KR100592511B1 - Release Controlled type Formulation Comprising Benzimidazole Derivatives and There Pharmaceutically Acceptable Salt with Increased Stability and Manufacturing Method thereof - Google Patents

Abstract

The present invention provides a pellet comprising at least one benzimidazole derivative or a pharmacologically acceptable salt thereof as an active substance and a cationic polymer: Stability in which at least one coating layer of an intermediate coating, a moisture barrier coating, and an enteric coating is formed as an outer coating layer of the pellet. This enhanced release controlled formulation and method for preparing the same are disclosed.

According to the above constitution, the benzimidazole derivative or pharmacologically acceptable salt thereof is electrostatically stabilized to have excellent resistance in an acidic environment and an aqueous environment.

Description

Release Controlled Type Formulation Comprising Benzimidazole Derivatives and There Pharmaceutically Acceptable Salt with Increased Stability and Manufacturing Method According to Benzimidazole Derivatives or Pharmacologically Acceptable Salts thereof as Active Material             

1 is a schematic structural diagram of an extruder used in an embodiment of the present invention

2A is a perspective view of a pelletizer usable in the present invention

Figure 2b is a left side view of the pelletizer usable in the present invention

2C is a cross-sectional view A-A of a pelletizer usable in the present invention.

Figure 3 is a result of measuring the content of the drug in the formulation according to the present invention

4 is a result graph of the dissolution test for the preparation according to the present invention

The present invention relates to a stability-controlled controlled release formulation having a benzimidazole derivative or a pharmacologically acceptable salt thereof as an active substance and a method for producing the same.

Benzimidazole derivatives are H ⁺ , K ⁺ -ATPase inhibitors and have antiulcer activity. Examples of such derivatives include lansoprazole (2-[[[3-methyl-4 (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] benzimidazole) and are currently widely used. Omeprazole (5-methoxy-3,5-dimethyl-2pyridinyl) methyl) sulfinyl) -1H-benzimidazole). These compounds are used for the treatment of gastric and duodenal ulcers.

Benzimidazole derivatives, including lansoprazole, omeprazole, and the like, have low solubility in water but are highly soluble in alkaline solutions containing negatively charged ions. Benzimidazole derivatives are unstable in aqueous solution, especially as pH decreases.

Therefore, in formulating these benzimidazole derivatives, it is required to be coated with an enteric coating agent or the like to avoid contact with gastric acid. However, since the conventional enteric coating material is acidic, there is a problem that can not be used as it is coated. To this end, an alkali material is added to the central core to increase the pH, or a method of performing enteric coating secondarily after performing neutral or alkaline coating firstly.

For example, the trade name Losec (Astrasa) is to introduce an inorganic alkalizing agent as a stabilizer to form a core, the core is coated with a water-soluble endothelial layer and finally enteric coating. However, this method requires the accuracy of the epidermal process to stabilize the active substance, and because it uses a large amount of sodium, it is not suitable for patients with limited sodium intake such as hypertension patients. There is also a problem that enteric coating is damaged by alkalizing agent and affects long-term stability.

On the other hand, the Republic of Korea Patent Publications 91-4579, 87-1005 discloses the form of a salt such as NaHPO ₄ as an alkalizing agent, but also supplied with anions that interfere with the stabilization of the active material may be inhibited rather than stabilization.

As an alternative to the problem of the conventional controlled release formulation, the inventors have completed the present invention while studying a new formulation that stabilizes the active substance, has a uniform content, and can completely release the drug.

It is an object of the present invention to be stable in an aqueous environment or an acidic environment, to significantly reduce the risk of drug loss caused during the production of the preparation, and to provide a formulation for oral administration containing the drug uniformly and a method for preparing the same. .

The present invention for achieving the above object is a pellet containing at least a benzimidazole derivative or a pharmacologically acceptable salt thereof as an active substance, and a cationic polysaccharide: the outer layer of the pellet as an intermediate film, moisture-proof film, enteric coating And controlled release controlled formulations having at least one coating layer formed thereon.

In another aspect, the present invention comprises the steps of extruding a combination comprising a benzimidazole derivative or a pharmacologically acceptable salt thereof as an active material and a cationic polysaccharide to form a filament: forming the filament into pellets; And a method for preparing a stable release controlled formulation comprising forming at least one coating layer of an intermediate coating, a moistureproof coating, or an enteric coating on the pellet.

