KR20040095521A - Oral dosage form of benzimidazoline compounds - Google Patents

Abstract

PURPOSE: Provided is oral dosage form of benzimidazoline derivatives which have improved acid stability and storage stability. Their manufacturing process is simplified and thus they are economically manufactured. CONSTITUTION: The oral dosage form of benzimidazoline derivatives is characterized by comprising a core layer which contains 1 part by weight of benzimidazole compounds, 0.5-5 parts by weight of non-ionic surfactant and 0.1-5 parts by weight of alkalizing agent, and an enteric coating layer which covers the core layer. Therefore, the derivatives have improved acid stability and storage stability.

Description

Oral preparation of benzimidazole derivatives {Oral dosage form of benzimidazoline compounds}

The present invention relates to oral preparations of benzimidazole-based compounds, and more particularly, to a core layer comprising a benzimidazole-based compound, a nonionic surfactant, and an alkalizing agent; And an oral preparation of a benzimidazole compound including an enteric coating layer obtained by enteric coating the core layer.

Benzimidazole-based compounds exhibit potent gastric secretion inhibitory activity as potent proton pump inhibitors and are widely used for the treatment of gastric ulcer and duodenal ulcer. However, the benzimidazole-based compound is a compound that is very unstable in acidic and neutral media, and thus is very unstable under acidic and neutral conditions, and thus easily decomposes or discolors. For example, omeprazole of benzimidazole-based compounds has been reported to have a very weak stability in acidic conditions with a half-life of less than 10 minutes in media below pH 4, 18 hours at pH 6.5 and about 300 days at pH 11 ( Fieldland and Cederberg, Scand J. Gastrology, Suppl. 108, 113-120 (1985)). Lansoprazole also increases in degradation rate with decreasing pH. Therefore, in order to orally administer a benzimidazole compound, it is necessary to coat it with enteric skin so as to prevent rapid decomposition in acidic gastric juice and reach the small intestine, an absorption site, upon oral administration. However, the direct enteric coating formulation of omeprazole is usually made of an acidic compound of polymers used as enteric skin material, and omeprazole is rapidly decomposed by direct or indirect contact with omeprazole, resulting in a severe discoloration of omeprazole and its content. There was a problem with long term storage because it decreased over time.

In order to solve this problem, Korean Patent Publication No. 91-4579 discloses that a core containing an alkali salt of omeprazole or an alkali salt of omeprazole mixed with an alkali reaction compound is coated with one or more inert endothelial layers. An enteric preparation is disclosed in which the endothelial coating core is further coated with enteric skin. That is, the present invention discloses a method of securing resistance to gastric juice of the benzimidazole compound by using the endothelial layer as a separation layer separating the alkaline core and the enteric skin. However, the formulation has a problem in that the process is complicated and long, such as the first coating and the second coating, so that the working time is long and the manufacturing cost is increased.

In addition, according to Korean Patent Publication No. 92-8161, in order to stabilize omeprazole, an amino acid selected from arginine, lysine or histidine, which is a water-soluble basic amino acid, is mixed into a core material, and hydroxymethyl, which is a water-soluble polymer, is used to stabilize the core material. An enteric preparation is disclosed in which a water-soluble coating layer is made of cellulose, hydroxyethyl cellulose, or the like, and then dried and coated with an enteric base. However, this method also uses complex basic amino acids as stabilizers, and coats with aqueous soluble endothelial layers and then enters enteric coatings.

In order to solve the above problems, the present inventors conducted a continuous study to improve the stability of the benzimidazole derivatives, and as a result of uniformly dispersing the benzimidazole derivative in a nonionic surfactant and an alkalizing agent to form a water-soluble The present invention has been completed by discovering that excellent acid stability and storage stability can be secured only by enteric coating without the process of coating with an inner skin layer.

The technical problem to be achieved by the present invention is to provide an oral preparation of a benzimidazole compound which can be economically prepared without the need for complicated processes.

