JP2004175768A - Method for producing stabilized omeprazole enteric coated tablet - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a stabilized omeprazole enteric coated tablet by coating a core tablet containing the omeplazole with an intermediate coating layer on the surface of the core tablet, then coating an enteric coating layer on the intermediate coated layer in this order without containing any alkali reactive compound in the core tablet and in the intermediate coated layer. <P>SOLUTION: This production method for stabilized omeprazole enteric coated tablets comprises (a) the step wherein the omeprazole, a vehicle, a disintegrator and a binder are mixed and granulated; (b) the step wherein a lubricant is added to the granules and the mixture is tableted to form the core tablet; (c) the step wherein the core tablet is coated with the intermediate coating layer of a water-soluble cellulose ether, then with the enteric coating layer. The core tablet and the intermediate coating layer are free from the alkali reactive compound and the granule prepared at the step (a) and the enteric tablet prepared in the step (c) are dried down less than 2% moisture content. <P>COPYRIGHT: (C)2004,JPO

Description

[0001]
【Technical field】
The present invention relates to a preparation for oral administration of omeprazole, and more particularly to a method for producing an omeprazole tablet provided with an enteric coating.
[0002]
[Prior art and problems]
Omeprazole, which has a gastric acid secretion inhibitory action, has been used for the prevention and treatment of gastrointestinal diseases such as gastric ulcer, gastritis, duodenal ulcer, and duodenitis.
[0003]
Omeprazole is known to be extremely unstable in acidic areas, such as gastric juice, and is rapidly degraded to lose its efficacy. Therefore, the preparation for oral administration must be enteric coated.
[0004]
As is well known, an enteric preparation is coated with an enteric coating which does not dissolve in gastric juice but dissolves in neutral or slightly alkaline intestinal digestive juice. However, since the polymer that forms the enteric film generally contains an acid group such as a free carboxyl group, it must be avoided to directly coat it with a solid preparation such as a tablet or granule in such a manner as to come into contact with omeprazole.
[0005]
JP-A-62-258320 and its divisional application, JP-A-5-294831, disclose an omeprazole and an alkali compound, an alkali salt of omeprazole, or a core portion containing an omeprazole alkali salt and an alkali compound, and optionally an alkali compound. A technique for obtaining an enteric coating formulation of omeprazole in which an enteric coating and an omeprazole are prevented from contacting by coating an excipient of a tablet containing or an intermediate layer of a water-soluble polymer and coating an enteric coating thereon. Have been.
[0006]
Japanese Patent Application Laid-Open No. 9-511257 discloses that an aqueous dispersion of omeprazole, an inert water-soluble polymer and excipients is coated on an inert core, and an intermediate coating layer containing the water-soluble polymer and excipients, A granular enteric omeprazole preparation obtained by coating an enteric coating thereon is disclosed.
[0007]
Japanese Patent Application Laid-Open No. 10-511117 describes enteric coated tablets of omeprazole in which a granule obtained in the same manner as above is once compression-molded into tablets, and then an intermediate coating layer and an enteric coating are applied.
[0008]
Since enteric polymers have a large number of carboxyl groups, it is preferable to avoid the presence of alkali-reactive compounds that react with the carboxyl groups in the core portion and / or the intermediate layer. Therefore, it is desired to provide a method for producing a stable omeprazole enteric tablet in which the core tablet containing omeprazole and the enteric film are separated by an intermediate layer without using an alkali-reactive compound.
[0009]
[Means for solving the problem]
In order to solve the above problems, the present invention provides:
a) granulating omeprazole, excipient and disintegrant with a binder;
b) a step of adding a lubricant to the granules and compressing them into core tablets;
c) a step of first coating the core tablet with a water-soluble cellulose ether interlayer and then an enteric coating;
The core tablet and the intermediate film do not contain an alkali-reactive compound, and the granulated product obtained in the step a) and the enteric coated tablet obtained in the step c) are dried until the water content becomes 2% or less. To provide a stable method for producing omeprazole enteric coated tablets.
[0010]
[Preferred embodiment]
The omeprazole enteric coated tablet of the present invention includes granulating omeprazole, an excipient and a disintegrant in a step a) using a binder. All components used for granulation are well known in the field of pharmaceutical formulation technology, and any of them can be used. For example, mannitol is used as an excipient, low-substituted hydroxypropylcellulose is used as a disintegrant, and an aqueous solution of polyvinylpyrrolidone (PVP) is sprayed and granulated on a mixture of both using a fluidized bed granulator. . The granules thus obtained are sufficiently dried in the same apparatus to a water content of 2% or less, preferably 1% or less.
