Pharmaceutical preparation for oral use

The present invention relates to a novel stable oral formulation containing omeprazole, to a process for the preparation of such a formulation, and to a method for effecting gastric juice secretion by protecting the gastrointestinal cells during use.

For example, according to EP-A1-0 005 129, omeprazole, 5-methoxy-2 ((((4-methoxy-3,5-dimethyl-2-pyridinyl) methyl) sulfinyl-1H-benzimidazole) is known as a potent inhibitor of gastric juice secretion. It has a potent inhibitory effect on gastric juice secretion (Lancet, Nov. 27, 1982, pp. 1223-1224) and may be used to treat gastric and duodenal ulcers.However, omeprazole is sensitive to the cleavage and transformation effects of acidic and neutral media. The half-life of omeprazole in aqueous solutions with pH <4 is less than 10 minutes. Similarly, at neutral pH, the preparation is rapidly degraded, e.g., at pH = 7, the half-life of omeprazole is about 14 hours, whereas at higher pH it is better in solution (Pilbrant and Cederberg, Scand, J. Gastroenterology 1985; 20 (suppl. 108) pp.113-120). In the solid phase, its durability profile is similar. Acid-reacting compounds catalyze the decomposition of omeprazole, and omeprazole is stabilized in a mixture with alkaline compounds. The durability of omeprazole is also affected by moisture and organic solvents.

From the foregoing, it is clear from the peculiarities of the sustainability of omeprazole that the dosage form of omeprazole for oral administration must be protected from contact with acidic gastric juice in order for the drugs to reach the small intestine without fracture.

Human pharmacological studies have shown that the rate of release of omeprazole from a dosage form contributes to the rate and amount of its absorption and digestive tract into the circulatory system (Pilbrant and Cederberg, Scand. J. Gastroenterology 1985; 20 (suppl. 108) p.113- 120). The fully absorbed dosage form must rapidly release the active drug in the immediate part of the gastrointestinal tract.

In order to obtain a dosage form of omeprazole in which omeprazole is protected against contact with acidic gastric juice, the core of the drug should be covered. However, common enteric coating layers are made from acidic compounds. If omeprazole is coated with such a conventional coating, it will be rapidly degraded by direct or indirect contact with acidic compounds; the product will change color and over time will lose omeprazole itself.

The core component containing omeprazole must also contain an alkaline reactive component to increase the stability of the preparation. When such an alkaline core is coated with a coating consisting of a conventional coating polymer such as, for example, cellulose acetate phthalate, the shell is dissolved in the proximal portion of the small intestine and the active drug remains in the core, the core. In this case, as long as the dosage form is in the stomach before it leaves and passes into the small intestine, some of the water in the gastric juice will diffuse through the shell into the core. Diffused gastric juice water will dissolve part of the core of the drug closer to the enteric coating layer, thereby forming an alkaline solution outside the enteric coating in the dosage form. This alkaline solution will interact with the enteric layer and eventually be able to dissolve it.

An enteric-coated dosage form of omeprazole has been reported by Pilbrant and Cederberg, cited above in Scand J. Gastroenterology 1985, 20 (suppl. 108) p.113-120. The article describes a conventional enteric-coated dosage form and claims that it exhibits acceptable storage stability for clinical trials. It has subsequently been found that the stability of this dosage form is not sufficient for long-term storage, which is necessary for the commercial dosage form.

The stability of omeprazole in its conventional dosage form is unsatisfactory, particularly as regards its resistance to moisture. Therefore, special moisture-resistant packaging has been applied to reduce this deficiency. However, this does not satisfactorily solve the problems associated with the modern distribution system and leads to a price increase. In these circumstances, there is a need for a more durable oral formulation of omeprazole.

DE-AI-3046 559 describes a method of coating a dosage form. First, the dosage form is coated with a water-insoluble layer containing microcrystalline cellulose followed by a second enteric coating layer for release of the active ingredient in the colon. This preparation will not produce the desired release of omeprazole in the small intestine.

US-A-2 540 979 describes an enteric-coated enteric-coated dosage form which combines enteric coating with a second and / or first coating of a water-insoluble wax. This method of preparation is not applicable to cores containing omeprazole since direct contact of omeprazole with substances such as cellulose acetate phthalate (CAF) causes degradation and discoloration of omeprazole.

DE-B2-23 36 218 describes a method for preparing a dialysis membrane consisting of a mixture of 1 or more conventional coating polymers and 1 or more insoluble cellulose derivatives. Such a membrane will not protect omeprazole from the effects of gastric juice.

DE-AI-I 204 363 describes a three-layer coating. The first layer is soluble in gastric juice but insoluble in small intestine juice. The second is water soluble regardless of pH, and the third is the enteric layer. The use of this preparation method or the method described in DE-AI-I 617 615 results in a dosage form insoluble in gastric juice and slowly soluble in small intestine juice. This method of preparation cannot be used for omeprazole as it is necessary in this case for the drug to be released rapidly in the small intestine.

DE-AI-12 04 363 discloses a three-layer coating that results in release of the active drug in the colon, which is not the purpose of this release.