In order to achieve the above object, the present invention is a core layer comprising a benzimidazole compound, a nonionic surfactant and an alkalizing agent; And it provides an oral formulation of the benzimidazole compound comprising an enteric coating layer enteric coating the core layer.

The present invention is explained in more detail.

I. Core layer

1. Configuration of Core Layer

Benzimidazole compounds used in the oral preparation of the present invention are omeprazole, lansoprazole, pantoprazole, rabeprazole or picoprazole.

The nonionic surfactant used in the oral preparation of the present invention increases the dispersion and mixing of the benzimidazole-based compound and the alkalizing agent to improve acid stability and storage stability, and contributes to rapid disintegration and elution. Examples of such nonionic surfactants include copolymers (polyoxamers and derivatives thereof) consisting of polyoxypropylene and polyoxyethylene, various polysorbates (twins), natural or hydrogenated vegetable as pharmaceutically acceptable nonionic surfactants. A reaction product (cremofo) between oil and ethylene glycol is possible, but is not limited thereto. Among these, poloxamer is preferably 188, 237, 338 and 407, most preferably poloxamer 188.

The alkalizing agent used in the oral preparation of the present invention increases the acid stability and fluidity of the benzimidazole compound, and specific examples thereof include alkali metal or alkaline earth metal such as calcium carbonate, magnesium carbonate, sodium carbonate, sodium hydrogen carbonate and the like. Alkali metals, such as carbonate, calcium hydroxide, sodium hydroxide, or the like, hydroxide of alkali metal, calcium silicate, etc. can be used. Of these, calcium silicate is particularly preferable.

Calcium silicate is a water-insoluble inert carrier, which improves the acid safety of benzimidazole-based compounds and storage stability of benzimidazole-based compounds as alkalizing agent, and the stability of benzimidazole-based compounds due to the property of rejecting water A core that is further improved and fluidity can be obtained.

Oral formulations of the present invention may include substances commonly used in the pharmaceutical, that is, excipients, disintegrants, binders and the like within a range that does not adversely affect the drug efficacy.

As the excipient, mannitol, lactose, microcrystalline cellulose, starch and the like can be used, and at least one selected from sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose and the like as a disintegrant Disintegrants can be used. As the binder, hydroxypropyl cellulose, polyvinylpyrrolidone, methyl cellulose, polyvinyl alcohol, starch and the like can be used.

In addition, glidants such as talc, magnesium stearate, pigments, antioxidants and the like may be added and used as necessary.

The amount of the surfactant used in the oral preparation of the present invention is preferably 0.1 to 5 parts by weight, more preferably 0.5 to 2.5 parts by weight based on 1 part by weight of the benzimidazole compound.

In addition, the amount of calcium silicate that is an alkalizing agent is preferably 0.1 to 5 parts by weight, and more preferably 0.2 to 2 parts by weight based on 1 part by weight of the nonionic surfactant. If the amount of calcium silicate is less than 0.1 part by weight, sufficient fluidity cannot be secured. If the amount of calcium silicate is more than 5 parts by weight, fluidity no longer improves, but there is a problem of preventing the leaching of the benzimidazole-based compound from the formulation.

It is preferable to contain 0.5-5 weight part of nonionic surfactants, and 0.1-5 weight part of alkalizing agents with respect to 1 weight part of benzimidazole type compounds.

2. Preparation of Core Layer

Oral preparations of the present invention comprises a core layer comprising a benzimidazole compound, a nonionic surfactant and an alkalizing agent; And an enteric coating layer obtained by enterically coating the core layer, and the core layer may be manufactured by a melting method or a dissolution method as follows.

First, according to the melting method, the nonionic surfactant is completely heated and melted at each melting temperature, and then the powder of the benzimidazole compound and the alkalizing agent is uniformly dispersed and cooled. The cooled mixture is triturated with semal and then apples to a suitable size to form a core.

