KR100274698B1 - Oral preparation of omeprazole and its preparation by multilayer alkali coatimg - Google Patents

Abstract

PURPOSE: A pharmaceutical formulation of omeprazole for oral administration consisted essentially of a repeated multicoat of an omeprazole layer and an alkali layer on a pellet or the like and an enteric coat is provided, which can maintain alkaline for a long period of time and be manufactured in a simple manner. CONSTITUTION: This formulation of omeprazole is prepared by the process consisting of: mixing refined sugar with a binding agent and forming a granular or pellet; dissolving omeprazole in a solvent selected from a binding agent, water, alcohol or dichloromethane and coating on a core having a moisture content of less than 1% by weight in the first stage; repeatedly coating 1 to 3 times in the second stage; and performing enteric coating.

Description

Oral preparation of omeprazole by multilayer alkali coating and preparation method thereof

The present invention relates to a stable and effective new oral preparation containing omeprazole, a method for preparing the same, and a method for treating gastric hyperacid system in the gastrointestinal tract by controlling gastric acid secretion using the preparation.

EP-A1-0 005 129 describes omeprazole, a gastric acid secretion inhibitor. It has good gastric acid secretion (Lancet, Nov. 27, 1982, pp. 1223-1224) and is known to be effective in the treatment of gastric ulcer and duodenal ulcer. However, since omeprazole is inferior in acidity and neutrality, when administered in a conventional oral dosage form, omeprazole is almost decomposed in the gastrointestinal tract, and methods for increasing the stability in the gastrointestinal tract have been studied.

British Patent No. 2,137,616 (October 10, 1984) reports the development of new salts to enhance the stability of omeprazole, but this is a development of completely new compounds, which entails enormous development costs and periods.

International Patent No. 8,600,913 (February 13, 1986) reports cyclodextrins and clathrates to inhibit the degradation of omeprazole in the gastrointestinal tract, but the stability and effectiveness in the underlying gastrointestinal tract are suspected.

Patent Publication No. 91-2356 discloses a method in which an alkali salt of omeprazole or an omeprazole and an alkaline substance are mixed to form a core and a separation layer is set for separation from the outermost enteric coating layer. However, this method must first prepare an alkaline coating using an extruder, a spherical granulator, or the like, and transfer it to a coater to coat one or more separator layers and perform recoat coating. Therefore, a large number of mechanical devices are required in the process, the formulation must be moved frequently during the operation, and the core, the membrane layer, and the enteric skin composition mechanism are all different, and therefore, three or more operations or coating composition mechanisms are required. In addition, this method does not address the changes in pH that can occur due to the different dissolution rates of omeprazole and alkaline substances in body fluids in the small intestine. It is unlikely to provide a stable pH until fully absorbed.

An object of the present invention is stable in an acidic or gastrointestinal environment and does not release the drug, but in a neutral, alkaline or small intestine environment, omeprazole and alkaline at an appropriate rate to be absorbed in the living body by alternately eluting a predetermined amount of omeprazole and an alkaline component. In addition to providing a formulation that enables the stable absorption of the omeprazole in the small intestine by releasing the substance, it provides a convenient method for its preparation.

The novel formulation of the present invention has the following features. Coating an omeprazole layer prepared by coating a suitable spherical or pellet-like internal material with an alkali-containing layer and repeating this process two or more times to maintain a pH suitable for continuous absorption of the omeprazole in the small intestine. do. Enteric coatings of this repeated coated intermediate foams or enteric coatings after further manipulations such as capsule filling or tableting do not elute or decompose in the stomach, but alternately release omeprazole and alkali from the small intestine, which is neutral or weakly alkaline. In this case, the same coating material may be used to coat the omeprazole and the alkali component, thereby simplifying the process.

In the oral preparation of the present invention, the omeprazole layer is constituted as follows.

The layer to be coated with omeprazole may be a pellet or spherical material composed of sugars such as non-pareil seed (Sizes 10 to 30) or inert ingredients which are commonly used for the preparation of pellets in the pharmaceutical preparation process. In addition, substances commonly used for antacids, for example, powders such as sodium bicarbonate, aluminum hydroxide, calcium hydroxide, magnesium hydroxide, Al ₂ O ₃ · 6 MgO · CO ₂ · 12H ₂ O or MgOAl ₂ O ₃ · 2SiO ₂ · nH ₂ O (Size 40 pass through) can also be used. Na, K, Mg, Ca, Li salts of phosphoric acid, carbonic acid, citric acid, tartaric acid, folic acid, other suitable inorganic weak acids or organic weak acids can also be used. In addition, PEG, PVP, PVA, HPC, MC, HMC, HPMC, AEA, gelatin, starch, CMC, Carbopol (Carbopol) and the like may be made of pellets or spherical granules in a conventional manner. Omeprazole is assembled into a centrifugal fluidized bed using PEG, PVP, PVA, HPC, MC, HMC, HPMC, AEA, gelatin, starch, CMC Carbopol, and suitable solvents commonly used for coating such as water, alcohols, dichloromethane, etc. Coating in a coater (eg CFGranulater, Freind Industries). The final formulation comprises two or more layers of omeprazole separated from one another.

In the oral formulation of the present invention, the alkali layer is constituted as follows.

The above omeprazole layer is a material commonly used for antacids, for example, sodium bicarbonate, aluminum hydroxide, calcium hydroxide, magnesium hydroxide, Al ₂ O ₃ · 6MgO · CO ₂ · 12H ₂ O, MgOAl ₂ O ₃ · 2SiO ₂ · nH ₂ 0 light (pass size 40 body) and PEG, PVP, PVA, HPC, MC, HMC, HPMC, AEA, gelatin, starch, CMC, Carbopol (Cobopol) and the like are coated in a conventional centrifugal fluidized bed assembly coater and the like. At least two alkali layers are separated from each other in the final formulation.