GB-AI 485 676 describes a process for preparing a foaming enteric formulation by coating an enteric layer with a core containing an active ingredient and a foaming system such as a combination of a carbonate and / or bicarbonate salt and a pharmaceutically acceptable acid. This method of preparation cannot be used for the formulation of omeprazole as contact of the acid with omeprazole in the core will cause degradation of omeprazole.

WO 85/03436 discloses a medicament in which the active ingredient in the core is mixed with buffering components such as, for example, sodium dihydride 3699 B rogen phosphate. In order to maintain a constant pH and constant diffusion rate, such a core is coated with a first layer controlling diffusion. Omeprazole should not be used in this preparation because of its rapid release in the small intestine. The enteric coating of the core portion would also adversely affect the storage stability of the dosage forms containing omeprazole.

The object of the present invention is to provide an enteric coated dosage form of omeprazole which is insoluble in acidic medium and rapidly dissolves in neutral medium and which is stable over long periods of storage. Uses of the dosage form are described as follows. The core containing omeprazole mixed with an alkaline compound or an alkali salt of omeprazole loosely mixed with an alkaline compound is applied in 2 or more layers. The first layer (s) is water-soluble or rapidly disintegrates in water and consists of non-acidic, in other words, inert, pharmaceutically acceptable substances. This first layer (s) separates the alkaline core material from the outer layer which is the enteric sheath. Finally, the enteric-coated dosage form is specifically treated to reduce the amount of water in the dosage form and thus increase the durability of the drug over long periods of storage.

Detailed Description of the Invention

The core part

Omeprazole is mixed with inert, more water-soluble, freely selected pharmaceutical ingredients to obtain the desired concentration of omeprazole, and with an alkaline-visual or inert pharmaceutically acceptable substance (or substances) to produce a pH <8 when absorbed by daLT 3699 B dolls. water or a small amount of water is added to the mixture. Such materials may be selected from, but are not limited to, sodium, potassium, calcium, magnesium and aluminum phosphoric acid, carbonic acid, citric acid, or other suitable weak inorganic or organic acid salts; as well as from substances used in the preparation of anti-acid preparations - hydroxides of aluminum, calcium, magnesium, magnesium oxide or complex substances such as A1₂O₃.6Mg. CO₂.12H₂O, (Mg₆Al₂ (OH) ₁₆CO₃.4H₂O), MgO. A1₂O₃.2SiO₂. nH₂0 or similar compounds; organic pH-buffering substances such as trihydroxymethylaminomethane or similar pharmaceutically acceptable ρΗ-buffering substances. High pH stabilization of the powder mixture can be achieved by using alkaline-acting omeprazole salts such as sodium, potassium, magnesium, calcium and 1.1. salts as described, for example, in EP-A2-124 495, alone or in admixture with one of the buffering agents described above.

Using conventional drug preparation procedures, the powder mixture is formed into small balls - peas, tablets, hard or soft gelatin capsules. These peas, tablets or capsules are used as a core part of the medicine during further preparation.

Different layer

The alkaline reactive core of omeprazole must be separated from the enteric coating layer (s) polymer (s) having free carboxylic groups which may otherwise cause degradation of omeprazole during coating or storage. This pre-sheath layer, also referred to as the separating layer, also serves as a pH-buffering zone in which hydrogen ions are diffused externally to the alkaline core 3699 B can react with two hydroxyl ions diffusing from the alkaline core towards the surface. The pH-buffering properties can be enhanced by the addition of a layer of compounds selected from the group of compounds commonly used for an acidic composition, such as magnesium oxide, hydroxide or carbonate, aluminum or calcium hydroxide, carbonate or silicate, complex aluminum / magnesium compounds, such as Al₂O₃.6MgO.CO₂12H₂0, (Mg₆Al₂ (OH) ₁₆CO₃.4H₂0), MgO .Al₂O₃.2SiO₂.nH₂0 or similar compounds; or other pharmaceutically acceptable pH-buffering compounds such as, for example, phosphorous, citric or other appropriate weak inorganic or organic salts of sodium, potassium, calcium, magnesium and aluminum.

The separating layer consists of one or more water-soluble inert layers containing optional pH-buffering compounds.

The separating layer (s) is applied to pellets or tablets by coating them in conventional manner using appropriate baths or drag bearings and water and / or other organic solvent for the shell solution. The barrier material is selected from pharmaceutically acceptable, water-soluble inert compounds or polymers used in film coatings such as sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylaminoacetate, polyvinylaminoacetate. The separating layer should have a thickness of at least 2 μη, preferably at least 4 µm for small spherical peas and at least 10 µm for tablets. The tablets may also be coated by other dry coating techniques. First, the tablet with omeprazole is compressed as described above. The tablet layer is pressed down using an appropriate tabletting machine. The outer, separating layer 3699B consists of pharmaceutically acceptable, water-soluble or rapidly disintegrating, tablet-forming materials. The separating layer shall be at least 1 mm thick. Conventional colorants, pigments, titanium dioxide, talc and other additives may also be included in the separating layer.

In the case of gelatin capsules, the capsule itself serves as a separating layer.