According to another method, the dissolution method, after dissolving the nonionic surfactant in a suitable solvent, the powder of the benzimidazole compound and the alkalizing agent are uniformly dispersed. The dispersion may be dried under reduced pressure to form apples of suitable size to form a core. In this case, the solvent may include ethanol, methylene chloride, chloroform, carbon tetrachloride, ethyl acetate, and the like, which are typically used to dissolve nonionic surfactants, but are not necessarily limited thereto. In consideration of the above, a solvent appropriately selected is used alone or in combination. The solvent is removed by conventional methods such as vacuum drying, vacuum drying or spray drying.

The cores prepared by the above method may be mixed with conventional additives, that is, disintegrants, binders, and the like, and may be prepared in uncoated tablets by conventional methods such as wet granulation, direct compression, direct tableting, or granulated using a conventional granulator. .

II. Enteric cortex

The core layer thus prepared is coated with an enteric base to form an enteric skin layer. The enteric base used for the outer skin layer is hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), methacrylic acid and methacrylic acid methyl ester copolymer (trade name; Eudragit). ), Other enteric coating materials and plasticizers can be used.

The enteric coating layer is formed by applying a solution of the enteric base dissolved in water and / or a suitable organic solvent to the core by conventional coating techniques such as pan coating or fluidized bed coating.

The preparations according to the present invention can be used for gastric ulcer, duodenal ulcer, reflux esophagitis and the like by reducing gastric acid secretion and providing gastrointestinal cell protective effect. The formulations are typically administered once to several times daily. A typical daily dose of an active drug is 5 to 40 mg.

According to the embodiment of the present invention, the oral preparation of the present invention can be prepared simply by melting or dissolving the core layer, it can be prepared simply without a complex process by enteric coating. In addition, the oral preparation of the present invention was found to show excellent acid resistance and dissolution properties in the acid resistance and dissolution test in artificial gastric juice and artificial intestinal fluid, it was confirmed that the storage stability is significantly improved.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the scope of the present invention is not limited thereto.

Example 1

40 g of floxamer 188 was heated at 80 ° C. to completely melt. 20 g of omeprazole and 20 g of calcium silicate were added to the melt of the floxamer 188 to disperse and cooled. The mixture was crushed and appled to 50 meshes. The said phloxamer 188; Calcium silicate; And 80 g of omeprazole mixed powder, 178 g of mannitol, 20 g of crospovidone, 0.5 g of silicon dioxide, and 1.5 g of magnesium stearate were mixed, and the weight of one tablet was 280 mg. The composition of the core is shown in Table 1. The prepared uncoated tablets were enteric coated by a conventional coating method. The composition of the core is shown in Table 1.

Example 2

20 g of omeprazole used in Example 1 was changed to 20 g of lansoprazole, and the same procedure as in Example 1 was carried out to obtain a tablet by a direct stroke method. The prepared uncoated tablets were enteric coated by a conventional coating method. The composition of the core is shown in Table 1.

Example 3

Except that 20g of omeprazole used in Example 1 was changed to 20g of pantoprazole was carried out in the same manner as in Example 1 to obtain a tablet by the direct hit method. The prepared uncoated tablets were enteric coated by a conventional coating method. The composition of the core is shown in Table 1.

Furtherance Example 1 Example 2 Example 3 Omeprazole 20 g - - Lansoprazole - 20 g - Pantoprazole - - 20 g Phloxamer 40 g 40 g 40 g Calcium silicate 20 g 20 g 20 g Mannitol 178 g 178 g 178 g Crospovidone 20 g 20 g 20 g Silicon dioxide 0.5g 0.5g 0.5g Magnesium stearate 1.5 g 1.5 g 1.5 g

Example 4

20 g of omeprazole and 10 g of floxamer 407 were dissolved in 1 liter of ethanol, and 20 g of calcium silicate was dispersed. The uniformly dispersed liquid was dried under reduced pressure to obtain a composite. The obtained composite was appled with a 50 mesh sieve, and then 50 g of the composite was mixed with 178 g of mannitol, 20 g of crospovidone, 0.5 g of silicon dioxide, and 1.5 g of magnesium stearate, and then directly ground to a tablet weight of 250 mg. The prepared uncoated tablets were enteric coated by a conventional coating method.

