New pharmaceutical preparation for oral use.

A new pharmaceutical preparation containing omeprazole as an active ingredient

Full description

Background of the invention

This invention relates to a new, stable pharmaceutical preparation containing omeprazole, for oral use, and to a method for manufacturing that preparation and its effect on the secretion of stomach acid and the protection of the stomach and intestines using that preparation. Omeprazole was discovered in the European patent (005129-EP-A1), which is a

5-Methoxy-2(((4-methoxy-3 and 5-dimethyl-2-pyridinyl)

Methyl (sulfinyl)-IH-benzaimidazole,

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

Effective in suppressing stomach acid secretion. Omeprazole has a strong anti-acid secretion activity (Lancet, November 27, 1982, pp. 1223-1224), (1223-1224. Lancet, Nov 27, 1982, p). It can also be used in the treatment of gastric and duodenal ulcers. ). However, omeprazole is susceptible to degradation and transformation in acidic and neutral environments. The half-life of omeprazole in aqueous solutions at a pH of less than 4 decreases to less than 10 minutes, and decomposition proceeds at a rapid rate in neutral media, meaning that at a pH of 7 the half-life of omeprazole is 14.

hour, while its stability in solution increases at higher pH levels (Pilbrant and Cederberg, Scand. J. Gastroenterology 1985; 20 (suppl. 108), pp. 113-120) (Pilbrant and Cederberg, Scand. J. Gastroenterology 1985; 20 (suppl. 108) P. 113-120) The stability aspect is similar to that of the solid state. The decomposition of omeprazole increases with active acidic compounds, and is also proven in mixtures of active alkaline substances. Moisture and organic solvents also affect the stability of omeprazole. From the above, it is clear that the oral dosage form of omeprazole must be protected when it comes into contact with acidic gastric juice so that it reaches the intestine without decomposition. It has been found from human pharmacological studies that the rate of release of omeprazole from pharmaceutical dosage forms can affect the degree of absorption of omeprazole into the general circulation (Bilbrandt and Cederberg, Scand, J. Gastroenterology 1985; 20 (No. 108), pp. 113-120).

(Pilbrant and Cederberg, Scand. J. Gastroenterology 1985; 20 (suppl. 108) p. 113-120).

Therefore, the bioavailable dose unit of omeprazole must be released quickly

The first part (Proximal part) of the digestive canal.

To obtain a pharmaceutical dosage form of omeprazole that does not come into contact with acidic gastric juice, the pills must be enteric coated. However, the usual enteric coatings are made of acidic compounds, and therefore omeprazole will naturally decompose if it is coated with these traditional coatings, whether it comes into direct or indirect contact with them, which leads to a change in the color of the preparation and a decrease in its content of enteric coatings.

Omeprazole over time.

To improve storage stability, pills containing omeprazole should contain alkaline-reactive components. When these pills are enteric coated with an amount of the traditional polymer used in enteric coatings, such as phthalate and cellulose acetate, which allows the coating and the active medicine present in the pill to dissolve in the first section of the small intestine, it will also allow water to leak out of the juices. Infection through the enteric coating to the pills during the time that dosage forms remain in the stomach and before their contents are emptied into the small intestine. Then, the water circulating from the gastric juice dissolves some parts of the grain in the enteric coating layer, forming an alkaline solution inside the coated dosage form. The alkaline solution interacts with the enteric coating and dissolves it accordingly.

Pellebrandt and Cederberg mentioned an enteric-coated dosage form in the aforementioned journal, Second J Gastroenterology 1985, 20 (No. 108). pp. 113-120.

(Scand. J. Gastroenterology 1985; 20 (suppl. 108) p. 113-120.

The published research paper described an enteric-coated dosage form and reported that it had acceptable storage stability for clinical studies. It was later found that the stability of that dosage form was insufficient for the long-term storage that occurs when pharmaceutical dosage forms are marketed. When a traditional formulation of omeprazole is made, its stability is not good, especially with regard to moisture resistance. Therefore, moisture-tight containers have been designated to reduce these problems. However, this is not the final solution to these problems in the drug distribution system nowadays, as it causes an increase in

Costs. Under these circumstances, the need arose to develop new enteric preparations of omeprazole characterized by better stability.

