances only in the intestinal environment. This goal was achieved by the appropriate selection of ingredients and the appropriate method of obtaining it. It also allows to obtain the preparation in favorable economic conditions.

According to the invention, omeprazole is used in the form of a powder diluted with roughly an equal amount of mannitol, so as to obtain a stable and homogeneous suspension and to ensure better uniformity of the omeprazole content during application to neutral dumplings formed from a mixture of sugar and starch.

The present invention therefore relates to a stable pharmaceutical composition consisting of omeprazole microgranules containing an inert core formed from sugar and starch, the active layer formed from a solution of omeprazole in mannitol in a ratio of 0.9 to 1.2, wherein the active layer of umepaaool contains about 10% by weight . carboxymethyl starch, 5 wt. of the sodium lauryl sulfate surfactant, and a solution of omeprazole in mannitol is applied to the neutral core with the help of a hydroxypropyl lometa locel as a highly viscous binder, in addition, it contains an additional protective coating on the surface of the active layer4

172 706 formed from mannitol, which is applied with hydroxypropyl methylcellulose as a high viscosity binder as well as an outer protective coating in the stomach environment, preferably formed from hydroxypropylmethyl cellulose phthalate and talc.

The invention also relates to a process for the preparation of a pharmaceutical composition consisting of omeprazole microgranules, in which dry diluted mannitol solution is applied to inert grains made of sugar and starch, and omeprazole and carboxymethyl starch as well as sodium lauryl sulfate using a high viscosity hydrating solution <^ k ^; ypr <^ i ^^ / l <^^^ 1 ^ t ^ I <^ <cellulose dissolved in a mixture of at least 80% ethanol and at most 20% water, then an additional protective coating formed of mannitol with hydroxypropyl methylcellulose as a high viscosity binder is applied to the surface of the active layer and an outer protective coating in the stomach is preferably formed from hydroxypropyl methylcellulose phthalate and talc. After each application of the dry solution, it is dried at a temperature of 35 ° C to 40 ° C for a period of time, allowing to reduce the water content of the active microgranules to 1% and the ethanol content to 2000 ppm., And to apply the diluted active solution and protective coatings in stomach environment, flat bottom turbines are used.

By diluted powder is meant according to the invention a mixture of omeprazole powder, mannitol powder, sodium lauryl sodium and carboxymethyl starch.

Preferably, the granulometry of the mixed powders is roughly equal, less than 100 microns.

By about equal amounts is meant a weight ratio of omeprazole powder to mannitol powder close to 1 i.e. between 0.9 and 1.2.

Inert cores made of sugar and starch in a weight ratio close to 4 parts per 1 part of omeprazole powder have an average diameter of 700 - 900 microns (0.7 mm to 0.9 mm).

The active ingredient layer or active layer applied to the inert grains is preferably from about 100 to 300 gm / 0.1 to 0.3 mm thick.

To ensure good stability of the active ingredient during storage of the microgranules according to the invention, the moisture content of the active layer is lower than 1% and preferably lower than 0.5%.

The preferred binding agent is hydroxyp ^ <^ j ^ p ^ łt ^^ c ^ t ^ t ^ l^<^^<^^ l^atl^aboutfor (HPMC), while the resistant coating in the stomach environment contains hydro phthalate] ^^; ^^ l ^ c ^ J ^ plll ^; m ^ 1 ^ tll^{<^}celluloses (HPMCP) or ammonium methacrylic acid copolymers and talc.

To meet the solubility criteria of microgranules in a test tube, according to which at least 75% of omeprazole should be dissolved after 30 minutes when the microgranules are placed in an aqueous medium with a pH of 6.8 and 37 ° C, to the initial mixture of omeprazole and mannitol is added about 10% carboxymethyl starch (Explotab® sold by Mendell) to achieve complete breakdown of the granules at a pH of 6.8, as well as about 5% of a surfactant such as sodium lauryl sulfate, which improves the solubilization of omeprazole in the intestinal environment.

In addition, binding solutions for applying the active layer to inert grains, and then an additional mannitol cover are used with high-viscosity solutions of the order of 15 centipoise (15 x 10 '³ Pa-s) hydroxy propyl methylcellulose (HPMC) (Pharmacoat® sold by Shinetsu). At least 80% ethanol and a maximum of 20% water are used to dissolve the mixture, e.g. a mixture of 10 parts water to 90 parts 95 ° ethanol in small amounts to minimize the solvent and water content in the granules as much as possible during the production of active granules.