Example 5

Except that 20 g of omeprazole used in Example 4 was changed to 20 g of lansoprazole and 10 g of Ploxamer 407 was changed to 10 g of Ploxamer 188, the same procedure as in Example 7 was carried out to obtain a tablet by the direct-acting method. The prepared uncoated tablets were enteric coated by a conventional coating method.

Example 6

80 g of floxamer188 was dissolved in 1 liter of ethanol, and calcium silicate was uniformly dispersed. This solution was sprayed in a fluid bed granulator (Glatt) to coat omeprazole powder. The coated benzimidazole compound was dried in an apparatus to obtain granules, which were prepared by tablets or pellets in a conventional manner. The uncoated tablets and pellets prepared were enteric coated by conventional coating methods.

Example 7

40 g of floxamer 188 was heated at 80 ° C. to completely melt. 20 g of omeprazole as a main component and 20 g of calcium silicate were added to the melt of the floxamer 188 to disperse and cooled. The mixture was crushed and appled into 50 bodies. 80 g of the omeprazole powder and 178 g of mannitol were added and mixed, and 2.6 g of hydroxypropyl cellulose dissolved in ethanol was gradually added, granulated by wet granulation, and dried. 18 g of crospovidone and 1.4 g of magnesium stearate were added thereto to obtain a tablet having a tablet weight of 280 mg. The prepared uncoated tablets were enteric coated by a conventional coating method.

Example 8

40 g of floxamer 188 was heated at 80 ° C. to completely melt. 20 g of lansoprazole and 20 g of calcium silicate were dispersed in the melt of the floxamer 188, followed by cooling. The mixture was crushed and appled into 50 bodies. 80 g of the lansoprazole powder, 178 g of mannitol, 20 g of crospovidone, 12 g of sodium starch glycolate, and 1.4 g of magnesium stearate, while slowly adding 1.6 g of polyvinylpyrrolidone K-30 dissolved in ethanol as a binder liquid, was added to conventional wet granules. The pellets were prepared by granulation and spheronization by the method. The prepared pellets were enteric coated by conventional coating methods.

(Test example)

In order to find out the characteristics of the oral preparation of the benzimidazole compound comprising a benzimidazole compound obtained in the above example, a core layer containing a nonionic surfactant and an alkalizing agent, and an enteric coating layer obtained by enteric coating of the core layer. The acid resistance, dissolution and storage stability tests were carried out using the enteric skin tablets of Examples 1 to 5 and the commercially available patent publication No. 91-4579 as comparative products, respectively.

Test Example 1 Acid Resistance Test

Each test preparation was stirred using a paddle at a speed of 100 rpm at 37 ° C, and after 2 hours using the enzyme-free artificial gastric fluid USP (1st solution) as a medium, the appearance of the test preparations remained intact and undamaged in the preparation. The actual amount of omeprazole present was measured and expressed as a percentage of the omeprazole contained in each test formulation. The results are shown in Table 2.

Test Example 2 Dissolution Test

In order to investigate the elution behavior of benzimidazole compounds in the small intestine, the paddle method of the dissolution test method at a stirring speed of 100 rpm at 37 ° C. was followed by a pH of 6.8 after 2 hours in the artificial gastric fluid (first liquid). After artificial measurement and transfer to intestinal fluid (second solution), the amount of omeprazole eluted after 30 minutes was measured and the results are shown in Table 2.