Patent 3046559 -DE - A1 describes a method for encapsulating a dosage form. The dosage form is covered with a water-soluble layer containing microcrystalline cellulose, then with a second enteric coating in order to obtain a releaseable dosage form.

Effective medicine in the colon. This method does not lead to the required release of omeprazole

In the small intestine.

US patent 2,540,979 describes an enteric-coated dosage form, where the enteric coat is bonded to a second and/or first coat of a waxy layer that does not dissolve in water. This preparation method cannot be used in the case of pills containing omeprazole, since direct contact between omeprazole and microcrystalline cellulose causes the omeprazole to deteriorate and change its color.

Patent 2336218 - DE - B2 describes a method for producing a dialysis membrane consisting of a mixture of conventional enteric coatings of polymers and one or more cellulose derivatives that are insoluble in water. This membrane does not provide adequate protection for omeprazole in acidic gastric juice.

Patent 1204363- DE - Al describes a method for forming three encapsulating layers. The first layer dissolves in gastric juice, but does not dissolve in intestinal juice. The second layer dissolves in water regardless of pH, while the third layer is enteric coated. This preparation, as well as the one prepared as described in Patent No. 1617615 - DE - Al, dissolve slowly in the intestines, but they do not dissolve in the juices.

Infectious diseases. These two preparations cannot be used with omeprazole because rapid release of the drug into the small intestine is required.

Patent 1204363 DE - Al describes a three-layer coating to achieve release of the drug into the intestine, and that purpose is beyond the scope of this invention.

Patent 1485676 - GB-A describes a method for obtaining a preparation that fizzles in the small intestine by coating pills containing the active drug with an enteric membrane and an effervescent system containing a carbonate and/or bicarbonate salt and a pharmaceutically acceptable acid. This composition cannot be used in dosage forms containing omeprazole because the presence of acid and its contact with omeprazole in the pills leads to the decomposition of omeprazole.

Patent 85/03436 WO also describes a pharmaceutical preparation in which pills containing active drugs are coated with pH-regulating components, for example, such as sodium dihydrogenphosphate, for the purpose of stabilizing the pH and the rate of diffusion, with a first layer that controls diffusion. This formulation cannot be used in the case of omeprazole as rapid release of that drug into the small intestine is required. Also, the direct coating of the enteric coating on the pills has a detrimental effect on the storage stability of those dosage forms containing

On omeprazole.

General description of the invention

This invention aims to provide enteric-coated dosage forms of omeprazole, which can resist dissolution in an acidic solution but dissolve quickly in alkaline intestinal media and maintain good stability during storage for long periods. The pills containing omeprazole are mixed with alkaline compounds, or optionally with an alkaline salt of omeprazole, with alkaline compounds, then coated in two or more layers, where the first layer or layers are soluble or rapidly disintegrating in water, and include inactive, non-acidic materials acceptable to pharmaceuticals. These layers separate the grain material from the outer layer that coats the intestine. The enteric-coated dose is treated in an appropriate manner to reduce the water content to a minimal level to obtain good stability of the dosage form during long-term storage. Detailed description

Core

Omeprazole is mixed with traditional pharmaceutical inactive ingredients, preferably soluble in water, to obtain the preferred concentration of omeprazole in the final mixture, and with an alkaline-reactive or inert, pharmaceutically acceptable substance (or several substances) that produces a fine layer with a specific pH around each molecule of omeprazole. Less than 7, and preferably not less than 8, when the water in those molecules is absorbed into the mixture or when water is added in small quantities to the mixture. These materials can be chosen from among the sodium, potassium, calcium, magnesium, and aluminum salts of acid. Phosphorus or phosphoric acid

Carbonic acid or citric acid, or any other inorganic or weak organic acids, without being limited to them only, or materials that are usually used in antacid preparations such as aluminum, calcium and magnesium hydroxides, or magnesium oxide, Or complex compounds such as aluminum oxide and magnesium oxide, Al2O3.6MgO.CO3. 12H2O

And tetrahydrate, Mg6Al2 (OH)16CO3.4H2O, and magnesium oxide, aluminum, and hydrated silicon, MgO.Al2O3. 2SiO2. nH2O n or similar compounds, or pH-regulating substances such as trihydroxymethylaminomethane, or other similar pH-regulating substances that are pharmaceutically acceptable. It is also possible to achieve a stable high pH in the powder mixture by using an alkaline reactive salt of omeprazole, such as sodium, potassium, magnesium, calcium, etc....

