KR20210054137A - Sustained-release pharmaceutical compositions for oral administration comprising rebamipide or pharmaceutically acceptable salt thereof - Google Patents

Abstract

The present invention provides a sustained-release pharmaceutical composition for oral administration once or twice a day, containing rebamipide or a pharmaceutically acceptable salt thereof and chitosan as an anti-gelling agent and a sustained-release polymer, or containing rebamipide or a pharmaceutically acceptable salt thereof, at least one anti-gelling agent selected from a group consisting of chitosan and an amino-methacrylate copolymer, and a sustained-release polymer.

Description

TECHNICAL FIELD [Sustained-release pharmaceutical compositions for oral administration comprising rebamipide or pharmaceutically acceptable salt thereof]

The present invention relates to a sustained-release pharmaceutical composition for oral administration comprising rebamipide or a pharmaceutically acceptable salt thereof. More specifically, chitosan is included as an anti-gelling agent and a sustained-release polymer; Or it relates to a sustained-release pharmaceutical composition for oral administration once a day or twice a day, comprising at least one anti-gelling agent and a sustained-release polymer selected from the group consisting of chitosan and amino-methacrylate copolymer.

Rebamipide (rebamipide) is a substance that acts to increase the blood flow of the gastric mucosa by increasing the mucous membrane that protects the gastric wall by promoting the production of prostaglandin, and is used for gastric mucosa protection, gastric ulcer and gastritis treatment. Miffy lifting lever and is sold under the trade name of a non-constant Costa ^TM information (Mucosta ^TM Tablets, Otsuka Pharmaceutical) containing 100 mg, it is administered orally three times a day. In order to increase the patient's medication convenience and compliance, it has been required to develop a rebamipide-containing pharmaceutical composition that can be administered once or twice a day.

Rebamipide is a very poorly soluble drug, and the solubility of rebamipide in an aqueous environment is about 0.0001% (w/v) at pH 3 and about 0.013% (w/v) at pH 7, which is more solubility in acidic conditions. Rebamipide has low dissolution rate and absorption rate in the gastrointestinal tract environment after oral administration, and in order to overcome this, efforts have been attempted to increase dissolution and bioavailability by designing a formulation by micronizing drug particles or by preparing a solid dispersion ( Korean Patent No. 10-1577871).

As a sustained-release formulation containing rebamipide, Korean Patent Publication Nos. 10-2012-0075029, 10-2018-0114515, 10-2013-0121717, 10-2015-0130916, and Korean patents registered No. 10-1269829 and the like have disclosed a sustained-release formulation using a gastric retention drug delivery system. However, the gastric retention drug delivery system requires the use of a swellable polymer, and there is a large variation in gastric retention time due to differences in the ability to discharge gastric contents from person to person. There is a risk of excretion without exhibiting a sustained-release characteristic due to aggregation, and there are disadvantages such as abdominal discomfort and food effects due to swelling in the stomach. Therefore, there is a need in the art to develop a rebamipide-containing sustained-release formulation suitable for oral administration once a day or twice a day.

The present inventors conducted various studies to develop a rebamipide-containing sustained-release formulation suitable for oral administration once a day or twice a day.

The present inventors believe that when rebamipide is formulated in the form of tablets or the like using a conventional sustained-release polymer, the desired level of drug is not released when administered orally, while maintaining the formulated form and being discharged to the outside of the body. I discovered that there is a problem. As a result of conducting various studies to find out the cause of this problem, when rebamipide is exposed to an aqueous environment for a long time, the micronized drugs aggregate with each other or the sustained-release polymer and rebamipide aggregate to maintain the gel-like properties. , It was found that the sustained-release preparation (eg, tablet) did not disintegrate even in an aqueous solution, and the dissolution rate and absorption rate in the body were lowered. In other words, in order to develop a rebamipide-containing sustained-release formulation suitable for oral administration once a day or twice a day, it was found that aggregation between drugs or gelation caused by aggregation between the sustained-release polymer and drugs must be prevented. I did. The present inventors have found that, as a result of formulating using a specific anti-gelling agent to prevent such a gelation phenomenon, a rebamipide-containing sustained-release preparation suitable for oral administration once a day or twice a day can be prepared. .