Example 1 Example 2 Example 3 Example 4 Example 5 Comparative product 2 hours after acid resistance test Amount of omeprazole (%) 99.9 99.5 99.7 100.1 99.9 89.8 Appearance of the formulation No change No change No change No change No change No change Dissolution rate After 30 minutes 92.3 89.3 90.5 89.4 90.7 81.4

As shown in Table 2, Examples 1 to 5 all showed good acid resistance and dissolution properties, and the dissolution rate was higher than the comparative agent as a result after 30 minutes.

Test Example 3 Storage Stability Test

1. Changes in appearance over time

In order to confirm the stabilizing effect by the nonionic surfactant or the nonionic surfactant and the alkalizing agent, Examples 1 to 5 and commercially available patent publication 91-4579 were used as comparative products under the accelerated conditions of 40 ° C. and 75% RH. The change over time was observed. The results are shown in Table 3.

Start date 1 week 2 weeks 4 Weeks Example 1 White No change No change No change Example 2 White No change No change No change Example 3 White No change No change No change Example 4 White No change No change No change Example 5 White No change No change No change Comparative Preparation White Brown Dark brown Dark brown

2. Change in content over time

Example 1 to 5 and the commercially available patent publication No. 91-4579 as a comparative product were evaluated after storage for 2 months in an unopened state under accelerated conditions of 40 ℃, 75% RH. The results are shown in Table 4.

Start date 2 weeks 1 month 2 months Example 1 100.2 94.4 93.4 91.0 Example 2 99.8 95.6 93.2 90.7 Example 3 101.0 96.5 94.5 91.2 Example 4 100.0 94.6 93.9 90.3 Example 5 100.2 95.0 93.5 89.2 Comparative Preparation 99.8 78.0 42.1 4.3

3. 6 months accelerated test

Example 1 to 5 and the commercially available patent publication No. 91-4579 as a comparative product were evaluated after storage for 6 months in a moisture-proof packaging under the accelerated conditions of 40 ℃, 75% RH. Under these conditions, six months of storage is equivalent to three years of storage at normal temperatures. The results are shown in Table 5.

Start date 2 months 4 months 6 months Example 1 100.5 99.9 99.7 99.4 Example 2 101.0 100.5 100.0 99.8 Example 3 99.9 99.6 99.7 99.5 Example 4 100.0 99.8 99.5 98.9 Example 5 100.2 100.0 99.0 99.3 Comparative Preparation 100.0 99.1 98.6 96.3

Since the oral preparation of the present invention does not require a complicated process in its preparation, it is possible to economically provide an oral preparation of a benzimidazole compound having improved acid stability and storage stability.

Claims (7)

A core layer comprising a benzimidazole compound, a nonionic surfactant, and an alkalizing agent; And oral formulation of the benzimidazole-based compound comprising an enteric coating layer enteric coating the core layer. The oral preparation of claim 1, wherein the benzimidazole compound is selected from the group consisting of omeprazole, lansoprazole, pantoprazole, rabeprazole, and picoprazole. The oral preparation of claim 1, wherein the nonionic surfactant is selected from the group consisting of poloxamer and derivatives thereof, polysorbate, cremofo. 4. The oral preparation of claim 3, wherein said floxamer and derivatives thereof are selected from the group consisting of phloxamer 188, phloxamer 237, phloxamer 338, and phloxamer 407. The oral preparation of claim 1, wherein the alkalizing agent is calcium silicate. Nonionic interface selected from the group consisting of benzimidazole-based compounds selected from the group consisting of omeprazole, lansoprazole, pantoprazole, labeprazole and picoprazole, floxamer 188, floxamer 237, floxamer 338 and floxamer 407 A core layer comprising calcium silicate as an activator and an alkalizing agent; And oral formulation of the benzimidazole-based compound comprising an enteric coating layer enteric coating the core layer. The oral preparation according to claim 1 or 6, wherein the core layer comprises 0.5 to 5 parts by weight of the nonionic surfactant and 0.1 to 5 parts by weight of the alkalizing agent based on 1 part by weight of the benzimidazole compound. .