Or the omeprazole salts described in Patent No. 495 124 - EP - A2, whether alone or in combination with a conventional buffer substance as previously described.

The powdered mixture is then formulated into small beads, i.e. pellets, tablets, or hard or soft gelatine capsules, using traditional pharmaceutical methods.

Pellets, granules and gelatin capsules are used as pills in further operation.

Separating layer

It is necessary to separate the core containing the reactive alkaloid omeprazole from the enteric coated polymer containing free carboxyl groups, otherwise decomposition of omeprazole will occur and its color will change during the packaging and storage process. The lined covering layer, which is later referred to as the insulating layer or separating layer, also acts as a pH-regulating area in which hydrogen ions spreading from the outside to the inside towards the alkaline core can interact with the hydroxide ions present in the alkaline core towards the surface of the coated grains. The pH-regulating properties of the separating layer can also be strengthened by introducing materials selected from the group of compounds commonly used in antacid formulations, such as magnesium oxide and its hydroxide or carbonate, aluminum or calcium hydroxide and its carbonate or silicate, and complex aluminum/magnesium compounds such as Al2O3.6MgO.CO2. 12H2O or Mg6Al2(OH)16CO3.4H2O or MgO.Al2O3.2SiO2nH2O or similar compounds, or any pharmaceutically acceptable pH-regulating compounds, such as salts of sodium, potassium, calcium, or Magnesium or aluminum for phosphorus and citric acids or any other suitable inorganic or weak organic acids.

The separating layer consists of one or more inert layers that are soluble in water and optionally contain pH-regulating compounds.

Endodontic tablets or pellets can be coated with a separating layer using traditional packaging methods, in a suitable packaging container or in a fluidized bed apparatus.

Using water and/or conventional organic solvents in the encapsulation solution. The separator material shall be selected from among pharmaceutically acceptable inert water-soluble compounds or polymers used in film coatings such as sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, methylcellulose, and hydroxymethyl cellulose. Hydroxypropyl methylcellulose and polyphenylacetal diethyl amino acetate. Polyvinyl acetal diethylaminoacetate or similar. The thickness of the separating layer is not less than 2 micrometers, for small granules it is not less than 4 micrometers, and for tablets it is not less than 10 micrometers.

Another method of packaging tablets can be done using dry packaging technology. The tablets containing omeprazole are compressed first as previously described, then a layer is compressed around those tablets using a suitable tableting machine. The outer separating layer consists of pharmaceutically acceptable excipients that dissolve in water or break down easily in water. The thickness of this separating layer shall not be less than 1 mm. Natural plasticizers, colorants, pigments, titanium dioxide, talc, and other additional materials can also be added to the separating layer. In the case of gelatin capsules, the gelatin capsule acts as a separating layer in itself.

Enteric coating layer

The enteric coating layer is used to wrap pulp covered with traditional packaging techniques, such as packaging in pan coatings or in a fluid bed, using solutions of polymers in water and/or appropriate organic solvents, or using latex suspensions of these polymers. Enteric coating polymers such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, and co-polymerized methyl esters of methacrylic acid can also be used methacrylic methyl ester / And methacrylic acid polymers, such as the compounds known under the brand name Eudragit ® L 12.5 Eudragit or Eudragit ® 100 L (Rohm Pharma) or similar compounds used in enteric coatings. Enteric coatings can also be used using water-polymer based suspensions such as Aquteric® (EMC), Eudragit® 55-L100 (Rom Pharma), and CE 5142 coating (BASF). The enteric coating can optionally contain a pharmaceutically acceptable plasticizer such as Cetanol, triacetin, citric acid esters, such as those known by the trade names Citroflex® (Pfizer), phthalic acid esters, dibutyl succinate, or similar plasticizers. Maximum plasticizer quantities are determined for each coated polymer