Active substances include benzimidazole derivatives or pharmaceutically acceptable salts thereof. They function as proton pump inhibitors and are characterized by being very sensitive to pH changes. Such benzimidazole-based compounds include compounds commonly referred to as conventional names such as lansoprazole, omeprazole, pantoprazole, and rabeprazole.

As used herein, the term "conjugate" refers to a mixture formulated with various auxiliary components to have strength and ductility suitable for extruding as a composition of an unmolded step prior to molding into pellets. Although strength and ductility suitable for extruding into filaments can be obtained empirically specifically through experiments, when extruding with an extrusion force of 1000 to 4000 N, preferably the cohesion of the coalescence is preferably 3.0 to 45 N.

Cationic polysaccharides among the components included in the association provide electrostatic stability of the active material by adsorption with -SO substituents that promote the decomposition of benzimidazole compounds in a water environment. In addition, the acidic environment provides the stability of the active material through the effect of structural shielding.

Examples of such cationic polysaccharides include water-soluble chitosan and oligo chitosan.

Other components that may be included in the combination include alkalizing agents, surfactants, excipients, and the like.

Alkalizing agents can be added in an effective amount to create the proper pH environment required for stabilization of the active ingredient. Therefore, the use may be limited when the environment of the acid-stable active ingredient is neutral or alkaline. Examples of the alkalizing agent include magnesium oxide, sodium monohydrogen phosphate, potassium monohydrogen phosphate, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, aluminum carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, hydrogen carbonate Potassium, aluminum phosphate, calcium phosphate, sodium phosphate, potassium phosphate, aluminum citrate, calcium citrate, sodium citrate, potassium citrate, arginine, lysine, histidine, eglumine, meglumine There is this.

Surfactants are pharmaceutically acceptable and include any kind of material used to aid in the dissolution and dissolution of the drug. Examples of these surfactants include one selected from the group of ionic and nonionic surfactants such as sodium lauryl sulfate, polysorbate, triethanolamine stearic acid, alkyl sulfonate, alkylaryl sulfonate, sorbitan esters, and flulons. There is more than one substance. The amount of the surfactant added varies depending on the dissolution pattern of the active material, but is preferably about 0.5 to 100% by weight based on the weight of the active material.

Examples of excipients that can be used to form the present invention include microcrystalline cellulose, cellulose powder, low substituted hydroxypropyl cellulose, cellulose acetate, croscarmellose sodium, calcium phosphate, calcium sulfate, corn starch, lactose, Mannitol, sorbitol, polyvinylpyrrolidone, talc, dexrate, dextrin, glucose, fructose, maltose, sucrose, kaolin, magnesium carbonate, magnesium oxide, polymethacrylate, hydroxypropylmethylcellulose, ethylcellulose, gelatin , Guar gum, xanthan gum, acrylate polymers or copolymers, or a mixture of two or more kinds.

Hereinafter, the composition process and the molding process of the association for molding into pellets will be described.

First, the active ingredient is suspended in a solvent, preferably water, ethanol or a mixed solvent of water and ethanol together with an alkalizing agent, a surfactant, and the like, and a solution in which a cationic polysaccharide is dissolved is mixed. An excipient is added to the mixed solution so as to have a predetermined strength and ductility.

1 shows a schematic structural diagram of an extrusion machine usable in the present invention.

In the extrusion process, a hydraulic extruder 1 having a plurality of holes 2 having a predetermined inner diameter on its bottom may be used. The union formed to have the appropriate strength and ductility is introduced into the extruder 1 to be molded as a cylindrical filament.

2A to 2C show a perspective view, a left side view and an A-A cross sectional view of a pelletizer for molding the filament obtained by the extrusion process from the union into pellets.

The pelletizer is provided with a set of forming rollers 4 and 5 required for forming the filament into a circular ring. The shaping roller is formed with a semicircular groove 6 having a constant inner diameter perpendicular to the rotational axis along the roller surface between the protruding surface 7 for cutting the extrudate. The pair of forming rollers 4 and 5 rotate in the up and down direction by making the semicircular grooves and the protruding surfaces correspond to each other. At this time, if the long cylindrical filament 3 is placed in parallel between the contact surfaces of the upper and lower rollers, the extrudate is rotated by two rollers rotating at different speeds from the upper and lower sides, and is cut by the protruding surface 7 of the roller. And compressed by a semicircular groove to form a ring having a constant inner diameter.