Accordingly, an object of the present invention is to provide a rebamipide-containing sustained-release pharmaceutical composition suitable for oral administration once a day or twice a day containing a specific anti-gelling agent.

According to one aspect of the present invention, rebamipide or a pharmaceutically acceptable salt thereof; And there is provided a sustained-release pharmaceutical composition for oral administration once a day or twice a day, comprising chitosan as an anti-gelling agent and a sustained-release polymer.

According to another aspect of the present invention, rebamipide or a pharmaceutically acceptable salt thereof; At least one anti-gelling agent selected from the group consisting of chitosan and amino-methacrylate copolymers; And there is provided a sustained-release pharmaceutical composition for administration once a day or twice a day containing a sustained-release polymer.

According to another aspect of the present invention, rebamipide or a pharmaceutically acceptable salt thereof; And chitosan as an anti-gelling agent and a sustained-release polymer; Or rebamipide or a pharmaceutically acceptable salt thereof; Chitosan or amino-methacrylate copolymers as anti-gelling agents; And a sustained-release first layer comprising a sustained-release polymer; And rebamipide or a pharmaceutically acceptable salt thereof, and an immediate release second layer comprising a pharmaceutically acceptable additive is provided. A multi-layered tablet showing a multiple release pattern of rebamipide is provided.

According to another aspect of the present invention, rebamipide or a pharmaceutically acceptable salt thereof; And chitosan as an anti-gelling agent and a sustained-release polymer; Or rebamipide or a pharmaceutically acceptable salt thereof; Chitosan or amino-methacrylate copolymers as anti-gelling agents; And sustained-release pellets or granules containing a sustained-release polymer; And an immediate-release pellet or granule comprising rebamipide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive thereof, and a capsule formulation exhibiting a multiple release pattern of rebamipide is provided.

According to another aspect, rebamipide or a pharmaceutically acceptable salt thereof; And chitosan as an anti-gelling agent and a sustained-release polymer; Or rebamipide or a pharmaceutically acceptable salt thereof; Chitosan or amino-methacrylate copolymers as anti-gelling agents; And a sustained-release core comprising a sustained-release polymer; And an immediate release shell comprising rebamipide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive thereof. There is provided a nucleated tablet showing a multiple release pattern of rebamipide.

When rebamipide is formulated in the form of tablets using a conventional sustained-release polymer, there is a problem that the desired level of drug is not released when administered orally, and the formulated form is maintained and discharged out of the body occurs. It was found by the present invention that this is caused by the aggregation of drugs in an aqueous environment and/or gelation due to aggregation of the sustained-release polymer and the drug by the present invention. The pharmaceutical composition according to the present invention contains a specific anti-gelling agent, that is, chitosan and/or an amino-methacrylate copolymer, thereby preventing aggregation between drugs or gelation due to aggregation between the sustained-release polymer and the drug. It can be formulated into a pharmaceutical composition suitable for oral administration once or twice a day.

1 shows the dissolution test results of the sustained-release tablet of the present invention (Example 2) and the tablet not containing an anti-gelling agent (Comparative Example 1).
Figure 2 shows the results of the dissolution test of the sustained-release tablet of the present invention (Example 4).
3 shows the plasma concentration profile obtained after administering the sustained-release tablet (Example 17) of the present invention and the control formulation to beagle dogs, respectively.

The present invention provides a sustained-release pharmaceutical composition comprising chitosan, which functions as an anti-gelling agent and a sustained-release polymer, that is, does not contain another sustained-release polymer. Specifically, the present invention relates to rebamipide or a pharmaceutically acceptable salt thereof; And it provides a sustained-release pharmaceutical composition for oral administration once a day or twice a day (hereinafter referred to as “first aspect” unless otherwise indicated) comprising chitosan as an anti-gelling agent and a sustained-release polymer.

The present invention also provides a sustained-release pharmaceutical composition comprising a chitosan and/or amino-methacrylate copolymer as an anti-gelling agent, and comprising a sustained-release polymer. Specifically, the present invention relates to rebamipide or a pharmaceutically acceptable salt thereof; At least one anti-gelling agent selected from the group consisting of chitosan and amino-methacrylate copolymers; And it provides a sustained-release pharmaceutical composition for administration once a day or twice a day (hereinafter, referred to as “second aspect” unless otherwise indicated) comprising a sustained-release polymer.