Enteric also usually ranges between 1 and 20% of the enteric-coated polymer. Dispersing and suspending materials such as talc, coloring materials, and dyes can also be added to the enteric coating layer. Thus, the particular preparation according to this invention includes ointments containing omeprazole. Mixed with an alkali-reactive compound, or pellets containing an alkali salt of omeprazole mixed with an alkali-reactive compound. The alkali reaction in the pulp and/or the alkali salt of the active compound, omeprazole, improves its stability. The grains suspended in water are a solution or suspension that has a higher pH than that of the solution in which the polymer is used for enteric coating. The pellets are covered with an inert coating that allows rapid dissolution or disintegration in water, and optionally contains a pH-regulating substance that separates the alkaline grains from the enteric coating. Without this separating layer, the resistance against the acid juice becomes short, and the stability of the dosage form during storage becomes unacceptably short. Finally, the lined dosage forms are coated with an enteric coating that makes them insoluble in acidic media and dissolves or disintegrates quickly in neutral or alkaline media, such as the fluids present in the anterior part of the intestine, which is the desired location for dissolution to occur.

Final dosage form

The final dosage form takes the form of a coated tablet, capsule, or granules packed in hard gelatin capsules, in the case of enteric-coated granules, or sachets or granules formulated in the form of tablets.

It is necessary for the water content to remain low in the final dosage form to ensure long-term storage stability (enteric-coated tablets, capsules, or granules containing omeprazole), and it is preferable that it does not exceed 1.5% by weight. Therefore, it is preferable that the final package containing hard gelatin capsules packed with enteric-coated granules contain a desiccant that reduces the water content in the gelatinous wall of the capsules, to a level such that the amount of water in the enteric-coated granules packed in the capsules does not exceed 1.5% by weight.

the operation

The process of manufacturing the oral dosage form represents another aspect of this invention. After manufacturing the pills, they are coated first with a separating layer, then with an enteric-coated layer, and the packaging is carried out as previously described.

The preparation according to this invention is particularly useful in inhibiting the secretion of stomach acid and/or producing a protective effect on the cells of the stomach and intestines. It is taken from one to several times daily. The daily dose of the active ingredient varies, as it depends on several factors, including the personal requirements of the disease, the method of administration, and the type of disease. In general, the daily dose ranges between 1 and 400 mg of omeprazole. The method of treating cases with the new dosage form constitutes another aspect of this invention.

The following examples explain this invention in detail.

Models

Form 1

Evaluate the effect of different magnesium compounds in the form of enteric-coated tablets. The tablet core was first manufactured using known techniques according to the formulations listed in Table 1, then coated with separating layers and then with an enteric coating layer as shown in Table 2.

<img file="SA56B1_D0001.tif" />

The tablets he obtained were stored in open packaging under so-called conditions

<img file="SA56B1_D0002.tif" />

Al-Majalah, i.e. 40°C and 75% relative humidity, and changes in appearance were noted over the course of

The time corresponds to storage under those conditions for six months, and storage at normal temperature for three years. This means that it is possible to ensure high stability sufficient for practical use if the drug remains undegraded for a week under accelerated conditions. The results are summarized in Table 3. From the table it can be seen that it is possible to achieve a clear effect represented by a noticeable stability when a magnesium compound is added to the inner separation layer.

Table 3: Improved effect of stability (appearance of preparations)

<img file="SA56B1_D0003.tif" />

All samples were evaluated as (white) in the previous table when they did not show any color changes even on the surfaces of the joints. Samples were evaluated as white-brown when there was a slight change in their appearance, with color changes noted above the joint surfaces. Table 4 shows the results of the stability test on the omeprazole preparation according to Model 1 (Formation No. IV-4). The formulation was stored in a closed glass vial at room temperature for the specified period of time. This shows that preparations with above-normal stability have been obtained.

<img file="SA56B1_D0004.tif" />

Form 2.

Uncoated granules

Mannitol powder 16150 gm

I non-anhydrous lactose 800 g

Hydroxypropyl cellulose 600 g

Microcrystalline cellulose. 400 g

Omeprazole 2000 gm

Sodium lauryl sulfate 50 g

Sodium dihydrogen phosphate 80 g

Distilled water 4400 g

Mix the dry ingredients (I) in a blender beforehand. Granulation fluid (II) containing the omeprazole suspension was added, then the mass was wet mixed until it became a suitable consistency. The wet mass was pressed in an extruder and formed into pellets.