The size of the final pellets can be controlled by adjusting the inner diameter of the plurality of holes 2 formed in the extruder or the size of the grooves 6 between the protruding surfaces formed in the forming roller of the pelletizer.

The present invention includes formulations wherein the pellets produced by the above process have a size of preferably 1 to 5 mm, more preferably about 1.5 to 2.5 mm.

In addition, the pellet is formed with at least one coating layer of an intermediate coating, a moisture barrier coating, and an enteric coating. As the material for forming the coating layer, one or more of the following polymers are used alone or in combination of two or more thereof, and are not necessarily limited thereto: methyl cellulose, hydroxyethyl cellulose, hydroxybutyl cellulose, and hydroxy. Propyl methyl cellulose, hydroxymethyl cellulose, polyoxyethylene glycol cellulose, hydroxymethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, chitosan, alginic acid, galactomannose, tragaganth, shellac, agar, gum arabic , Guar rubber and xanthan rubber, polyacrylic acid copolymer, methacryl copolymer, polyvinylacetate phthalate, polyethylene oxide, polypropylene oxide or other suitable enteric coating film polymers known in the art.

The coating layer material does not require any particular limitation, but is dissolved or diluted in an organic solvent such as alcohol, acetone, methylene chloride, or a mixed solvent of water and these solvents, and is usually in the range of 1.5 to 30% by weight depending on the height of the viscosity. Is added.

Hereinafter, the content of the present invention will be described in more detail with reference to Examples. However, these examples are only presented to understand the content of the present invention, and the scope of the present invention should not be construed as being limited to these embodiments.

<Examples 1 and 2>

As shown in Table 1, the water-soluble chitosan (average molecular weight 200,000) polymerized with glucosamine having a cation was dissolved in an appropriate amount of distilled water (molar equivalent of 30 mg of lansoprazole), and the solution was lansoprazole and SLS, an alkalizing agent. Sodium dihydrogen phosphate (Na ₂ HPO ₄ ) was added to the dissolved aqueous solution. In this case, lansoprazole having a structural anion with chitosan has excellent stability in aqueous solution due to electrostatic stability. The solution was then sonicated for a sufficient time.

Separately, microcrystalline cellulose (Avicel PH102), low-substituted hydroxypropyl cellulose (L-HPC), and mannitol were measured as shown in Table 1 below, mixed and fed in advance, and then mixed with the solution.

After sufficient union, the above union was put into an extruder having a plurality of holes having an inner diameter of 2.00 mm, molded into a long cylindrical filament, and finally formed into pellets using a pelletizer. The pellets were then dried for 1 to 2 days in a cool, airy shade. After drying, the first coating treatment with 4% by weight of hydroxypropyl methyl cellulose (HPMC) coating solution dissolved in distilled water in a coating pen, and 12% by weight of hydroxypropyl methyl cellulose phthalate dissolved in acetone, ethanol, cetyl alcohol ( Enteric coating layer was formed with HPMCP) coating solution.

TABLE 1

Prescription Example 1 Example 2 Chitosan (AMW = 20 only) 13 13 D.W q.s q.s Lansoprazole 30 30 Sodium lauryl sulfate 0.8 0.5 Sodium hydrogen phosphate 14 12 D.W q.s q.s Avicel PH-102 52 52 L-HPC LH-11 52 52 Mannitol 148 150 HPMC 6cp appr.12.4 appr. 12.4 D.W q.s q.s HPMCP appr. 37.2 appr. 37.2 Acetone q.s q.s ethanol q.s q.s Cetyl alcohol q.s q.s sum 359.4 359.4 Unit: mg

<Examples 3 to 8>

In order to improve the disintegration rate of lansoprazole pellets as shown in Table 2, water-soluble chitosan (average molecular weight 200,000 or less, 10,000 or less), as an excipient, especially croscarmellose (Ac-di-sol), microcrystalline cellulose (Avecel PH102), low-substituted hydroxypropylcellulose (L-HPC) and mannitol contents were varied and associated in the same manner as in Examples 1-2 above.

After sufficient union, the above union was put into an extruder having a plurality of holes having an inner diameter of 2.00 mm, molded into a long cylindrical filament, and finally formed into pellets using a pelletizer. The pellets were then dried for 1 to 2 days in a cool, airy shade. After drying, the coating was first coated with 4% by weight of hydroxypropylmethylcellulose (HPMC) coating solution dissolved in distilled water in a coating pen, and then 12% by weight of hydroxypropylmethylcellulose phthalate (HPMCP) dissolved in acetone, ethanol, and cetyl alcohol. ) The enteric coating layer was formed from the coating liquid.