The pharmaceutical composition of the present invention contains rebamipide or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutically acceptable salts of rebamipide include, without limitation, salts derived from pharmacologically or physiologically acceptable amino acids and bases. Examples of the amino acid include lysine, alanine, arginine, tryptophan, and the like. Examples of the base include an alkali metal (eg, sodium or potassium), an alkaline earth metal (eg, magnesium), and the like. Rebamipide or a pharmaceutically acceptable salt thereof may be used in a therapeutically effective amount, for example, in the range of 80 mg to 500 mg, preferably 150 mg to 300 mg per unit tablet. It may be contained.

The pharmaceutical composition of the present invention includes chitosan and/or an amino-methacrylate copolymer as an anti-gelling agent. The anti-gelling agent prevents drug release from being hindered by aggregation of the drug in a low pH environment such as the stomach after oral administration, or the aggregation of the drug and the sustained-release polymer, and the drug is slowly released in the pharmaceutical composition. It plays a role in allowing it to be released. That is, the anti-gelling agent functions to continuously release the drug while preventing the formation of a release-controlling film in the form of a gel.

In the pharmaceutical composition of the present invention, as the chitosan, chitosan having a degree of deacetylation of 70% or more may be preferably used. If the degree of deacetylation is less than 70%, the drug may not exhibit sustained release due to insufficient release control function.

In the pharmaceutical composition of the present invention according to the first aspect, chitosan may not contain an additional sustained-release polymer by acting as an anti-gelling agent and a sustained-release polymer. In the pharmaceutical composition of the present invention according to the first aspect, chitosan may simultaneously play a role of preventing the agglomeration of the drug and the sustained release function of the drug in the pharmaceutical composition even at a low pH. In the pharmaceutical composition of the present invention according to the first aspect, chitosan is present in a range of 20 to 200 parts by weight, preferably 40 to 150 parts by weight, more preferably 70 to 120 parts by weight, based on 100 parts by weight of rebamipide. I can. In the pharmaceutical composition of the present invention according to the first aspect, when the content of chitosan is less than 20 parts by weight based on 100 parts by weight of rebamipide, the ability to prevent gelation may decrease, and when it exceeds 200 parts by weight, the release of the drug is controlled. You may lose your ability.

The pharmaceutical composition of the present invention according to the second aspect comprises chitosan and/or an amino-methacrylate copolymer as an anti-gelling agent. In the pharmaceutical composition of the present invention according to the second aspect, the anti-gelling agent may be present in the range of 20 to 200 parts by weight, preferably 20 to 150 parts by weight, based on 100 parts by weight of rebamipide. In the pharmaceutical composition of the present invention according to the second aspect, when the content of the anti-gelling agent is less than 20 parts by weight based on 100 parts by weight of rebamipide, the ability to prevent gelation may decrease, and when it exceeds 200 parts by weight, the drug The ability to control emissions may be impaired. When the pharmaceutical composition of the present invention according to the second aspect contains an amino-methacrylate copolymer and chitosan as an anti-gelling agent, the weight ratio of the amino-methacrylate copolymer and chitosan is 1:1 to 10, preferably 1 : It may be in the range of 2 to 8. In one embodiment, the amino-methacrylate copolymer may be a copolymer in which butyl methacrylate, (2-dimethylaminoethyl) methacrylate, and methyl methacrylate are copolymerized in a molar ratio of 1:2:1. have. As the amino-methacrylate copolymer, commercially available Eudragit E PO (Evonik Industries) or the like may be used.