The pellets were dried and classified into appropriate sizes.

Coated Pellets Omeprazole Uncoated Pellets 6000 gm

Hydroxypropyl cellulose 240 g

Distilled water 4800 g

Spray the polymer solution (III) over the uncoated pellets in a fluidized bed apparatus. Spray guns were also placed above the liquefied cradle.

Enteric coated pellets

Lined balls 500 g

Hydroxypropylmethylcellulose phthalate 57 g

IV cetyl alcohol 3 g

Acetone 540 g

Ethanol 231 g

The polymer solution (IV) was sprayed over the lined pellets in the cradle liquefaction device, and the spray guns were placed over the cradle. After drying until the water content reached 0.5%, the enteric-coated pellets were classified and packed into hard gelatin capsules in an amount of 225 mg, equivalent to 20 mg of omeprazole. 30 capsules are packed in one sealed package with desiccant.

Form 3

This model shows that a variety of polymers can be used in lining, such as hydroxypropyl methylcellulose and hydroxypropyl cellulose.

Polyvinylpyrrolidone is polyethylene glycol and polyvinyl alcohol. Uncoated pellets

Mannitol powder 1620.0g

I anhydrous lactose 80.0 g

Hydroxypropyl cellulose 60.0 g

Microcrystalline cellulose 40.0 g

Omeprazole 0.200 gm

II Sodium lauryl sulfate 1.0 g

Sodium dihydrogen phosphate 9.3 g

Distilled water 515.0 g

Uncoated pellets were prepared as in Model 2.

Padded balls

Omeprazole pellets uncoated 500 g

III Polyvinylpyrrolidone. 20 gm

Ethanol 400g

The lining pellets were prepared as described in Model 2. Enteric coated pellets

Lined balls 500g

Hydroxypropylmethylcellulose phthalate 45 g

IV cetyl alcohol 5 g

Acetone 219 g

Ethanol 680g

Enteric-coated pellets were prepared as described in Sample 2. The model consists of 4 uncoated pellets

Mannitol powder 0 161 gm

I non-anhydrous lactose 80 g

Hydroxypropyl cellulose 60g

Microcrystalline cellulose 40g

Omeprazole 200 gm

Pluronic II Pluronic F68 10 g

Disodium hydrogen phosphate 24 g

Distilled water 450 g

Uncoated pellets were prepared as described in Model 2. Padded balls

Uncoated pellets 500g

III Polyvinylpyrrolidone 30 gm

Ethanol 400g

The lining pellets were prepared as described in Model 2. Enteric coated pellets

Lined balls 500g

Hydroxypropylmethylcellulose phthalate 45g

IV cetyl alcohol 5 g

Methylene chloride 371 g

Ethanol 680g

Enteric-coated pellets were prepared as described in Sample 2.

Form 5

This model shows that a number of types of polymers can be used as enteric coating materials, such as cellulose acetate phthalate, polyvinyl acetate (phenyl alcohol phthalate), hydroxypropyl methylcellulose phthalate, and poly(methacrylic acid/methacrylic acid methyl esters). Polymers can be used with or without a plasticizer, such as polyethylene glycolate, triacetin, dimethylpolysiloxane, Citroflex®, cetyl alcohol, stearyl alcohol, and diethyl phthalate. Enteric-coated pellets can also be manufactured from water-based polymer suspensions such as Aquatric (FMC) and Eudragit® 55-100. L, Envelope 5142 CE (BASF)

Uncoated pellets

Lactose powder 277 g

I non-anhydrous lactose 118g

Hydroxypropyl cellulose 25g

Colloidal silica 25g

Omeprazole 50.0 gm

Sodium lauryl sulfate 0.5 gm

II Disodium hydrogen phosphate 2.0 g

Sodium dihydrogen phosphate 1.0 gm

Distilled water 170.0 g

Uncoated pellets were prepared as previously described. Padded balls

The uncoated pellets were coated as described in Model 2. Enteric coated pellets

Lined pellets 0.500 g

Udragit II 100 L 45.0 gm

Stearyl alcohol 4.5 gm

Ethanol 1320.0 g

Enteric-coated pellets were prepared as previously described.