TABLE 2

Prescription Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Chitosan (AMW = 20 only) 10 - - - - - Chitosan (AMW = 1 only or less) - 10 10 10 10 10 D.W q.s q.s q.s q.s q.s q.s Lansoprazole 30 30 30 30 30 30 Sodium lauryl sulfate 0.8 0.8 0.8 0.8 0.8 0.8 Sodium hydrogen phosphate 14 14 14 14 14 14 D.W q.s q.s q.s q.s q.s q.s Ac-di-sol 20 20 - 20 20 20 Avicel PH-102 - - 20 250 - - L-HPC LH-11 100 100 100 - 250 - Mannitol 150 150 150 - - 250 HPMC 6cp appr.12.4 appr. 12.4 appr. 12.4 appr. 12.4 appr. 12.4 appr. 12.4 D.W q.s q.s q.s q.s q.s q.s HPMCP appr. 37.2 appr. 37.2 appr. 37.2 appr. 37.2 appr. 37.2 appr. 37.2 Acetone q.s q.s q.s q.s q.s q.s ethanol q.s q.s q.s q.s q.s q.s Cetyl alcohol q.s q.s q.s q.s q.s q.s sum 374.4 374.4 374.4 374.4 374.4 374.4 Unit: mg

<Examples 9-12>

10 mg of chitosan (less than 10,000) was dissolved in distilled water as shown in Table 3, and then lansoprazole and poloxamer F127 as a surfactant and meglumine as an alkalizing agent were mixed in a suspension dissolved in distilled water. To this was added croscarmellose (Ac-di-sol), low substituted hydroxypropyl cellulose (L-HPC) and mannitol as excipients.

After sufficient coalescing, the pellets were prepared and coated by the same process as in Examples 1 and 2 above.

TABLE 3

Prescription Example 9 Example 10 Example 11 Example 12 Chitosan (AMW = 1 only or less) 10 10 10 10 D.W q.s q.s q.s q.s Lansoprazole 30 30 30 30 Poloxamer F127 2 2 2 2 Meglumine 16 16 16 16 D.W q.s q.s q.s q.s Ac-di-sol - 10 30 40 L-HPC LH-11 140 140 140 140 Mannitol 100 100 100 100 HPMC 6cp appr.12.4 appr. 12.4 appr. 12.4 appr. 12.4 D.W q.s q.s q.s q.s HPMCP appr. 37.2 appr. 37.2 appr. 37.2 appr. 37.2 Acetone q.s q.s q.s q.s ethanol q.s q.s q.s q.s Cetyl alcohol q.s q.s q.s q.s sum 347.6 357.6 377.6 387.6 Unit: mg

<Examples 13-14>

10 mg of chitosan (less than 10,000) was dissolved in distilled water as shown in Table 4, and then lansoprazole, poloxamer F127 as a surfactant, and meglumine as an alkalizing agent were mixed in a suspension dissolved in distilled water. To this was added croscarmellose (Ac-di-sol), low substituted hydroxypropyl cellulose (L-HPC) and mannitol as excipients.

After sufficient coalescing, the pellets were prepared and coated by the same process as in Examples 1 and 2 above.

TABLE 4

Prescription Example 13 Example 14 Chitosan (AMW = 1 only or less) 10 10 D.W q.s q.s Lansoprazole 30 30 Poloxamer F127 4 6 Meglumine 16 16 D.W q.s q.s Ac-di-sol 30 30 L-HPC LH-11 140 140 Mannitol 100 100 HPMC 6cp appr.12.4 appr. 12.4 D.W q.s q.s HPMCP appr. 37.2 appr. 37.2 Acetone q.s q.s ethanol q.s q.s Cetyl alcohol q.s q.s sum 379.6 381.6 Unit: mg

<Examples 15-16>

10 mg of chitosan (10,000 or less) was dissolved in distilled water as in the composition of Table 5, and then lansoprazole, poloxamer F127 as a surfactant, and meglumine as an alkalizing agent were mixed in a suspension dissolved in distilled water. To this was added croscarmellose (Ac-di-sol), low substituted hydroxypropyl cellulose (L-HPC) and mannitol as excipients.

