JP2002363080A - Method for producing stable oral anti-ulcer preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing an enteric coated tablet containing an anti-ulcer medicine having a fundamental skeleton of substituting 2- pyridylmethylsulfonyl group at the 2 position of benzimidazole (Omeprazole, Lansoprazole or Rabeprazole) as a main ingredient and excellent in preservation stability. SOLUTION: This method for producing the stable oral anti-ulcer preparation comprises forming granules containing a mixture of the anti-ulcer medicine selected from the group consisting of the Omeprazole, Lansoprazole and Rabeprozole with an alkaline compound or an alkali salt of the above compound, coating the granules with a film-forming water soluble polymer, forming tablets from the coated granules and coating the obtained uncoated tablets with an enteric polymer.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention relates to omeprazole,
The present invention relates to a method for producing an oral preparation (enteric tablet) of an anti-ulcer drug selected from the group consisting of lansoprazole and rabeprazole.

[0002] Omeprazole, lansoprazole and rabeprazole are classes of anti-ulcer drugs known as proton pump inhibitors. These compounds are 2
A pyridinylmethylsulfinyl group having a basic skeleton of a benzimidazole ring bonded to the 2-position; and different substituents on the pyridine ring and the benzimidazole ring.

[0003] These compounds are extremely unstable in aqueous solutions having an acidic pH value. Therefore, when they are orally administered as a preparation, they are decomposed by gastric juice before reaching the small intestine, which is the absorption site, so that the expected medicinal effect cannot be obtained. For this reason, the formulation must be coated with an enteric coating to protect it from degradation by gastric juices.

[0004] The above compounds also undergo decomposition when in contact with acidic substances even in a dry state. Since the polymers for enteric coatings can generally be considered as solid acids having free carboxyl groups, the storage stability of the formulation in which the active ingredient is in contact with the enteric substance is unacceptably low.

[0005] There are several prior arts aimed at solving this problem. Among them, Japanese Patent Publication No. 5-69807 and Japanese Patent No. 2740993 disclose a water-soluble or water-soluble tablet excipient or polymer between a core portion containing omeprazole and an alkali compound and an enteric film, which is decomposed rapidly with water. An internal preparation in which at least one intermediate coating layer comprising a film-forming compound is provided to avoid contact between omeprazole and an enteric coating is described. Instead of a mixture of omeprazole and an alkali compound, its alkali salt may be used, and the intermediate coating layer may contain a pH buffering alkali compound.

When an enteric coated tablet is manufactured based on this technique, omeprazole and an alkali compound are granulated using an excipient and a binder to form granules, and a lubricant is added to the granules to form a tablet. Make nuclei (naked tablets). Then, one or two intermediate layers are coated on the bare tablet, and finally, an enteric coating is applied. This method involves at least two coating operations on the tablet after compression, and the total surface area of the interlayer cannot be greater than the total surface area of the enteric coating. It must be thicker or have more than one interlayer.

[0007] An object of the present invention is to reduce the number of coatings after tableting to one, and to provide an enteric coated tablet with a water-soluble protective film or layer having a total surface area much larger than that of the enteric coating. The purpose of the present invention is to increase the stability of enteric coated tablets containing omeprazole or an anti-ulcer drug having the same basic skeleton.

[0008]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a mixture of an anti-ulcer drug selected from the group consisting of omeprazole, lansoprazole and rabeprazole with an alkali compound or granules containing an alkali salt of the drug, and granulate the granules. Is coated with a film-forming water-soluble polymer, the coated granules are compressed, and the resulting naked tablet is coated with an enteric polymer.

[0009]

[Detailed description] As mentioned above, omeprazole, lansoprazole and rabeprazole (hereinafter referred to as "the main drug")
That. The stability in the gastrointestinal tract and at the time of storage cannot be satisfactorily secured unless coexisting with an alkali compound. Specific examples of the alkali compound that can be used for this purpose are disclosed in the cited prior art, and these can be used in the present invention. Among them, sodium hydrogen carbonate or a coprecipitate thereof with aluminum hydroxide is preferred.
Instead of a mixture of the base compound and the alkali compound, an alkali salt of the base compound can be used.

[0010] The mixture of the base compound and the alkali compound (or the alkali salt of the base compound) is formed into granules by a conventional method together with conventional excipients. Excipients are selected from those commonly used in the pharmaceutical industry, such as lactose, corn starch, microcrystalline cellulose and the like. When a binder is used, it is selected from conventional ones, and typical examples thereof include methylcellulose, hydroxypropylcellulose, and polyvinylpyrrolidone. As the granulation method, any known method, for example, a fluidized bed granulation method can be used.

The dried and sized (sieved) granules are then provided with a coating corresponding to the prior art interlayer. Coating is performed by a wet or dry method using a water-soluble film-forming polymer or a mixture thereof with a water-soluble filler. Water-soluble, film-forming polymers that can be used to coat the granules are described in the cited patent 2,740,099.
No. 3 can be selected. Hydroxypropyl cellulose is preferred. Fillers can be selected from water-soluble sugars and sugar alcohols commonly used as excipients in tablets, with lactose and mannitol being preferred. The water-soluble polymer then may be of the same type as used for granulation of the granules containing the active ingredient. For example, hydroxypropylcellulose (HPC) can be used as a binder and coating agent for the granules. Any known method can be adopted for the coating method.
Among them, the fluidized bed coating method is preferable because the same equipment as that for granulation can be shared. After coating, drying and sizing (sieving)
Thus, granules for tableting are obtained.