In the pharmaceutical composition of the present invention according to the second aspect, the sustained-release polymer controls the rate at which moisture penetrates into the composition in the pharmaceutical composition after oral administration or controls the rate at which rebamipide is released inside the composition. Plays a role. The sustained-release polymer includes a sustained-release polymer used in the field of pharmaceuticals, for example, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, polyethylene Oxide, polyvinyl alcohol, polyvinylpyrrolidone, xanthan gum, guar gum, carbomer, carrageenan, sodium alginate, polymethacrylate copolymers (e.g. Eudragit L, Eudragit S, Eudragit FS, Eudragit RS, Eudragit NS, Eudragit NE, etc.), glyceryl bihinate, glyceryl monostearate, cetyl alcohol, and stearyl alcohol. In one embodiment, the sustained-release polymer may be preferably hydroxypropyl methylcellulose, carrageenan, or polyethylene oxide, more preferably hydroxypropyl methylcellulose. The sustained-release polymer may be present in a range of 10 to 100 parts by weight, preferably 10 to 80 parts by weight, more preferably 30 to 70 parts by weight, based on 100 parts by weight of rebamipide. When the content of the sustained-release polymer is less than 10 parts by weight, the ability to control the release of the drug is deteriorated, and it may be difficult to exhibit a release characteristic suitable for administration twice a day or once a day. In addition, when the content of the sustained-release polymer exceeds 100 parts by weight, the sustained-release polymer forms a gel-like release-controlling film together with the drug, so that the drug is not released and remains in the pharmaceutical composition and may be excreted out of the body. .

The pharmaceutical composition of the present invention may further include one or more additives selected from the group consisting of a diluent, an alkalinizing agent, a lubricant, a binder, a surfactant, a colorant, and a flavoring agent. The additive may be used in an amount commonly used in the field of pharmaceuticals, and may be appropriately determined by a person skilled in the art.

Examples of the diluent include lactose, glucose, microcrystalline cellulose, crystalline cellulose, calcium dihydrogen phosphate or a hydrate thereof (for example, dihydrate), mannitol, isomalt, sorbitol, pregelatinized starch, sucrose, starch (corn starch, potato Starch, etc.), lactitol, xylitol, dextrose, dextran, betacyclodextrin, a mixture of lactose and cellulose (e.g., cellactose), a mixture of silica and microcrystalline cellulose (e.g., Prosolve), maltitol And low-substituted hydroxypropyl cellulose.

Examples of the alkalizing agent include meglumine, potassium hydrogen phosphate, sodium hydrogen phosphate, magnesium oxide, calcium carbonate, calcium hydrogen carbonate, sodium hydrogen carbonate, sodium carbonate, magnesium hydroxide, sodium hydroxide, potassium hydroxide, and the like.

Examples of the binder include polyvinylpyrrolidone, gelatin, copovidone, hydroxymethyl cellulose, corn starch, sucrose, and the like.

Examples of the surfactant include sodium lauryl sulfate, polysorbate (polysorbate 80, polysorbate 60, polysorbate 40, etc.), sucrose fatty acid esters, and hydrogenated castor oil (cremophor RH 40, etc.). do.

The lubricant is stearic acid or a salt thereof (for example, magnesium stearate, calcium stearate, etc.), aluminate metasilicate or a salt thereof, stearyl fumaric acid or a salt thereof (sodium stearyl fumarate, etc.), light anhydride silicic acid, palmitic acid, Talc, carnauba wax, hydrogenated vegetable oil, mineral oil, polyethylene glycol, and the like.

The pharmaceutical composition of the present invention may have a variety of formulations, for example, tablets, compressed granules, pellets, and the like. Formulations such as tablets, compressed granules, and pellets may be prepared by a granule compression method, and for example, may be prepared by a dry granulation method or a wet granulation method.

In one embodiment, the pharmaceutical composition of the present invention in tablet form may be prepared by a manufacturing method comprising the following steps: (a) rebamipide or a pharmaceutically acceptable salt thereof, chitosan, and pharmaceutically acceptable Possible additives (e.g., diluents, etc.) are mixed or at least one selected from the group consisting of rebamipide or a pharmaceutically acceptable salt thereof, chitosan and amino-methacrylate copolymers, anti-gelling agents, sustained-release polymers, And mixing a pharmaceutically acceptable additive (eg, a diluent, etc.); (b) preparing dry granules from the mixture obtained in step (a) into roller compacts; And (c) mixing the dry granules obtained in step (b) with pharmaceutically acceptable additives (eg, diluents, lubricants, etc.), and tableting.

In another embodiment, the pharmaceutical composition of the present invention in tablet form may be prepared by a manufacturing method comprising the following steps: (a') rebamipide or a pharmaceutically acceptable salt thereof, chitosan, and pharmaceutically Mixing acceptable additives (e.g., diluents, etc.) or rebamipide or a pharmaceutically acceptable salt thereof, at least one selected from the group consisting of chitosan and amino-methacrylate copolymers, anti-gelling agent, sustained-release polymer , And pharmaceutically acceptable additives (eg, diluents, alkalizing agents, etc.); (b') preparing wet granules using a binder solution and drying the mixture obtained in step (a'); And (c') mixing the wet granules obtained in step (b') with pharmaceutically acceptable additives (eg, alkalizing agents, lubricants, etc.) and tableting.