After sufficient coalescing, the pellets were prepared and coated by the same process as in Examples 1 and 2 above.

TABLE 5

Prescription Example 15 Example 16 Chitosan (AMW = 1 only or less) 10 6 D.W q.s q.s Lansoprazole 30 30 Poloxamer F127 2 2 Meglumine 9 30 D.W q.s q.s Ac-di-sol 40 40 L-HPC LH-11 140 140 Mannitol 100 100 HPMC 6cp appr.12.4 appr. 12.4 D.W q.s q.s HPMCP appr. 37.2 appr. 37.2 Acetone q.s q.s ethanol q.s q.s Cetyl alcohol q.s q.s sum 378.6 397.6 Unit: mg

<Examples 17-19>

10 mg of chitosan (10,000 or less) was dissolved in distilled water as in the composition of Table 6, and then lansoprazole, poloxamer F127 as a surfactant, and meglumine as an alkalizing agent were mixed in a suspension dissolved in distilled water. To this was added croscarmellose (Ac-di-sol), low substituted hydroxypropyl cellulose (L-HPC) and mannitol as excipients.

After sufficient coalescing, the pellets were prepared and coated by the same process as in Examples 1 and 2 above.

In Example 19 of Table 6, 10 mg of chitosan (up to 10,000) was dissolved in distilled water, and then lanoxprazole was added to the poloxamer F127 as a surfactant and meglumine as an alkalizing agent was mixed in a suspension dissolved in distilled water. To this was added croscarmellose (Ac-di-sol), low substituted hydroxypropyl cellulose (L-HPC) and mannitol as excipients.

After sufficient coalescing, the pellets were prepared and coated by the same process as in Examples 1 and 2 above.

TABLE 6

Prescription Example 17 Example 18 Example 19 Chitosan (AMW = 1 only or less) 10 10 10 D.W q.s q.s q.s Lansoprazole 30 30 0 Poloxamer F127 2 2 2 Meglumine 12 16 16 D.W q.s q.s q.s ethanol q.s q.s q.s Ac-di-sol 40 40 40 L-HPC LH-11 140 140 140 Mannitol 100 100 100 HPMC 6cp appr.12.4 appr. 12.4 appr. 12.4 D.W q.s q.s q.s HPMCP appr. 37.2 appr. 37.2 appr. 37.2 Acetone q.s q.s q.s ethanol q.s q.s q.s Cetyl alcohol q.s q.s q.s sum 379.6 381.6 357.6 Unit: mg

<Examples 20-22>

10 mg of chitosan (less than 10,000) was dissolved in distilled water as shown in the following Table 7, and then the lansoprazole and poloxamer F127, a surfactant, and meglumine were respectively changed and mixed in a suspension dissolved in distilled water. To this was added croscarmellose (Ac-di-sol), low substituted hydroxypropyl cellulose (L-HPC) and mannitol as excipients.

After sufficient coalescing, the pellets were prepared and coated by the same process as in Examples 1 and 2 above.

TABLE 7

Prescription Example 20 Example 21 Example 22 Chitosan (AMW = 1 only or less) 10 10 10 D.W q.s q.s q.s Lansoprazole 30 30 30 Poloxamer F127 2 2 2 Meglumine 0 32 64 D.W q.s q.s q.s ethanol q.s q.s q.s Ac-di-sol 40 40 40 L-HPC LH-11 140 140 140 Mannitol 100 100 100 HPMC 6cp appr.12.4 appr. 12.4 appr. 12.4 D.W q.s q.s q.s HPMCP appr. 37.2 appr. 37.2 appr. 37.2 Acetone q.s q.s q.s ethanol q.s q.s q.s Cetyl alcohol q.s q.s q.s sum 381.6 403.6 435.6 Unit: mg

<Examples 23-25>

As shown in the composition of Table 8, 30 mg of lansoprazole was dissolved in distilled water and the same amount of ethanol together with 2 mg of poloxamer F127 and 24 mg of meglumine, and then mixed with glucosamine dissolved in an appropriate amount of distilled water. To this was added croscarmellose (Ac-di-sol), low substituted hydroxypropyl cellulose (L-HPC) and mannitol as excipients.

After sufficient coalescing, the pellets were prepared and coated by the same process as in Examples 1 and 2 above.