Enteric coating

The semi-coated cores are coated with an enteric coating layer using conventional coating techniques such as bath or waveguide coating with polymers dissolved in water and / or organic solvents, or their latex suspensions. For the enteric coating layer, polymers such as cellulose acetate flatate, hydropropyl methylcellulose phthalate, carboxymethylcellulose, copolymerized methacrylic acid / methacrylic acid methyl esters may be used, such as, for example, compounds known under the tradenames Eudragit® L 12, ® L 100 (Rohm Pharma) or similar compounds for enteric coating. Dispersion polymers such as Aquateric® (FMC Corporation), Eudragit® L100-55 (Rohm Pharma), Coating CE 5142 (BASF) can also be used for the enteric coating layer. The enteric coating layer may contain any pharmaceutically acceptable adhesive such as cetanol, triacetin, citric acid esters such as those known under the tradename Citroflex (Pfizer), phthalic acid esters, dibutyl succinate or the like. materials. The amount of adhesive is usually optimized for each enteric coating layer polymer (ams) and is typically from 1 to

20% of the total polymer content of this layer. The enteric coating layer may include dispersants such as talc, colorants and pigments.

Thus, according to the invention, a special preparation consists of a core containing omeprazole mixed with an alkaline-visual compound or a core consisting of an omeprazole alkaline salt mixed with an alkaline-visual compound. An alkaline reacting core material and / or an alkaline salt of the active ingredient, omeprazole, increases the durability of omeprazole. The cores, suspended in water, form a solution or suspension having a pH greater than that of the solution containing the polymer used for enteric coating. The core is coated with an inert water-soluble or rapidly disintegrating layer containing a pH-buffering substance which separates the alkaline core from the enteric coating layer (shell). Without this separating layer, the resistance to gastric juice would be too low and the storage stability would be unacceptably short. The semi-coated dosage form is finally coated with an enteric coating (coating) that renders the dosage form insoluble in acidic medium and rapidly degradable / soluble in a neutral or alkaline medium such as that of the small intestine, e.g. at the point where her melting is desired.

Final dosage form

The final dosage form is either an enteric-coated tablet or capsule or, in the case of enteric-coated peas, the peas are divided into hard gelatine capsules or the pills are formed into tablets. For long-term storage stability, it is essential that the water content of the final dosage form containing omeprazole (enteric-coated tablets, capsules or peas) is very low at 1.5% by weight. As a result, the final packaging containing the hard gelatin capsules filled with enteric-coated peas should also contain desiccants to reduce the water content of the gelatin shell to a level not exceeding that of the enteric-coated pellets. 1.5% by weight.

The course of preparation

The process of making an oral dosage form forms a further aspect of the invention. Once the core is made, the latter is coated with a separating layer followed by an enteric coating. Coating as described above.

According to the invention, the preparation is particularly suitable for inhibiting gastric juice secretion and / or for protecting the gastrointestinal cells. It is used from 1 and several times a day. the usual daily dose of the active ingredient will vary and will depend on a variety of factors, such as the patient's individual need, the type of treatment and the disease. In general, the daily dose of omeprazole may range from 1 to 400 mg. Under these conditions, a method of treatment using a novel oral dosage form forms a further aspect of the invention.

The invention is described in detail in the following examples:

EXAMPLES example

The effect of various magnesium compounds on enteric-coated tablets was evaluated. First, the cores of the tablets were prepared in the usual manner in the composition shown in Table 1, and then coated with the separating and enteric layers in the composition shown in Table 2.

table. Composition of tablet core (mg)

<td>Composition no.</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td><td> 6</td><td> 7</td>

<td>Omeprazole</td><td> 15,0</td><td> 15, 0</td><td> 15,0</td><td> 15,0</td><td> 15,0</td><td> 15,0</td><td> 15,0</td>

<td>Lactose</td><td> 134,0</td><td> 119,0</td><td> 119,0</td><td> 119,0</td><td> 118,8</td><td> 118, 5</td><td> 119,0</td>

<td>Hydroxypropyl Cellulose (Low Replacement)</td><td> 5, 0</td><td> 5,0</td><td> 5,0</td><td> 5,0</td><td> 5,0</td><td> 5, 0</td><td> 5,0</td>

<td>Hydroxypropyl cellulose</td><td> 1,0</td><td> 1,0</td><td> 1,0</td><td> 1,0</td><td> 1,0</td><td> 1,0</td><td> 1,0</td>

<td>Because</td><td> 5,0</td><td> 5,0</td><td> 5,0</td><td> 5,0</td><td> 5, 0</td><td> 5,0</td><td> 5,0</td>

<td>Well₂HPO₄</td><td> -</td><td> 15,0</td><td> -</td><td> -</td><td> 0,2</td><td> -</td><td> -</td>

<td>Well lauryl sulfate</td><td> -</td><td> -</td><td> -</td><td> -</td><td> -</td><td> 0,5</td><td> -</td>

<td>MgO</td><td> -</td><td> 15,0</td><td> -</td><td> -</td><td> -</td><td> -</td><td></td>

<td>Mg (OH)₂</td><td> -</td><td> -</td><td> -</td><td> 15,0</td><td> 15,0</td><td> 15, 0</td><td> -</td>