[0011]
The dried granules are mixed with a lubricant such as magnesium stearate and tableted in step b) after sizing.
[0012]
The uncoated tablet thus obtained is successively coated with an intermediate film and an enteric film in step c). For the coating of the intermediate coating and the enteric coating, known techniques such as fluidized bed coating or pan coating can be used.
[0013]
The coating liquid for the intermediate film is prepared by dispersing a filler (extender pigment) such as talc and a coloring pigment such as titanium dioxide in an aqueous solution of a water-soluble cellulose ether such as hydroxypropylcellulose and hydroxypropylmethylcellulose. can do.
[0014]
Polymers that form enteric coatings are well known. Any enteric polymer can be used. Among them, hydroxypropylmethylcellulose acetate succinate (AQOAT manufactured by Shin-Etsu Chemical Co., Ltd.) or a coating solution can be prepared using water or a mixture of water and ethanol, or Methacrylic acid-methyl methacrylate copolymer (Eudragit L30D-55) is preferred. The coating liquid can be prepared by dispersing a filler such as talc, a coloring pigment such as titanium dioxide, and if necessary, a plasticizer in an aqueous solution or dispersion of the enteric polymer.
[0015]
The obtained enteric coated tablet is dried again to a water content of 2% or less, preferably 1% or less of the whole tablet.
[0016]
By drying to a moisture of 2% or less, preferably 1% or less at the granulation stage and the final enteric-coated stage in this manner, the alkali-reactive compound is not present in the core portion containing omeprazole and the intermediate coating layer. It is possible to produce omeprazole enteric coated tablets that are stable during storage.
[0017]
The following examples illustrate the invention without intending to limit it.
[0018]
【Example】
20 parts by weight of omeprazole, 105.7 parts by weight of mannitol, and 7 parts by weight of low-substituted hydroxypropylcellulose are charged into a fluidized bed granulator, and an aqueous solution of 2.5 parts by weight of PVP K-25 is sprayed on the mixture in a fluidized state. And granulated. After the end of spraying, the granulated product was thoroughly dried to a moisture content of 1% or less and sized.
[0019]
Next, 0.7 parts by weight of magnesium stearate was mixed with the sized granules, and the mixture was compressed into tablets containing 20 mg of omeprazole per tablet to obtain uncoated tablets.
[0020]
Separately, 3.78 parts by weight of hydroxypropylmethylcellulose and 0.63 parts by weight of hydroxypropylcellulose were dissolved in an appropriate amount of water, and 0.3 part by weight of talc and 1.29 parts by weight of titanium dioxide were dispersed to prepare an intermediate coating solution. .
[0021]
The enteric coating solution was 13.9 parts by weight of Eudragit L30D-55 (4.17 parts by weight as solid content), 0.42 parts by weight of triethyl citrate, 0.42 parts by weight of talc, 0.04 parts by weight of titanium dioxide. Was prepared by dispersing in a suitable amount of water.
[0022]
The uncoated tablet obtained above was sequentially coated with the above intermediate coating solution and enteric coating solution, and finally dried until the total water content became 1% or less, to obtain an omeprazole enteric coated tablet.
[0023]
[Stability test]
The enteric coated tablet obtained above was pulverized in a mortar, 0.2 g of the tablet was weighed, and the water content was measured by the Karl Fischer method.
[0024]
Enteric coated tablets are sealed in PTP + aluminum pillow (silica gel), glass bottle (silica gel), and polyethylene bottle (silica gel), and stored at 40 ° C x 75% RH for 1 month and 3 months. Then, the residual ratio of omeprazole in the tablets was measured by liquid chromatography (HPLC). Table 1 shows the results.
[0025]

Claims (5)

a) granulating omeprazole, excipient and disintegrant with a binder;
b) a step of adding a lubricant to the granules and compressing them into core tablets;
c) a step of first coating the core tablet with a water-soluble cellulose ether interlayer and then an enteric coating;
The core tablet and the intermediate film do not contain an alkali-reactive compound, and the granulated product obtained in the step a) and the enteric coated tablet obtained in the step c) are dried until the water content becomes 2% or less. For producing stable omeprazole enteric coated tablets. The method for producing an omeprazole enteric tablet according to claim 1, wherein the water content of the granulated product and the enteric tablet is 1% or less. The excipient used in step a) is mannitol, the disintegrant is low-substituted hydroxypropylcellulose, and the water-soluble cellulose ether used in step c) is a mixture of hydroxypropylmethylcellulose and hydroxypropylcellulose. A method for producing the enteric coated tablet of 1 or 2 above. 4. The omeprazole enteric coated tablet according to claim 1, wherein the intermediate film and the enteric film contain talc and a coloring pigment. A stable omeprazole enteric coated tablet produced by the production method according to any one of claims 1 to 4.