TABLE 8

Prescription Example 23 Example 24 Example 25 Glucosamine 8 10 14 D.W q.s q.s q.s Lansoprazole 30 30 30 Poloxamer F127 2 2 2 Meglumine 24 24 24 D.W q.s q.s q.s ethanol q.s q.s q.s Ac-di-sol 40 40 40 L-HPC LH-11 140 140 140 Mannitol 100 100 100 HPMC 6cp appr.12.4 appr. 12.4 appr. 12.4 D.W q.s q.s q.s HPMCP appr. 37.2 appr. 37.2 appr. 37.2 Acetone q.s q.s q.s ethanol q.s q.s q.s Cetyl alcohol q.s q.s q.s sum 387.6 389.6 393.6 Unit: mg

<Examples 26-28>

As shown in Table 9, 30 mg of lansoprazole was dissolved in distilled water and the same amount of ethanol together with poloxamer F127 and meglumine, followed by mixing 14 mg of oligochitosan previously dissolved. To this was added croscarmellose (Ac-di-sol), low substituted hydroxy propyl cellulose (L-HPC) and mannitol as excipients.

After sufficient coalescing, the pellets were prepared and coated by the same process as in Examples 1 and 2 above.

TABLE 9

Prescription Example 26 Example 27 Example 28 Oligochitosan 14 14 14 D.W q.s q.s q.s Lansoprazole 30 30 30 Poloxamer F127 2 4 6 Meglumine 24 24 24 D.W q.s q.s q.s ethanol q.s q.s q.s Ac-di-sol 40 40 40 L-HPC LH-11 140 140 140 Mannitol 100 100 100 HPMC 6cp appr.12.4 appr. 12.4 appr. 12.4 D.W q.s q.s q.s HPMCP appr. 37.2 appr. 37.2 appr. 37.2 Acetone q.s q.s q.s ethanol q.s q.s q.s Cetyl alcohol q.s q.s q.s sum 393.6 395.6 397.6 Unit: mg

<Examples 29-31>

As shown in the composition of Table 10, 30 mg of lansoprazole was dissolved in distilled water and the same amount of ethanol together with poloxamer F127 and meglumine, followed by mixing different weights of oligochitosan. To this was added croscarmellose (Ac-di-sol), low substituted hydroxypropyl cellulose (L-HPC) and mannitol as excipients.

After sufficient association, the pellets were prepared and coated by the same procedure as in Examples 1-2.

TABLE 10

Prescription Example 29 Example 30 Example 31 Oligochitosan 8 10 14 D.W q.s q.s q.s Lansoprazole 30 30 30 Poloxamer F127 2 2 2 Meglumine 12 16 24 D.W q.s q.s q.s ethanol q.s q.s q.s Ac-di-sol 40 40 40 L-HPC LH-11 140 140 140 Mannitol 100 100 100 HPMC 6cp appr.12.4 appr. 12.4 appr. 12.4 D.W q.s q.s q.s HPMCP appr. 37.2 appr. 37.2 appr. 37.2 Acetone q.s q.s q.s ethanol q.s q.s q.s Cetyl alcohol q.s q.s q.s sum 381.6 385.6 393.6 Unit: mg

Experimental Example 1 Content Measurement

The amount of 20 capsules (corresponding to 0.6 g of lansoprazole) was precisely weighed in the pellets prepared according to the above examples, and the contents were mixed well. Then, 30 mg of the corresponding amount of lansoprazole was precisely weighed from the mixture. 25 mL of 0.25 mol / L sodium hydroxide was added thereto, followed by ultrasonic shaking, followed by dissolution of 25.0 mL of ethanol and about 150 mL of 0.235 mol / L sodium hydrogen phosphate. 0.235 mol / L sodium hydrogen phosphate was further added to this solution to make an exact 250 mL, followed by filtration. 25.0 mL of this filtrate was accurately taken into a 100 mL volumetric flask and 0.235 mol / L sodium hydrogen phosphate was added to make a total amount of 100 mL. This was filtered and used as the sample liquid.

Separately, 30 mg of lansoprazole standard was precisely weighed. 25 mL of 0.25 mol / L sodium hydroxide, 25.0 mL of ethanol, and about 150 mL of 0.235 mol / L sodium hydrogen phosphate were added thereto, followed by ultrasonic extraction. 0.235 mol / L sodium hydrogen phosphate was further added to the solution, followed by 250 ml, followed by filtration. 25 mL of this filtrate was accurately taken into a 100 mL volumetric flask and 0.235 mol / L sodium hydrogen phosphate was added to make a total amount of 100 mL. This was filtered to give a standard solution.