<td>Synthetic Hydro- talcitis 1A1₂O₃.6MgCO₂.12H₂01</td><td></td><td></td><td></td><td></td><td></td><td></td><td> 15, 0</td>

<td>Total:</td><td> 160,0</td><td> 160,0</td><td> 160,0</td><td> 160,0</td><td> 160, 0</td><td> 160,0</td><td> 160,0</td>

<td colspan="2">Table 2. Composition of coating layers</td><td colspan="3">(mg)</td>

<td>Composition no.</td><td>I</td><td>II</td><td>III</td><td>IV</td>

<td>Separating layer (inner)</td><td></td><td></td><td></td><td></td>

<td>Hydroxypropyl Cellulose</td><td> -</td><td> 2,0</td><td> 2,0</td><td> 2,0</td>

<td>Magnesium hydroxide</td><td> -</td><td> -</td><td> 0,3</td><td> -</td>

<td>Synthetic hydrotalcite</td><td> -</td><td> -</td><td> -</td><td> 0,3</td>

<td>Separating layer (outer):</td><td></td><td></td><td></td><td></td>

<td>Hydroxypropyl Cellulose</td><td> -</td><td> 2,0</td><td> 2,0</td><td> 2,0</td>

<td>Enteric coating:</td><td></td><td></td><td></td><td></td>

<td>Hydroxypropyl methylcellulose</td><td></td><td></td><td></td><td></td>

<td>phthalate</td><td> 7,0</td><td> 7,0</td><td> 7,0</td><td> 7,0</td>

<td>Cetyl alcohol</td><td> 0,5</td><td> 0, 5</td><td> 0,5</td><td> 0,5</td>

Tablets of this composition were kept open in so-called accelerated conditions, i.e. 40 ° C and 75% relative humidity, and observed for a change in appearance over time. 6 months in these conditions is equivalent to 3 years in normal conditions. This means that a sufficiently high level of sustainability sufficient for practical use can be achieved if the drug remains unchanged for about 1 week under these conditions. The results are summarized in Table 3.

3 table. Stabilizing effect (Appearance of preparation)

<td rowspan="2">Covering</td><td rowspan="2">layer</td><td colspan="2">Cores</td><td colspan="2">part material</td>

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

<td>I In the beginning</td><td></td><td>CA.</td><td>A</td><td>AA</td><td>AA</td>

<td>60 ° C, after 7</td><td>days</td><td>ED</td><td>C</td><td>CC</td><td>CD</td>

table (continued)

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

<td>40 ° C, 75% SD; after 7 days</td><td>F</td><td>E</td><td>B</td><td>B</td><td>B</td><td>B</td><td>E</td>

<td>II In the beginning</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td>

<td>60 ° C, after 7 days</td><td>E</td><td>B</td><td>A</td><td>A</td><td>A</td><td>A</td><td>C</td>

<td>40 ° C, 75% SD; after 7 days</td><td>E</td><td>D</td><td>A</td><td>A</td><td>A</td><td>A</td><td>D</td>

<td>III In the beginning</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td>

<td>60 ° C, after 15 days</td><td>B</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td>

<td>40 ° C, after 30 days</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td>

<td>40 ° C, 75% SD; After 15 days</td><td>B</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td>

<td>IV In the beginning</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td>

<td>60 ° C, after 15 days</td><td>B</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td>

<td>40 ° C, after 30 days</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td>

<td>40 ° C, 75% SD; after 15 days</td><td>B</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td>

<td colspan="2">A: White. B: White and in places</td><td>Brown,</td><td>C:</td><td>barely</td><td>barely</td><td colspan="2">Brown,</td>

<td>D: light brown, E: brown, F:</td><td colspan="2">dark</td><td>Brown</td><td></td><td></td><td></td><td></td>

As shown in Table 3, a significant stabilizing effect is achieved when a magnesium compound is present in the inner partitioning layer.

All samples evaluated as A (white) in the table had not changed color even at the cracked surface. For example, Grade B (white with patches of brown) had no change in appearance, only the areas of the cracked surface were discolored.

Table 3 shows the results of the omeprazole durability test using formulation 4-IV of Peptide 3699B. The product was stored in a sealed glass vial at room temperature for a specified period of time. We can see that preparations of unusual durability have been obtained.

table covering tablets)

The durability of omeprazole formulations, layered, is coated with enteric formulation no. 4-IV

<td></td><td>Storage period</td><td>Appearance</td><td>Omeprazole content (%)</td>

<td>Test</td><td>in the beginning</td><td>White</td><td> 100, 0</td>

<td>1 year</td><td>at room temperature</td><td>White</td><td> 99, 9</td>

<td>2 years</td><td>at room temperature</td><td>White</td><td> 100,0</td>

example

Unopened peas

II

Matitol powder

Anhydrous lactose

Hydroxypropyl Cellulose

Microcrystalline cellulose

Omeprazole

Sodium lauryl sulfate

Disodium hydrogen phosphate

distilled water

16150 g 800 g 600 g 400 g

2000 g 50 g 80 g

4400 g

Dry ingredients (I) are mixed in a mixer. A granulating liquid (II) containing omeprazole in suspension is added and the mass is wet mixed to a certain consistency. The wet mass is pressed through an ex20 truder to form peas. The peas are dried and sized to the appropriate size.