Form 6

Formulations with sodium salt of omeprazole

Uncoated pellets

Omeprazole sodium salt 339g

Mannitol powder 2422g

Non-aqueous lactose 120g

I Hydroxypropyl Cellulose 90g

Microcrystalline cellulose 60g

II Sodium Lauryl Sulfate 7g

Distilled water 650 g

The preparation was prepared as described in Sample 2 except that the sodium salt of omeprazole was added with the other ingredients in Mixture 1.

Padded balls

Uncoated pellets 500g

III Propyl methylcellulose hydroxide 20g

Aluminum hydroxide/magnesium carbonate 4g

Distilled water 400 g

B III padded pellets 500g

IV Hydroxypropyl Methyl Cellulose 20g

Distilled water 400 g

The uncoated pellets were coated with two liner layers III and IV in the cradle fluid device, respectively, as previously described. Enteric-coated pellets

Lined balls 500g

Hydroxypropylmethylcellulose phthalate 57g

Cetyl alcohol 3g

V acetone 540g

Ethanol 231 g

Enteric-coated pellets were prepared as described in Sample 2.

Forms 7 and 8

Formulations of the magnesium salt of omeprazole

Model number.

Uncoated pellets 7 8

Magnesium salt of omeprazole 222 g 222 g

I Mannitol powder 1673g 1473g

Microcrystalline cellulose 100g 100g

Hydroxymagnesium - 200g

Sodium Lauryl Sulfate 5g 5g

II Distilled water 500 g 375 g

The preparation is made as described in Model 2 except that the magnesium salt of omeprazole is used

It may be added with the other ingredients in mixture I.

Sample

Lined balls 7 and 8

Uncoated pellets 500 g

Hydroxymethylpropyl cellulose 20 g

Distilled water 400 g

The pellets were prepared as described in Model 2.

The two models

Enteric coated pellets 7 and 8

Lined balls 500g

Hydroxypropylmethylcellulose phthalate 57g

IV cetyl alcohol 3g

Acetone 540g

Ethanol 231 g

Enteric-coated pellets were prepared as described in Sample 2. Forms 9 and 10

Disc manufacturing model number

Pills 9 10

Omeprazole 400 gm -

Omeprazole sodium salt equivalent to 400 gm Omeprazole - 426 gm

I non-aqueous lactose 1420g 1409g

Cross-linked polyvinylpyrrolidone 100 g 100 g

Anhydrous sodium carbonate 15 g

II Methyl Cellulose 12 g 12 g

Distilled water 200 gm 200 gm

Magnesium stearate 30 gm 30 gm

Carefully mix the powder mixture I until it is homogeneous, then granulate it with solution II. The wet mass was dried in a bed dryer using air at 50°C for 30 minutes. Then squeeze the dry mixture through a sieve with an opening size of 0.5 mm. After mixing with magnesium stearate, the granular product was pressed in a tablet making machine using molds with a diameter of 6 mm. The weight of the tablet reached 100 mg.

Subcoating

Tablets containing omeprazole are coated with approximately 10% by weight of hydroxychloroquine

Propyl methyl cellulose from aqueous solution using a perforated laminator

perforated coating pan apparatus.

Tablets containing the sodium salt of omeprazole were coated using a dry packaging technique. The tablets were prepared containing the following: -

Non-aqueous lactose 4000g

Polyvinylpyrrolidone (PVP) 180g

Ethanol 95% 420g

Magnesium stearate 42g

This is done by granulating the lactose with a solution of PVP in ethanol, then drying the granules. After drying, the granules were mixed with magnesium stearate. The granule mass was dry-coated around the tablet grains of Model 9 using a Manesty Dry Cota® flattening machine. The weight of the dry coated tablet was 475 mg. The tablet contained 20 mg of omeprazole.

Enteric packaging

The resulting coated tablets were enteric coated using the same coating solution.

Hydroxypropyl methylcellulose phthalate 1500g

Cetyl alcohol 105g

Methylene chloride 15000 g

Isopropanol 15000g

Distilled water 3150 g

Packaging was carried out in a perforated container packaging device. About one kilogram of coating solution was used for every kilogram of tablets. Compare models I, II and III

These models show that the buffer salt used affects the properties of enteric-coated omeprazole tablets when they are not coated. To obtain a product that can be stored for a long time, a large amount of buffer salt is used. At the same time, these tablets show poor acid resistance properties, and they also differ from the previous Model 4.