Finally, according to the method of preparing stable omeprazole granules according to the invention, a coating of microgranules resistant in the stomach environment, formed from hydroxypropy phthalate, locomulose (HPMCP) phthalate (HP 50 R sold by Shinetsu) in a solution of 80-20 mixture is applied by weight of acetone and 95 ° ethanol, as the outer layer after priming the active microgranules of omeprazole and mannitol, by spraying 33% sucrose syrup in a 44/56 water / ethanol mixture by weight, the total weight of sucrose in this syrup being about 25% relative to the amount of final coating that is resistant in the stomach environment. This outer shell contains talc as a lubricant. During the entire course of the various application and coating phases, the temperature is maintained and drying between the individual phases is carried out at rr »* No.> 11

U.IlUłAVX \.

_____ Λ -...

jr *

temperature from 35 ° C to 40 ° C so that the content of solvent and water is as low as possible, the final content being less than 1% water and 2000 ppm for ethanol.

Other features and benefits of the invention are explained in the following examples:

Example 1. A method of producing omeprazole microgranules with a content of 8.41% by weight.

All these amounts are expressed in kg dry weight for a final amount of 237.80 kg microgranules with 84.1 mg omeprazole per gram microgranules.

Composition

Inert sugar and starch beans 80.00

Active layer

Omeprazole 20.00

Mannitol 20.00

Carboxymethyl starch (CMA) 4.00

Sodium lauryl sulfate 2.00

Additional protective coating

Mannitol 50.00

Sucrose 8.00

HPMC 15 cp (centipoise, 15 x 10 '³ Pa-s) 3.20

Coating resistant in the stomach environment

HPMCP 32.00

Talc 18.60

237,80

The method according to the invention consists in the preparation of a diluted solution of 20 kg omeprazole in 20 kg mannitol in the presence of 4 kg CMA and 2 kg sodium lauryl sulfite, then applying this dry solution to 80 kg of neutral sugar-starch granules, the diameter of which is from 0.7 to 0 , 9 mm using a 4% HPMC solution (1.6 kg) in water (20 parts) with 95 ° ethanol (80 parts) in a disc turbine with an inclined flat bottom, then on the protection of the thus obtained active grains with 50 kg of mannitol applied with the remainder of the HPMC solution (or 1.6 kg), in turn on the priming of the granules thus protected with 33% sugar syrup (8 kg of sucrose), formed from 44 parts of water into 56 parts 95 ° ethanol and finally applying a protective coating in the stomach environment in the amount of 32 kg HPMCP in the form of a 7.5% solution in a mixture of 80 parts of 95 ° ethanol per 20 parts of acetone.

The granules thus obtained have a resistance in the stomach environment higher than 85% in an environment with a pH of 1.2, because after 2 hours at 37 ° C the amount of omeprazole not released in this environment is 91.7%. In an aqueous environment with a pH of 6.8, the solubility index of the granules after '30 minutes is 92% or above 75%, which is the smallest acceptable standard.'

After 12 and 24 months, the appropriate resistance values ​​in the stomach are 92.1% and 92.8%, and the solubility at pH 6.8 is 91.4% and 93.8% under the same operating conditions.

In addition, the very light beige color of the microgranules stored in the form of capsules in glass bottles with a closure fitted with a dehydrating insert at room temperature and external humidity of 60%, remains uniform for a period of at least 24 months.

Example II Durability tests.

Stability test of omeprazole performed on 4 batches of capsules containing the microgranules of the invention and one batch of microgranules. Controlled lots, storage conditions, methods of analysis as well as results are given below.

172 706

1. Partiekontrolowane

Omeprazole capsules

C 458-1-2, C 458-1-6, C 458-2-3 and C 458-2-4 omonraznl

j.rJ. gir

UQM 001-3

<td>batches</td><td>production date</td><td>Storage time (months)</td>

<td>C 458-1-2</td><td>June 1983</td><td> 36</td>

<td>C 458-1-6</td><td>February 1984</td><td> 36</td>

<td>C 458-2-3</td><td>September 1984</td><td> 24</td>

<td>C 458-2-4</td><td>October 1984</td><td> 24</td>

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

2. Storage conditions 25 ° C, relative humidity 60%

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

37 ° C, relative humidity 20-30%, 90%

50 ° C, relative humidity 80%

Cools the ark

3. Sample analysis a. Capsules Dissolving the sample

A. For the determination of omeprazole, enter the contents of 5 capsules into a 250 ml volumetric flask, then introduce 200 ml of methanol-ammonia (95-5) solution and stir with a magnetic stirrer for 30 minutes. Make up with the same solvent. Filter and dilute with 10 ml filtrate and 100 ml dichloromethane in a 100 ml volumetric flask, then make up to volume with methanol-ammonia-dichloromethane (24-1-75).