A lubricant such as magnesium stearate and, optionally, a disintegrant such as partially pregelatinized starch (PCS) are added to the coated granules thus formed, and the mixture is compressed into tablets. Create

[0013] Finally, a conventional enteric coating is applied to the naked tablet to give the antiulcer preparation of the present invention. Enteric coating polymers and coating methods are also well known in the pharmaceutical industry. Specific examples of the enteric substance include cellulose derivatives such as cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, and hydroxypropylmethylcellulose acetate succinate, and acrylics such as (meth) acrylate / (meth) acrylic acid copolymer (trade name Eudragit). It is a system polymer. Among them, a polymer such as Eudragit L100 which can use aqueous ethanol as a medium is preferable. This is because the use of an organic solvent that is harmful to the environment can be avoided in all steps from granulation to enteric coating.

According to the invention, the total surface area of the membrane or layer corresponding to the intermediate layer of the prior art, in which the active substance is isolated from contact with the enteric substance, can be considerably larger than the total area of the enteric coating. This can enhance the protective effect of the separator or layer. In addition, the process is simplified, which is advantageous in terms of production efficiency.

[0015]

EXAMPLES The present invention will be described in more detail with reference to the following examples for omeprazole. It will be apparent that similar results can be obtained by using lansoprazole or rabeprazole as the active ingredient. In Examples, “%” and “parts” are based on weight unless otherwise specified.

Example 1 Formulation of core tablet: Ingredients per tablet Charged amount Omeprazole 20 mg 80 parts Lactose 97 mg 388 parts Corn starch 7 mg 28 parts Kumulite ¹⁾ 2.5 mg 10 parts HPC ²⁾ 2 mg 8 parts PCS ³⁾ 5 mg 20 parts Mg stearate 1.5 mg 6 parts ──────────────────合計 Total 135mg 540 parts 1) Aluminum hydroxide / sodium bicarbonate co-precipitate 2) Hydroxypropyl cellulose 3) Partially pregelatinized starch

Operation: Omeprazole, lactose and corn starch were mixed, granulated by a fluidized bed granulation method using a 3 w / v% aqueous solution of 6 parts of HPC as a binder, dried, and sized into granules of 42 mesh pass.

Next, the granules were coated with a 2 w / v% aqueous solution of 2 parts by weight of HPC in a fluidized bed and dried. PCS and magnesium stearate were added to the granules, and the mixture was compressed into tablets to obtain plain tablets.

Formulation of enteric coating solution: Ingredients per tablet Charged amount Eudragit L100 2.7 mg 101 .25 parts PEG6000 0.1 mg 3.75 parts Talc 0.2 mg 7.5 parts Purified water ３375 parts ^* ethanol (99.5%) ────1125 parts ^* ────────体積 Total 3.0mg * Volume part expressed in ml / g

Operation: The coating solution of the above formulation was coated by a spray method.

Example 2 Core Tablet Formulation: Ingredients per tablet Charged amount Omeprazole 20 mg 80 parts Lactose 95.5 mg 382 parts Corn starch 7 mg 28 parts Cumulite 2.5 mg 10 parts HPC 3.5 mg 14 parts PCS 5 mg 20 parts Magnesium stearate 1.5 mg 6 parts ─────────────────合計 Total 135mg 540 parts

Procedure: The total amount of omeprazole, all of cumulite, 232 parts of lactose and 2 parts of HPC were mixed, and 30%
15 parts (volume) of ethanol was added, kneaded, extruded and sized. The sized product is placed in a fluidized bed granulator and HPC6 part 3
Fluid granulation using w / v% aqueous solution as a binding liquid
The granules were sized to mesh pass.

The granules were coated with a liquid obtained by adding 150 parts of lactose to a 2 w / v% aqueous solution of 6 parts of HPC, dried, and mixed with PCS and magnesium stearate to obtain naked tablets. Enteric coating was performed under the same conditions and operation as in Example 1.

Stability Evaluation The enteric coated tablet of Example was stored at a temperature of 60 ° C. for 2 weeks.
The omeprazole content at the initial stage and after storage was measured, and the residual ratio (%) of oprazole was calculated when the initial value was 100, and the following results were obtained.

Enteric coated tablet residual rate% {} Example 1 102.6% Example 2 99.5%

From these results, it is clear that the addition of the alkali compound and the coating of the granules before tableting greatly contribute to the storage stability of omeprazole.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Maki Tatsumi 26-7 Ichibancho, Kadoma-shi, Osaka Towa Pharmaceutical Co., Ltd. (72) Inventor Kazuyoshi Asada 26-7 Ichibancho, Kadoma-shi, Osaka Towa F-term in the Central Research Laboratories of Pharmaceutical Company 4C076 AA45 BB01 CC16 DD25 DD28 DD30 DD41 EE09H EE23H EE32H EE38 FF06 FF09 FF25 FF65 GG12 GG14 GG16 4C086 AA01 BC39 GA07 GA08 MA02 MA05 MA07 MA35 MA52 NA03 ZA68 ZA68 ZA68

Claims (5)

[Claims] 1. A mixture of an anti-ulcer drug selected from the group consisting of omeprazole, lansoprazole and rabeprazole with an alkali compound or granules containing an alkali salt of the drug is granulated, and the granules are formed into a film-forming water-soluble polymer. And coated tablets are compressed,
A method for producing a stable oral anti-ulcer formulation, comprising coating the obtained naked tablet with an enteric polymer. 2. The method according to claim 1, wherein the alkali compound is sodium hydrogen carbonate or its coprecipitate with aluminum hydroxide. 3. The method of claim 1, wherein the granules are coated with a film-forming water-soluble polymer containing a water-soluble filler. 4. The method according to claim 1, wherein hydroxypropylcellulose is used for granulation and / or coating of the granules. 5. The method according to claim 1, wherein a lubricant and a disintegrant are added to the coated granules for tableting.