Model numbers

Uncoated pellets III II I

Mannitol powder 1610 gm 1610 gm 1610 gm

Non-aqueous lactose 80 g 80 g 80 g

I Hydroxypropyl Methyl Cellulose 60g 60g 60g

Microcrystalline cellulose 40g 40g 40g

Omeprazole 200g 200g 200g

II Pluronic F68 10g 10g 10g

Disodium hydrogen phosphate 2 g 8 g 24 g

Distilled water 450 g 450 g 450 g

Uncoated pellets were prepared as described in Model 2 above. Enteric coated pellets

Uncoated pellets 500g

III Hydroxypropylmethylcellulose phthalate 45g

Cetyl alcohol 5g

Methylene chloride 371 g

Ethanol 680g

The coated pellets were prepared as described in Model 2 by Model IV

This wording is similar to its counterpart in Model 6 above, but without a lining.

Uncoated pellets

Omeprazole sodium salt 339g

Mannitol powder 2422g

I non-aqueous lactose 120g

Hydroxypropyl cellulose 90g

Microcrystalline cellulose 60g

Sodium lauryl sulfate 7g

II Distilled water 650g

Make the preparation as described in Form 6 above.

Enteric coated pellets

Uncoated pellets 500g

Hydroxypropylmethylcellulose phthalate 57g

III Cetyl alcohol 3g

Acetone 540g

Ethanol 231 g

Enteric-coated pellets were prepared as described in Sample 2 above. Model V

This formulation is similar to its counterpart in the previous Model 8, but without the lining layer of uncoated balls

Magnesium salt of omeprazole 222 g

Mannitol powder 1473g

I Microcrystalline cellulose 100g

Magnesium hydroxide 200g

Sodium lauryl sulfate 5g

II Distilled water 375 g

Enteric coated pellets

Uncoated pellets 500g

Hydroxypropylmethylcellulose phthalate 57g

III Cetyl alcohol 3g

Acetone 540g

Ethanol 231 g

The pellets were prepared as described in Model 2 above.

Properties of enteric-coated pellets

For the preparations belonging to models 2-8 and the aforementioned contrast models V-I, one or both of the following studies were conducted together. air resistance

The resistance of the formulations to air was studied by adding them to the prepared solution according to the US Pharmacopoeia (without enzyme) and stirring them at a rate of 100 revolutions/minute at 37°C. After two hours, the amount of omeprazole was calculated, which remained unchanged in the formulations.

The rate of dissolution in the buffer solution

To determine the rate of dissolution in the small intestine, the formulations were added to the buffer solution in a dissolution device, according to the US Pharmacopoeia, No. 2 (paddle), and stirred at a rate of 100 revolutions/minute at 37°C. After 10 or 30 minutes, I calculated the amount of omeprazole that had dissolved. The results were recorded in the following Table 5: -

<img file="SA56B1_D0005.tif" />

* The stability of the formulation was studied during storage in glass vials containing a dried substance. After a month of storage at +50°C, the formulation according to Model 4 was truly intact and without any change in appearance or physical-chemical specifications. The color of the pellets of Models I and II changed and became brown due to decomposition, while they remained

The Model III pellets retain their original white colour.

* * The formulations of Models 7 and 8 were white in color and were not affected by the packaging process. The color of the enteric-coated pellets changed according to Model V, as the enteric coating was placed directly on the pills according to Model 8, during the actual enteric coating process.

Another comparative test

This model shows the effect of moisture content in the preparations of this invention on stability during storage.

The stability of omeprazole pellets according to this invention was compared with the stability of omeprazole pellets with a high water content. Omeprazole granules were prepared in accordance with this invention with a water content of 1%. Two other samples of the same formulation were adapted to a water content of 2% and 5%, respectively. The three formulations were stored after filling them in airtight containers that did not contain a drying agent, for a month at 50°C.