B. For the determination of decomposition products, dissolve the contents of 2 capsules in 8 ml of methanol-ammonia (95-5) solution, stirring with a magnetic stirrer for 30 minutes. Filter and dilute with 2.5 mL filtrate with dichloromethane to 100 mL. Inject immediately.

Apparatus and conditions

CLHP camera equipped with a UV detector.

7 gm silica pre-column, 15 mm long by 3.2 mm internal diameter (Brownlee or equivalent).

Column containing Lichrosorb Si 60.5 gm, 124 mm long by 4 mm internal diameter (Hibar Merck or equivalent).

Flow: 1 ml / min Reading at 280 nm Injection: 40 gl

System Check

After receiving a solid baseline, the system is checked as follows:

Dissolve 5 mg of standard omeprazole and 5 mg of sulfone, corresponding to quality H 168/66 (whose developed formula is given below), in 100 ml of mobile phase. Inject 40 g several times to obtain a consistent retention time (difference between two injections &lt;1%.

<img file="PL172706B1_D0001.tif" />

OCH,

The retention time for omeprazole is 10 minutes and for sulfone H 168/66 - 8 minutes.

172 706

Initial column: Column:

EćUŁa S.aCjGnanUu Injection method: Integrator:

b. Micro granules

Determination of omeprazole content in microgranules

The content of omeprazole in microgranules is determined by ultraviolet spectrophotometer after separation by high performance liquid chromatography.

reagents

Acetonitrile for CLHP (e.g. Carlo Erba No. 412409)

Dibasic sodium phosphate (Na2HPOą)

Monobasic sodium phosphate (NaHPOą, H2 O)

Distilled water

Reference substance: omeprazole

Apparatus

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

stainless steel series columns:

15 cm high, 3.2 mm internal, 7 pm granulometry, 12.5 cm diameter, 4 mm internal. gr ^ in ^ ult ^ n ^ titti ^ a 5 pm,

T &lt;Ό ti 1 Q u / ivrnu0utu im am, in quantities of 20 pl (e.g. WISP 712 automatic syringe),

LCI100 Perkin Elmer or Waters 645 Data Module.

Testing of resistance in the stomach and solubility environment

The microgranules are mixed for 2 hours in a suitable medium at a constant temperature (37 ° C ± 0.5 ° C) in a dissolution device.

Apparatus

The device used for dissolution is the paddle apparatus described in the European Pharmacopoeia. Rotation speed: 100 rpm.

Volume used: 500 ml environment at pH 12. Additive 400 ml ί ^ 'ά ^ ίΛν / ι at pH 7.6.

Environment

Environment I: Acidic environment for resistance testing.

Into a 1-liter volumetric flask, add 2 grams of sodium chloride and 7 ml of concentrated hydrochloric acid (37%). Make up to volume with distilled water. Stir until dissolved. The solution should reach a pH of 1.2 ± 0.05.

Environment II: environment with a pH of 7.6 (additive)

0.235 M solution of dibasic sodium phosphate (Na2HPOą). Prepare 1 liter of solution for 2 dishes.

4. Results and conclusions

The results are summarized in the tables below.

During the determination of the impurity content, two main impurities were detected in all samples. In result tables, they are designated by symbols I and I '.

A: Storage period (months),

B: Storage conditions - ° C, relative humidity,

C: Appearance.

Rneprazole capsules lot C458-1-2

<td>AND</td><td></td><td>B</td><td>C</td><td>D</td><td>E</td><td>AND %</td><td>F AND' %</td><td>Other %</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td><td> 6</td><td> 7</td><td> 8</td><td> 9</td>

<td> 0</td><td></td><td></td><td>and</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>and</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>and</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>and</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>

172 706

cd table

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td><td> 6</td><td> 7</td><td> 8</td><td> 9</td>

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

<td> 18</td><td> 25</td><td> 60</td><td>and</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>and</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>and</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>refrigerator</td><td></td><td>and</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, corresponding, c = colored not corresponding

Omeprazole capsules lot C458-1-6

<td>AND</td><td></td><td>Τ » ABOUT</td><td>V-</td><td>t- \ IA</td><td>E AT</td><td>AND %</td><td>F 17 % %</td><td>Other %</td>

<td> 0</td><td></td><td></td><td>and</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>and</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>and</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>and</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>and</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>and</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 colspan="2">refrigerator</td><td>and</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>and</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 colspan="2">refrigerator</td><td>and</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, corresponding, c = colored not corresponding