Semi-coated peas

Unopened peas of omeprazole 6000 g

Hydroxypropyl methylcellulose 240 g

Distilled water 4800 g

The polymeric solution (III) is sprayed onto the uncoated beads in a drag bearing machine. Sprayers are mounted above the pull bearing.

Enteric-coated peas

Semi-coated peas 500 g

Hydropropyl methylcellulose phthalate 57 g

IV Cetyl alcohol 3 g

Acetone 540 g

Ethanol 231 g

Polymeric solution (IV) is sprayed onto semi-coated pellets in a drag bearing machine with sprinklers mounted above. Dried enteric-coated pellets of up to 0.5% water are filled into hard gelatin capsules containing 225 mg equivalent to 20 mg omeprazole. After 30 capsules are packed in desiccant containers.

example

This example demonstrates that various polymers can be used for semi-coating, e.g., hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohols.

<td colspan="3"> 16</td>

<td colspan="2">Unopened peas</td><td></td>

<td></td><td>Mannitol powder</td><td>1620 g</td>

<td></td><td>Anhydrous lactose</td><td>80g</td>

<td>I</td><td>Hydroxypropyl cellulose</td><td>60g</td>

<td></td><td>Microcrystalline cellulose</td><td>40g</td>

<td></td><td>Omeprazole</td><td>200 g</td>

<td></td><td>Sodium lauryl sulfate</td><td>1.0 g</td>

<td>II</td><td>Disodium hydrogen phosphate</td><td>9, 3 g</td>

<td></td><td>distilled water</td><td>515g</td>

<td colspan="2">Unopened peas are prepared as baby.</td><td>described in 2</td>

<td colspan="2">Semi-coated peas</td><td></td>

<td></td><td>Unopened peas of omeprazole</td><td>500 g</td>

<td>III</td><td>Polyvinylpyrrolidone</td><td>20g</td>

<td></td><td>Ethanol</td><td>400g</td>

<td colspan="2">Semi-coated peas are prepared</td><td>as described</td>

in the example.

Enteric-coated peas

Semi-coated peas 500 g Hydroxypropyl methylcellulose phthalate 45 g Cetyl alcohol 5 g Acetone 219 g Ethanol 680 g

<td colspan="2">Enteric coating</td><td>covered with pea</td>

<td colspan="3">prepared as described in Example 2.</td>

<td colspan="2">Example 4</td><td></td>

<td colspan="2">Unopened peas</td><td></td>

<td></td><td>Mannitol powder</td><td>1610 g</td>

<td></td><td>Anhydrous lactose</td><td>80g</td>

<td>I</td><td>Hydroxypropyl Cellulose</td><td>60g</td>

<td></td><td>Microcrystalline cellulose</td><td>40g</td>

<td></td><td>Omeprazole</td><td>200 g</td>

<td></td><td>Pluronic F68</td><td>10g</td>

<td>II</td><td>Disodium hydrogen phosphate</td><td>24g</td>

<td></td><td>distilled water</td><td>450g</td>

<td colspan="2">Unopened peas are prepared</td><td>as described in 2</td>

<td colspan="2">baby.</td><td></td>

<td colspan="2">Semi-coated peas</td><td></td>

<td></td><td>Unopened peas</td><td>500 g</td>

<td>III</td><td>Polyvinylpyrrolidone</td><td>30g</td>

<td></td><td>Ethanol</td><td>400g</td>

<td colspan="3">Semi-coated peas are prepared as described in 2</td>

<td colspan="2">baby.</td><td></td>

Enteric-coated peas

Semi-coated peas 500 g Hydroxypropyl methylcellulose phthalate 45 g Cetyl alcohol 5 g Methylene chloride 371 g Ethanol 680 g

Enteric-coated pellets are prepared as described in Example 2.

example

This example demonstrates that a variety of polymers may be used to prepare the enteric coating layer, e.g. esters). The polymers can be used without or with form-forming agents such as polyethylene glycol, triacetin, dimethylpolysiloxane. Citroflex®, cetyl alcohol, stearyl alcohol, diethyl phthalate.

Enteric-coated pellets may also be prepared using aqueous polymer dispersions, such as Auarearic (FMC Corporation), Eudragit® L 100-55, Coating CE 5142 (BASF).

Unopened peas

Lactose powder 277 g Lactose anhydrous 118 g Hydroxypropyl cellulose 25 g Colloidal silicon 25 g

Omeprazole 50 g Sodium lauryl sulphate 5 g Disodium hydrogen phosphate 0.1 g Distilled water 170 g

Unopened peas are prepared as described above.

Semi-coated peas

Uncoated peas are semi-coated as described in Example 2.

Enteric-coated peas

III

Semi-coated peas 500 g Eudragit L 100 45 g Stearyl alcohol 4.5 g Ethanol 1320 g

Enteric-coated peas are prepared as described above.

example &lt;

&gt; Composition with omeprazole sodium.