After that period, the containers were opened, and the pellets were assayed to determine the amount of omeprazole in them by high-performance liquid chromatography. The percentage of omeprazole content in the formulation corresponding to this invention was 98.5 of the original value. The other two formulations, which contained 2 and 5% water, were completely decomposed, leaving only traces of intact omeprazole.

Discussion

From the results recorded in Table 5, it can be seen that an omeprazole-containing formulation that has acceptable acid resistance can be prepared using the conventional enteric coating technique (see Forms I, II, and V for example). However, it can be noted that the stability of the formulations according to Forms I, II and III during storage is unacceptable, due to the occurrence of a color change indicating the decomposition of omeprazole during short-term storage at high temperatures (Forms I and II) or even during the enteric coating process as well.

When the amount of alkaline substances in the grains increases to a level at which omeprazole reaches acceptable storage stability (Form III), or if an alkali-reactive salt of omeprazole is used in preparing the grains (Form IV), the resistance to dissolution in acidic media decreases to an unacceptable degree. Unless a separating layer is used in accordance with this invention, which leads to the active substance actually decomposing in the stomach, and thus no suppressive activity for gastric acid secretion occurs.

When the preparation is made according to the invention by following Model 4, for example, it is possible to obtain good resistance against stomach acid in addition to good stability during long-term storage. This contradicts the formulations of models I, II, and III, where it is possible to achieve either acceptable resistance to acids, or good stability when stored only, that is, not both. The same comparison can be made between the formulations of Model V in which the separating layer has been eliminated. The two models differ in one additional aspect

Magnesium hydroxide as a buffering material for grains of Model 8. This also leads to improved resistance to acids and stability when stored in Form 8 compared to Form 7.

Additional comparative testing demonstrates the great importance of reducing the water content in...

Lotions.

Thus, the preparation is manufactured in the following way to obtain pharmaceutical formulations for oral use, as it is characterized by good stability during long-term storage, and good stability while remaining in the stomach after oral administration.

A) Mix omeprazole with an alkali-reactive compound, or alkaline compounds

The reaction, or the alkali salt of omeprazole with the alkali reaction compound,

Optionally, it is then shaped into pills.

b) The pellets are covered with one or more lined layers of inert layers that dissolve or disintegrate quickly in water, in order to separate the reactive alkaline pellets from the

Intestinal covering. The lining layer may optionally contain structured compounds

For pH.

C) The lined pulp is covered with an enteric coating that does not dissolve in acidic media, and optionally contains plasticizers.

Biopharmaceutical studies

Hard gelatin capsules were given according to Model 2 to twelve young male volunteers, in the following manner:

The volunteers came to the laboratory in the morning after abstaining from food since 10 pm the night before the test day. A zero time blood sample was taken, then each person took an omeprazole capsule according to Model 2 with 150 ml of water. Other blood samples were taken during the day.

In another experiment, the same volunteers took 20 mg of omeprazole in the form of a suspension of finely ground omeprazole in a solution of sodium bicarbonate in water.

People took a sodium bicarbonate solution immediately before taking omeprazole, then four times at 10-minute intervals after taking the drug, to reduce the breakdown of omeprazole in the stomach. Determine the concentration of omeprazole in blood by high-performance liquid chromatography (Persson, Lagerstrom and Grundevik. Scand J Gastroenterol 1980, 20 (n 108), 71-77). (suppl).

The average concentrations in plasma are listed in Table 6.

Table 6

Plasma concentration of omeprazole (µmol/L) after a single oral dose of 20 mg of the drug in the form of a hard gelatin capsule according to Model 2, and in the form of a suspension of fine omeprazole in a solution of sodium bicarbonate.

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Although the maximum amount in plasma was found after different periods, the two formulations are bioequivalent. The average relative amount of bioavailable from the capsules was 85% ± 23% (standard error) (.S.D) compared to the suspension. The comparison was based on the total area under the plasma concentration curves for each sample versus time.

Thus, it was possible to obtain a preparation with uniform bioavailability from two pharmaceutical forms, namely capsules and suspension, in accordance with this invention, as they contained the active compound in its finely crushed form. However, it should be noted that when the suspension is taken, the patient must take sodium bicarbonate in batches to reduce the breakdown of omeprazole in the stomach before it is absorbed in the intestine.