Omeprazole capsules lot C458-2-3

<td>AND</td><td></td><td>B</td><td>C</td><td>D</td><td>E</td><td>T and %</td><td>F AND' %</td><td>Other %</td>

<td> 0</td><td></td><td></td><td>and</td><td> 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 colspan="2">refrigerator</td><td>and</td><td> 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</td><td> 60</td><td>and</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 colspan="2">refrigerator</td><td>and</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</td><td> 60</td><td>and</td><td> 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 colspan="2">refrigerator</td><td>and</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> 25</td><td> 60</td><td>and</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</td><td> 60</td><td>and</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, b = colored, corresponding, c = colored not corresponding

172 706

Omeprazole capsules lot C458-2-4

<td>AND</td><td></td><td>B</td><td>C</td><td>D</td><td>E</td><td>AND %</td><td>F AND' %</td><td>&lt;£ ί</td>

<td> 0</td><td></td><td></td><td>and</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.</td><td> 60</td><td>and</td><td> 5</td><td> 20,8</td><td> &lt;0,5</td><td> &lt;0,5</td><td> &lt;0,2</td>

<td>I2</td><td> 25</td><td> 60</td><td>and</td><td> 5</td><td> 20,3</td><td> &lt;0,5</td><td> &lt;0,5</td><td> &lt;0,2</td>

<td>I8</td><td> 25</td><td> 60</td><td>and</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 colspan="2">refrigerator</td><td>and</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</td><td> 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, corresponding, c = colored, not corresponding.

Omeprazole microgranules UQM 00I-3 A: Shelf life (months)

B: Storage conditions - ° C, relative humidity C: Appearance

D: Omeprazole content (mg / g)

E: Test of resistance in the stomach environment F: Solubility test -%

<td>AND</td><td></td><td>B</td><td>C</td><td>D</td><td>E</td><td>F</td>

<td> 0</td><td></td><td></td><td>and</td><td> 78,0</td><td> 95,9</td><td> 95,0</td>

<td>AND</td><td> 25</td><td> 55-65</td><td>and</td><td> 80,8</td><td> 93,9</td><td> 94,0</td>

<td></td><td> 30</td><td> 30-40</td><td>and</td><td>8I, 2</td><td> 94,4</td><td> 95,0</td>

<td></td><td> 37</td><td> 20-40</td><td>and</td><td> 80,4</td><td> 97,0</td><td> 97,0</td>

<td></td><td> 37</td><td> 90</td><td>and</td><td> 77,6</td><td> 97,5</td><td>I00,0</td>

<td>Ί</td><td> 25</td><td> 56-65</td><td>and</td><td>8I, 4</td><td>9I, 6</td><td> 92,0</td>

<td></td><td> 30</td><td> 30-40</td><td>and</td><td>79, AND</td><td> 95,7</td><td> 96,0</td>

<td></td><td> 37</td><td> 20-40</td><td>and</td><td> 80,2</td><td> 92,0</td><td> 93,0</td>

<td></td><td> 37</td><td> 90</td><td>c</td><td>4I, 9</td><td> -</td><td> -</td>

a = white, b = colored, corresponding, c = colored, not corresponding.

The capsules show good stability in the refrigerator and at 25 ° C for up to 36 months storage. The concentration of all impurities is lower than 0.50%.

The content of impurities increases a little more with temperature and humidity and this may be enough to cause the granules to color.

Loose microgranules show good stability for 3 months at room temperature and 55-65% relative humidity, 30 ° C and 30-40% relative humidity and 37 ° C and 20-30% relative humidity, and at during the first month at 37 ° C and 90% relative humidity.

Period of validity

Based on the results obtained, the specificity is stable for 36 months, provided that the 25 ° C is not exceeded during this period.

norms

I. Appearance of a hard gelatin capsule containing white to beige more or less dark granules without extraneous particles of about 235 mg Φ I0%

18.0-22.0 mg capsule (9CM 10%)

2. Average weight

3. Omeprazole content

172 706

4. Acid resistance&gt; 85%

5. Release at pH 6.8&gt; 75%

6. Decomposition products total content &lt;2.0% individual content&gt; 0.5%.

It will be obvious that one skilled in the art will be able to incorporate variants into the methods of making the microgranules of the invention, in particular using encapsulation devices that coat in a fluidized layer instead of the flat-bottomed turbines described above, or also using methacrylic polymers as materials to protect in the stomach environment (e.g. . Eudragit® L 100-55 or L 30 D from Rohm &amp; Hass) or other resistant polymers in the stomach without exceeding the scope and scope of the invention.

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