Unopened peas

Omeprazole Sodium 339 g Mannitol Powder 2422 g Lactose Anhydrous 120 g Hydroxypropyl Cellulose 90 g Microcrystalline Cellulose 60 g

Sodium lauryl sulfate 7 g

Distilled water 650 g

The formulation is prepared as described in Example 2 with the exception that omeprazole sodium is added to blend I with other ingredients.

Semi-coated peas

Unopened peas 500 g

Hydroxypropyl methylcellulose 20 g

Aluminum hydroxide / magnesium carbonate 4 g

Distilled water 400 g

Peas, semi-coated

III composition 500 g

Hydroxypropyl methylcellulose 20 g

Distilled water 400 g

The uncovered peas are covered with two pre-sheathed layers, in the III and IV pull bearing apparatus, as described above.

Enteric-coated peas

Semi-coated peas 500 g

Hydroxypropyl methylcellulose phthalate ^ 7 g

V Cetyl alcohol 3 g

Acetone 540 g

Ethanol 231 g

The enteric coating layer is covered with peas as described in Example 2.

and 8 examples

Composition with omeprazole magnesium salt

Unopened peas

Example #

<td></td><td></td><td> 7</td><td></td><td> 8</td><td></td>

<td></td><td>Magnesium salt of omeprazole</td><td> 222</td><td>g</td><td> 222</td><td>g</td>

<td></td><td>Mannitol powder</td><td> 1673</td><td>g</td><td> 1473</td><td>g</td>

<td>I</td><td>Microcrystalline cellulose</td><td> 100</td><td>g</td><td> 100</td><td>g</td>

<td></td><td>Magnesium hydroxide</td><td> -</td><td></td><td> 200</td><td>g</td>

<td></td><td>Sodium lauryl sulfate</td><td> 5</td><td>g</td><td> 5</td><td>g</td>

<td>II</td><td>distilled water</td><td> 500</td><td>g</td><td> 375</td><td>g</td>

The preparation is prepared as described in Example 2 with the exception that the magnesium salt of omeprazole is mixed in mixture I with other ingredients.

Semi-coated peas

Example 7 and 8

Unopened peas 500 g

Hydroxypropyl methylcellulose 20 g

Distilled water 400 g

The peas are prepared as described in Example 2.

Enteric-coated peas

Example 7 and 8

Semi-coated peas

Hydroxypropyl methylcellulose phthalate

IV

Cetyl alcohol

Acetone

Ethanol

500 gg 3 g 540 g 231 g

Enteric-coated pellets are prepared as described in Example 2.

and 10 examples

Manufacture of tablets

Tablet core

Example #

10

<td>Omeprazole Omeprazole sodium equivalent to 400 g of omeprazole</td><td> 400</td><td>g</td><td> 426</td><td>g</td>

<td>Anhydrous lactose</td><td> 1420</td><td>g</td><td> 1409</td><td>g</td>

<td>Polyvinylpyrrolidone, crosses coupled</td><td> 100</td><td>g</td><td> 100</td><td>g</td>

<td>Intravenous sodium carbonate</td><td> 15</td><td>g</td><td> -</td><td></td>

<td>Methylcellulose</td><td> 12</td><td>g</td><td> 12</td><td>g</td>

<td>distilled water</td><td> 200</td><td>g</td><td> 100</td><td>g</td>

<td>Magnesium stearate</td><td> 30</td><td>g</td><td> 30</td><td>g</td>

The powder I is thoroughly homogenized and granulated with solution II. The wet mass is dried in a drag bearing dehumidifier at + 50 ° C for 30 minutes. The dried mixture is squeezed through a 0.5 mm mesh. After mixing with magnesium stearate, the granules are tabletted in a tabletting machine using 6 mm slits. The tablet weight is 100 mg.

Pre-coating

Omeprazole tablets are coated with about 10% by weight of hydroxypropyl methylcellulose in aqueous solution using a perforated bath bath.

Omeprazole sodium tablets are coated with a pre-apical layer using a dry coating method. Composition of tablet granulate

Anhydrous lactose 4000 g Polyvinylpyrrolidone (PVP) 180 g Ethanol 95% 420 g Magnesium stearate 42 g

It is prepared in this way. The lactose is granulated with a PVP solution in ethanol and dried. Magnesium stearate is then added with mixing.

Using a Manestry Dry Cota Tablet Machine, the core of the tablets of Example 9 is dry coated with granulate. Coated tablets weight 475 mg. Each tablet contains 20 mg of omeprazole.

Enteric coating

Half-coated tablets are enteric-coated using the same coating solution:

Hydroxypropyl methylcellulose phthalate 1500 g Cetyl alcohol 105 g Methylene chloride 15000 g Isopropanol 15000 g Distilled water 3150 g

A perforated bath tub is used for coating. Approximately 1 kg of coating solution is used for 1 kg of tablets.

COMPARATIVE EXAMPLES

Examples I, II and III

These examples show that the buffered salt used has significance to the properties of enteric-coated pellets if the latter are not coated with a pre-coat. A high amount of buffered salt is required to obtain a higher residence time pro15. At the same time, this type of peas has a low acid resistance. Let us also compare with Example 4, described above.