In another embodiment, the pharmaceutical composition of the present invention in the form of compressed granules may be prepared by a manufacturing method comprising the following steps: (a'') rebamipide or a pharmaceutically acceptable salt thereof, chitosan, and Mixing pharmaceutically acceptable additives (eg, diluents, etc.) or anti-gelling agent selected from the group consisting of rebamipide or a pharmaceutically acceptable salt thereof, chitosan and amino-methacrylate copolymers, Mixing a sustained-release polymer and a pharmaceutically acceptable additive; (b'') kneading the mixture obtained in step (a'') using a binding liquid, and compression molding using an extruder; And (c'') sphericalizing the compression molded product obtained in step (b'') in a spherical granulator.

In another embodiment, the pharmaceutical composition of the present invention in the form of a pellet may be prepared by a manufacturing method comprising the following steps: (a''') comprising rebamipide or a pharmaceutically acceptable salt thereof and chitosan A mixture of rebamipide or a pharmaceutically acceptable salt thereof, an anti-gelling agent selected from the group consisting of chitosan and amino-methacrylate copolymers, and a mixture of a sustained-release polymer are combined with a binding solution (aqueous solution containing a binding agent) Or dispersing in an ethanol solution); And (b'") spraying the dispersion obtained in step (a'") onto seeds such as sugar seeds to prepare pellets.

In the above embodiments, the mixing may be performed according to a conventional method used in the field of pharmaceuticals. In addition, the preparation of the dry granules or the preparation of tablets, compressed granules, and pellets through the preparation of wet granules may be carried out according to a conventional method used in the field of pharmaceuticals. It can be performed by compressing using a compactor or the like. The tableting may also be performed according to a conventional method used in the field of pharmaceuticals. The tableting pressure can be appropriately adjusted so that a hardness of about 6-15 kp is obtained.

When the pharmaceutical composition of the present invention is in the form of a tablet, it may further include a conventional coating layer such as a film coating layer. The film coating layer is a conventional film such as polyvinyl alcohol, hydroxypropyl cellulose, xanthan gum, lactose, hydroxypropyl methylcellulose, triacetin, polyvinylpinolidone, polyethylene glycol, propylene glycol, talc, titanium dioxide, and pigment. It may contain components for forming a coating. Film coating formation may be performed through a method such as spray coating according to a conventional method.

The present invention may also be formulated in the form of a formulation having a multiple release pattern, including the sustained-release pharmaceutical composition described above. The formulation having the multiple release pattern is a multilayer tablet (preferably a bilayer tablet) comprising a sustained-release layer and an immediate-release layer, and It may be in the form of a tablet (ie, a nucleated tablet) having a core-shell structure including a capsule, a sustained-release core, and an immediate-release shell. The sustained-release layer, sustained-release pellets or granules, and sustained-release core may be formulated according to a conventional method using the sustained-release pharmaceutical composition described above. In addition, the immediate-release layer, the immediate-release pellets or granules, and the immediate-release shell may be formulated from commercially available rebamipide-containing immediate-release preparations according to a conventional method.

For example, the present invention relates to rebamipide or a pharmaceutically acceptable salt thereof; And chitosan as an anti-gelling agent and a sustained-release polymer; Or rebamipide or a pharmaceutically acceptable salt thereof; Chitosan or amino-methacrylate copolymers as anti-gelling agents; And a sustained-release first layer comprising a sustained-release polymer; And a multilayer tablet showing a multiple release pattern of rebamipide comprising an immediate release second layer comprising rebamipide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive.

The present invention also relates to rebamipide or a pharmaceutically acceptable salt thereof; And chitosan as an anti-gelling agent and a sustained-release polymer; Or rebamipide or a pharmaceutically acceptable salt thereof; Chitosan or amino-methacrylate copolymers as anti-gelling agents; And sustained-release pellets or granules containing a sustained-release polymer; And capsules showing multiple release patterns of rebamipide or immediate-release pellets or granules containing rebamipide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive.