20 μl of the sample solution and the standard solution were tested according to the Pharmacopoeia General Test Liquid Chromatography method under the following conditions, and the peak areas Ar and As of lansoprazole were calculated, and then the amount of lansoprazole contained in the pellet was calculated. Indicated.

Amount of lansoprazole (mg) = Amount of lansoprazole standard (mg) x

A _t is the peak area of the example sample and A _s is the peak area of the standard product.

[Operation Conditions]

Column: A column filled with 5 μm octadecylsilylated silica gel in a stainless steel tube having a diameter of 4.6 mm and a length of 15 cm.

Detector: ultraviolet absorbance photometer (wavelength 270 nm)

Mobile phase: Acetonitrile: 0.1M KH ₂ PO ₄ (40:60)

Flow rate: 1mL / min

Experimental Example 2 Dissolution Test

Pellets corresponding to 30 mg of lansoprazole were correctly taken. Using eluate 900mL of 1% w / v of polysorbate 80 (Tween80) in pH 6.8 phosphate buffer (Pharmacopoeia) was tested at 100 revolutions per minute in accordance with the second method of the General Test Methods elution test. After elution test for 30 minutes, 10 mL of eluate was taken and filtered. 5.0 mL of this filtrate was taken, and then 1.0 mL of 0.25 mol / L sodium hydroxide solution was added thereto, mixed well to obtain a sample solution.

Separately, 30 mg of lansoprazole standard was precisely weighed and dissolved in 10.0 mL of ethanol, and then eluent was added to the solution to make 100 mL accurately. 5.0 mL of this solution was taken, and the eluate was added to exactly 50 mL, followed by filtration. 5.0 mL of this filtrate was taken, and then 1.0 mL of 0.25 mol / L sodium hydroxide solution was added thereto, mixed well to obtain a sample solution.

Dissolution rate of lansoprazole (C ₁₆ H ₁₄ F ₃ N ₃ O ₂ S) in 1 tablet =

W _s : Taken amount of lansoprazole standard (mg)

W _t : Corresponding amount of lansoprazole in one tablet (mg)

C: content of lansoprazole standard (%)

Experimental results showed that almost all active drugs were eluted.

Experimental Example 3 Stability Test

The lansoprazole content in the pellets measured by high performance liquid chromatography after storing the chitosan pellets obtained in Example 31 at 25 ° C., 37 ° C., 50 ° C., 66% and 0% for one month is shown in Table 11.

TABLE 11

division Initial content 25 ℃ 37 ℃ 50 ℃ (For 1 month) 66% RH 99.7 96.83 91.67 22.71 0% RH 100.1 99.91 98.24 96.32 unit(%)

It can be seen from Table 11 that the formulation of the present invention exhibits sufficient stabilization of the active ingredient even in harsh conditions. It can also be seen that when the formulation is stored at low humidity, it contributes more synergistically to stabilization. Therefore, in the process of industrially using the active ingredient according to the present invention, for example, it can be expected to contribute more synergistically to the stabilization of the active ingredient when stored or distributed at room temperature in PTP packaging or the like.

According to the present invention, the benzimidazole derivatives or pharmacologically acceptable salts thereof are electrostatically stabilized to have excellent resistance in acidic and aqueous environments.                     

Processing into pellets also significantly reduces the risk of drug loss incurred during the production of the formulation and enables the production of formulations with a uniform content of the drug.

Claims (16)