In the present invention, the enteric coating layer is configured as follows.

The enteric coating is prepared by further subjecting the repeated coating to a polymer suspended or dissolved in a solvent used in conventional enteric coating. Examples that can be used as enteric polymers include HPMCP, CAP, Eudragit and the like. The enteric coating layer may add additives such as pharmaceutically acceptable plasticizers, coloring agents, light blocking agents, and the like.

Therefore, the special preparation according to the present invention is a preparation in which an omeprazole layer and an alkali layer are repeatedly coated on a pellet or the like, followed by enteric coating. The repeated coated alkali layer keeps the alkaline stability suitable for storage stability of omeprazole and absorption in the small intestine for a long time.

The present invention is embodied by the following examples and comparative examples. Granules were prepared using different numbers of coating layers and different alkalis, and their appearance changes were evaluated by storing them in open form under accelerated and long term storage conditions. In addition, the change of the appearance in acidic liquid was observed over time.

[Comparative Example]

The internal granules of the comparative formulation were assembled by extrusion granulation at a ratio of omeprazole 20, sodium bicarbonate 20, lactose 60, corn starch 60 instead of using a white sugar core. And coating with the enteric coating composition A to make the thickness of the coating layer more than 30 micrometers.

EXAMPLE

Put sucrose into a gyroshifter, sort out 250-840 micrometers (about 20-60 mesh) of sucrose crystals into a centrifugal electric granulator (trade name: CFGranulator, industry) while rotating the vessel at a suitable speed. At the same time as spraying the aqueous solution of% hydroxypropyl cellulose, fine powder of mannitol (100 mesh or less) was injected at a suitable speed, and granulated until a suitable spherical shape was obtained. The particles were dried under the conditions of 40-75 ° C. so that the water content (110 ° C., 15 minutes) was 1.0% or less.

The 5% hydroxypropyl cellulose-isopropyl alcohol solution was sprayed and coated with a material corresponding to the first layer. After the coating was completed, the second layer of the corresponding substance was injected and coated. After completing the multi-coating in the same manner and dried at 40-60 ℃ to less than 2% moisture content (110 ℃, 15 minutes). Finally, enteric coating (enteric coating composition A) was performed so that the thickness of the enteric coating was 30 micrometers or more.

TABLE 1

* OPZ: omeprazole, A: sodium bicarbonate, B: magnesium oxide, C: hydrotaxite, D: calcium carbonate, E: sodium bicarbonate + hydrotalcite (1: 1)

** Unit is mg (based on one dose = omeprazole 20mg)

The private coating composition A was as follows.

Experimental Example 1: The change over time of the appearance of the preparation under the storage conditions.

The observation result of the change of the appearance with time at each storage condition of each formulation of a comparative example and an Example is shown in following Table 2.

TABLE 2

* 1: white, 2: white brown, 3: light brown, 4: brown, 5: dark brown

Experimental Example 2: Acid Resistance Test.

The enteric pellets prepared in the previous examples and the comparative examples were subjected to an acid resistance test by the following method. Immediately, experiments were performed at 100 rpm for an amount corresponding to 20 mg as omeprazole using a basket method using a disintegration test No. 1 solution of the Korean Pharmacopoeia General Test Method at 37 ° C. The results are shown in Table 3 below.

TABLE 3

Acid resistance test result (pH 1.2, 37 ℃

* 1: white, 2: white brown, 3: light brown, 4: brown, 5: dark brown

As described above, the oral preparation of omeprazole according to the present invention is excellent in storage stability and acid resistance, and can maintain alkalinity suitable for absorption in the small intestine for a long time, and can be easily manufactured in a single coating machine. It can be seen that the formulation.

Claims (1)

White sugar is polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), methyl cellulose (MC), hydroxymethyl cellulose (HMC), hydroxypropylmethyl To a core mixed with at least one binder selected from cellulose (HPMC), carboxypolymethylene (Carbopol), gelatin and starch, molded into spherical granules or pellets in a conventional manner and adjusted to a moisture content of 1% or less; Omeprazole may be selected from polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), methyl cellulose (MC), hydroxymethyl cellulose (HMC), hydroxypropyl methyl cellulose (HPMC), A first step of selecting one or more binders selected from gelatin, starch or carboxypolymethylene (Carbopol) and coating them by dissolving or suspending in a solvent selected from water, alcohol or dichloromethane; At least one alkali coating material selected from sodium bicarbonate, aluminum hydroxide, calcium hydroxide, magnesium hydroxide, Al ₂ O.6MgO.12H ₂ O or MgO.Al ₂ O ₃ .2SiO ₃ .nH ₂ O is selected from polyethylene glycol (PEG) and polyvinyl. Pyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), methyl cellulose (MC), hydroxy methyl cellulose (HMC), gelatin, starch carboxymethyl cellulose sodium (CMC Na) or carboxy poly Coating the second process of coating by dissolving or suspending one or more binders selected from methylene (Carbopol) and one or more solvents selected from water, lower alcohols or dichloromethane, one to three times; An omeprazole multilayer coating oral preparation prepared by enteric coating in a conventional manner with at least one component selected from hydroxypropylmethylcellulose phthalate (HPMCP) or cellulose acetate phthalate (CAP) as an enteric polymer.