Unopened peas

Example #

<td></td><td>I</td><td>II</td><td>III</td>

<td>Mannitol powder</td><td>1610 g</td><td>1610 g</td><td> 1610</td>

<td>Anhydrous lactose</td><td>80g</td><td>80g</td><td> 80</td>

<td>Hydroxypropyl Cellulose</td><td>60g</td><td>60g</td><td> 60</td>

<td>Microcrystalline cellulose</td><td>40g</td><td>40g</td><td> 40</td>

I

Omeprazole

Pluronic F68

Disodium hydrogen phosphate

distilled water

<td> 200</td><td>g</td><td> 200</td><td>g</td><td> 200</td>

<td> 10</td><td>g</td><td> 10</td><td>g</td><td> 10</td>

<td> 2</td><td>g</td><td> 8</td><td>g</td><td> 24</td>

<td> 450</td><td>g</td><td> 450</td><td>g</td><td> 450</td>

Uncoated peas are prepared as described in Example 2.

Enteric-coated peas

Uncoated peas 500 g Hydroxypropyl methylcellulose phthalate 45 g Cetyl alcohol 5 g Methylene chloride 371 g Ethanol 680 g

The peas are covered as described in Example 2.

Example IV

The composition is the same as that given in Example 6 above, but no pre-coat is used.

Unopened peas

Omeprazole Sodium 339 g

Mannitol powder 2422 g

Anhydrous lactose 120 g

Hydroxypropyl cellulose 90 g

Microcrystalline cellulose

II

Sodium lauryl sulfate

Distilled water g 650 g

The preparation is prepared as described in Example 6.

Enteric-coated peas

III

Uncoated peas 500 g Hydroxypropyl methylcellulose phthalate 57 g Cetyl alcohol 3 g Acetone 540 g Ethanol 231 g

The peas are covered as described in Example 2.

Example V

The composition is the same as in Example 8 above, but no pre-sheath is used.

Unopened peas

Magnesium salt of omeprazole

Mannitol powder

Microcrystalline cellulose

Magnesium hydroxide

Sodium lauryl sulfate

distilled water

222 g 1473 g

100 g 200 gg 375 g

The preparation is prepared as described in Example 8.

Enteric Coating Peas

Uncoated peas 500 g Hydroxypropyl methylcellulose phthalate 57 g Cetyl alcohol 3 g Acetone 540 g Ethanol 231 g

The peas are covered as described in Example 2 above.

Properties of pellets coated with enteric coating

The following studies were conducted with preparations prepared in accordance with Example 28 and Comparative IV.

Acid resistance

The formulations were tested in this manner, prepared according to the above formulations, immersed in gastric fluid USP (enzyme-free) at 100 rpm at 37 ° C. After 2 hours, determine the amount of omeprazole remaining.

Rate of dissolution in buffer

To determine the rate of dissolution in the small intestine, the formulations were dipped in buffer. Buffer solution at 37 ° C in USP dissolution apparatus no. 2, rotating at 100 rpm. After 10 or 30 minutes determine the amount of omeprazole dissolved. Study data are shown in Table 5.

table

<td>Pavyz- jio</td><td>Omeprazole mg / g</td><td>Acid resistance, intact omeprazole</td><td colspan="3">(%) amount of omeprazole dissolved at different pH and after 10 or 30 min.</td>

<td>No.</td><td></td><td>kis (%) after 2 or.</td><td>o. 0</td><td>pH</td><td>min</td>

<td> 2</td><td> 89,2</td><td> 95</td><td> 100</td><td> 6, 8</td><td> 10</td>

<td> 3</td><td> 90,0</td><td> 96</td><td> 91</td><td> 6,0</td><td> 10</td>

<td> 4</td><td> 88,0</td><td> 89</td><td>X)</td><td></td><td></td>

<td> 5</td><td> 82,0</td><td> 93</td><td> 70</td><td> 7,5</td><td> 30</td>

<td> 6</td><td> 81,3</td><td> 87</td><td> 93</td><td> 6, 8</td><td> 10</td>

<td> 7</td><td> 91,0</td><td> 95</td><td>XX)</td><td></td><td></td>

<td> 8</td><td> 89, 0</td><td> 98</td><td>xx)</td><td></td><td></td>

<td>I</td><td> 93, 0</td><td> 97</td><td>X)</td><td></td><td></td>

<td>II</td><td> 92,0</td><td> 94</td><td>x)</td><td></td><td></td>

<td>III</td><td> 94,0</td><td> 58</td><td>x)</td><td></td><td></td>

<td>IV</td><td> 86, 5</td><td> 4</td><td></td><td></td><td></td>

<td>v</td><td> 91,0</td><td> 93</td><td>xx)</td><td></td><td></td>

x) The stability of this formulation was investigated by storing it in 5 bottles with drying equipment. After 1 month storage at + 50 ° C, the formulation prepared in Example 4 remained virtually intact with no change in physicochemical properties. The peas prepared according to Examples I and II were reddish and disintegrated, whereas the peas prepared according to Example III remained the original white.

xx) Preparations prepared according to the composition of Example 7 were white and did not discolour during coating.