Pellets comprising at least benzimidazole derivatives or pharmacologically acceptable salts thereof as the active substance and cationic polysaccharides: Stability-enhanced release-formulated formulation in which at least one coating layer of an intermediate coating, a moistureproof coating, and an enteric coating is formed as an outer coating layer of the pellet. The method of claim 1, The pellet further comprises an effective amount of an alkalizing agent to create an appropriate pH environment required for stabilization of the active ingredient. The method of claim 1, The active ingredient is selected from lansoprazole, pantoprazole and rabeprazole. The method of claim 1, Cationic polysaccharides are agents selected from water soluble chitosan, oligo chitosan The method of claim 2, The alkalizing agent is magnesium oxide, sodium dihydrogen phosphate, potassium monohydrogen phosphate, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, aluminum carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydrogen carbonate, aluminum phosphate, calcium phosphate, Sodium Phosphate, Potassium Phosphate, Aluminum Citrate, Calcium Citrate, Sodium Citrate, Potassium Citrate, Arginine, Lysine, Histidine, Eglumin, Meglumine The method of claim 1 wherein the pellets Single or two type selected from the group of ionic and nonionic surfactants such as sodium lauryl sulfate, polysorbate, stearic acid triethanolamine, alkyl sulfonate, alkylaryl sulfonate, sorbitan esters, and fluorones as surfactants Formulations containing the above mixed ingredients The method of claim 1 wherein the pellets As an excipient, microcrystalline cellulose, cellulose powder, low substituted hydroxypropyl cellulose, cellulose acetate, croscarmellose sodium, calcium phosphate, calcium sulfate, corn starch, lactose, mannitol, sorbitol, polyvinylpyrrolidone, talc, deck Straight, dextrin, glucose, fructose, maltose, sucrose, kaolin, magnesium carbonate, magnesium oxide, polymethacrylate, hydroxypropylmethylcellulose, ethylcellulose, gelatin, guar gum, xanthan gum, acrylate polymer or copolymer Formulations comprising one or more mixed ingredients selected from the group of The method of claim 1, The coating layer is methyl cellulose, hydroxyethyl cellulose, hydroxybutyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, polyoxyethylene glycol cellulose, hydroxymethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, chitosan Alginic acid, galactomannose, tragaganth, shellac, agar, gum arabic, guar rubber and xanthan rubber, polyacrylic acid copolymer, methacryl copolymer, polyvinylacetate phthalate, polyethylene oxide, polypropylene oxide Formulations comprising only one or two or more mixed ingredients Extruding an association comprising a benzimidazole derivative or pharmacologically acceptable salt thereof with at least an active substance and a cationic polysaccharide to form a filament: Shaping the filament into pellets; And Method for producing a stable release controlled formulation comprising the step of forming at least one coating layer of the intermediate film, moisture-proof film, enteric coating film in the pellet The method of claim 9, The combination further comprises an effective amount of alkalizing agent to create an appropriate pH environment required for stabilization of the active ingredient. The method of claim 9, Active ingredient is selected from lansoprazole, omeprazole, pantoprazole, and labeprazole The method of claim 9, Cationic polysaccharide is a production method selected from water-soluble chitosan, oligo chitosan The method of claim 10, The alkalizing agent is magnesium oxide, sodium dihydrogen phosphate, potassium monohydrogen phosphate, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, aluminum carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium hydrogen carbonate, aluminum phosphate, calcium phosphate, Sodium Phosphate, Potassium Phosphate, Aluminum Citrate, Calcium Citrate, Sodium Citrate, Potassium Citrate, Arginine, Lysine, Histidine, Eglumin, Meglumine, a method for producing a mixture characterized in that it is single or two or more selected from the group The method of claim 9, wherein the association is Single or two selected from the group of ionic and nonionic surfactants such as sodium lauryl sulfate, polysorbate, triethanolamine stearic acid, alkyl sulfonate, alkylaryl sulfonate, sorbitan esters, and fluorones as surfactants Method for producing a mixture of more than one species The method of claim 9, wherein the association is As an excipient, microcrystalline cellulose, cellulose powder, low substituted hydroxypropyl cellulose, cellulose acetate, croscarmellose sodium, calcium phosphate, calcium sulfate, corn starch, lactose, mannitol, sorbitol, polyvinylpyrrolidone, talc, deck Straight, dextrin, glucose, fructose, maltose, sucrose, kaolin, magnesium carbonate, magnesium oxide, polymethacrylate, hydroxypropylmethylcellulose, ethylcellulose, gelatin, guar gum, xanthan gum, acrylate polymer or copolymer Manufacturing method characterized in that the single or mixed components of two or more selected from the group of The method of claim 9, The coating layer is methyl cellulose, hydroxyethyl cellulose, hydroxybutyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, polyoxyethylene glycol cellulose, hydroxymethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, chitosan , Alginic acid, galactomannose, tragaganth, shellac, agar, gum arabic, guar rubber and xanthan rubber, polyacrylic acid copolymer, methacrylic copolymer, polyvinylacetate phthalate, polyethylene oxide, Method for producing a single or a mixture of two or more selected from the group of polypropylene oxide.

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