Enteric-coated pellets prepared according to Example V, wherein the cores prepared according to Example 8 were directly enteric-coated without the separating layer, had already changed color during application.

Further comparative test (test)

This example illustrates the effect of moisture content on the storage stability of formulations prepared according to the present invention.

The stability of the omeprazole pellets prepared according to the invention was compared with the stability of the omeprazole pellets having a higher water content. Omeprazole peas prepared according to the invention contained 1% water. The other two portions prepared according to the same composition only had different amounts - 2% and 5% respectively. The three variants are packed in desiccant containers and stored at + 50 ° C for 1 month. The containers were then opened and the omeprazole content was evaluated (by HPLC). The formulation according to the present invention contained 98.5% of the initial amount of omeprazole. Meanwhile, preparations containing 2% and 5% water, respectively, were completely degraded and contained only traces of omeprazole.

DISCUSSION - DISCUSSION

It can be seen from the data in Table 5 that omeprazole-containing acid-resistant preparations can be prepared using conventional coating techniques (see, for example, Examples I, II and V). However, it is evident that the storage durability of the listed preparations is unacceptable as they change color, indicating degradation of omeprazole, storage at higher temperatures for a short period (Examples I and II) or even during coating (Example V).

If the alkaline content of the core is increased to a level where the storage stability of omeprazole is acceptable (Example III) or if the alkaline reacting salt of omeprazole (Example IV) is used, the acid resistance of the preparation becomes unacceptably low. , the active substance is already excreted in the stomach and has no effect on the secretion of gastric juice.

When prepared according to the invention, for example Example 4, the preparation has good resistance to gastric juice and also good storage stability. This result is in stark contrast to that obtained in the preparation of Examples I, II and III, where only acceptable acid resistance or acceptable durability is achieved, but not both. A similar view can be seen by comparing Examples 7 and 8 prepared according to the invention with Example V without a separating layer. 7th The preparation of Example 8 differs from the preparation of Example 8 in that magnesium hydroxide is used in the core portion of the latter as a buffer. This improves acid resistance as well as storage stability, as seen in Example 8 versus 7.

Further comparative testing indicates the importance of low water content in the preparation.

For the preparation of an oral omeprazole formulation having good long-term stability and also gastric stability, the following formulation was prepared.

(a) The core is prepared by mixing omeprazole with an alkaline reacting compound or compounds, or by mixing an alkaline reacting salt of omeprazole with an alkaline reacting compound.

(b) The core shall be coated with one or more inert, water-soluble or rapidly disintegrating layers separating the alkaline-reactive core from the enteric sheath. The precoat layer may contain pH-buffering compounds.

Biopharmaceutical studies using hard gelatine capsules prepared according to Example 2 in healthy young male volunteers were as follows:

Volunteers came to the laboratory in the morning, fasting from 10 pm. A blood sample was taken from them. Take 1 capsule of omeprazole with 150 ml tap water. Blood samples were taken during the day. In another test, the same volunteers took 20 mg of omeprazole in the form of a suspension in micronized omeprazole sodium bicarbonate in water. To minimize the risk of omeprazole degradation in the stomach, volunteers drank sodium bicarbonate solution before drinking, and drank it 4 more times every 10 minutes. after taking the medication. Plasma omeprazole concentrations were measured by high performance liquid chromatography (Persson, Lagerstrom and Grundevik, Scand J. Gastroenterol 1985, 20, (suppl. 108), 71-77. The data are shown in Table 6.

table

Concentrations of omeprazole (oral plasma concentrations of omeprazole in a single dose of 20 mg of omeprazole in hard gelatine capsules prepared according to Example 2 or as a suspension of micronized omeprazole in sodium bicarbonate solution.

Time (min) Capsule suspension

<td colspan="2"> 10</td><td> 0,84</td>

<td> 20</td><td></td><td> 0, 90</td>

<td> 30</td><td> 0,03</td><td> 0, 84</td>

<td> 45</td><td></td><td> 0, 64</td>

<td> 60</td><td> 0,22</td><td> 0,44</td>

<td> 90</td><td> 0, 36</td><td> 0,24</td>

<td> 120</td><td> 0,39</td><td> 0,13</td>

<td> 150</td><td> 0,29</td><td></td>

<td> 180</td><td> 0,20</td><td> 0,04</td>

<td> 210</td><td> 0, 10</td><td></td>

<td> 240</td><td> 0,05</td><td> 0,01</td>

<td> 300</td><td> 0,02</td><td> 0</td>

<td> 360</td><td> 0,01</td><td></td>

<td> 420</td><td> 0</td><td></td>

Although peak plasma concentrations occur at different times, the two formulations are bioequivalent. The mean relative bioavailability of the capsules compared to suspension was 85% + 23% (SD). Comparison of the total total individual concentration over time curves.

Thus, the preparation of the capsules according to the invention gives the preparation with the same bioavailability as the suspension containing the same amount of micronized active ingredient. However, it should be noted that the patient should also take sodium bicarbonate solution as often as possible to reduce the prebsorption of omeprazole in the stomach when using the suspension.