The present invention also relates to rebamipide or a pharmaceutically acceptable salt thereof; And chitosan as an anti-gelling agent and a sustained-release polymer; Or rebamipide or a pharmaceutically acceptable salt thereof; Chitosan or amino-methacrylate copolymers as anti-gelling agents; And a sustained-release core comprising a sustained-release polymer; And a nucleated tablet showing a multiple release pattern of rebamipide comprising an immediate release shell comprising rebamipide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive.

In the formulation having a multiple release pattern according to the present invention, the immediate-release layer, the immediate-release pellet or granule, and the immediate-release shell release all rebamipide or a pharmaceutically acceptable salt thereof within 1 hour, and the sustained-release layer , The sustained-release pellets or granules, and the sustained-release core are preferably formulated to continuously release rebamipide or a pharmaceutically acceptable salt thereof for 6 hours or more.

Hereinafter, the present invention will be described in more detail through Examples and Test Examples. However, the following Examples and Test Examples are for illustrating the present invention, and the present invention is not limited thereto.

Example 1.

A sustained-release tablet containing rebamipide was prepared according to the ingredients and contents of Table 1 below. The content of each component in Table 1 represents the content per tablet (mg). Rebamipide, chitosan, isomalt, sodium carbonate, amino-methacrylate copolymer, magnesium aluminate metasilicate, hydroxypropyl methylcellulose 2208, and polyvinyl pinolidone are each apologized to a 20 mesh sieve, and then rotated at high speed. Put in a granulator and mixed for about 3 minutes. To the obtained mixture, 0.06 mL of ethanol was added per tablet as a binding solution and kneaded for 5 minutes. The combined product was dried in a fluid bed granulator for 2 hours, applesed through a 16 mesh sieve, and then meglumine appled through a 20 mesh sieve was added and mixed for 10 minutes. Magnesium stearate was added to the finally obtained mixture, mixed for 5 minutes, and then compressed in a tablet press to have a hardness of 6 to 15 kp to prepare a sustained-release tablet.

ingredient mg/tablet Rebamifeed 150 Chitosan 116.7 Amino-methacrylate copolymer (Eudragit E PO) 33.3 Hydroxypropyl methylcellulose 2208 (100 cps) 33.3 Magnesium aluminate metasilicate (Neusilin US2) 6.7 Sodium carbonate 50 Isomalt 75 Polyvinyl pinolidone (PVP K90) 5 Meglumine 25 Magnesium stearate 5 Tablet weight per tablet (mg) 500

Example 2.

A sustained-release tablet containing rebamipide was prepared according to the ingredients and contents of Table 2 below. The content of each component in Table 2 represents the content per tablet (mg). Rebamipide, chitosan, isomalt, sodium carbonate, magnesium aluminate metasilicate, and polyvinyl pinolidone were each apologized through a 20 mesh sieve, and then put into a high-speed rotary granulator and mixed for about 3 minutes. To the obtained mixture, 0.06 mL of ethanol was added per tablet as a binding solution and kneaded for 5 minutes. The combined product was dried in a fluid bed granulator for 2 hours, applesed through a 16 mesh sieve, and then meglumine appled through a 20 mesh sieve was added and mixed for 10 minutes. Magnesium stearate was added to the finally obtained mixture, mixed for 5 minutes, and then compressed in a tablet press to have a hardness of 6 to 15 kp to prepare a sustained-release tablet.

ingredient mg/tablet Rebamifeed 150 Chitosan 183.3 Magnesium aluminate metasilicate 6.7 Sodium carbonate 50 Isomalt 75 Polyvinyl pinolidone (PVP K90) 5 Meglumine 25 Magnesium stearate 5 Tablet weight per tablet (mg) 500

Examples 3 to 16.

According to the components and contents of Tables 3 and 4 below, in the same manner as in Example 1, a sustained-release tablet containing rebamipide was prepared. The content of each component in Tables 3 and 4 represents the content (mg) per tablet.

ingredient Example (mg/tablet) 3 4 5 6 7 8 9 Rebamifeed 90 200 150 150 150 150 90 Chitosan 55 82.2 165 165 150 116.7 60 Amino-methacrylate copolymer
(Eudragit E PO) - 82.2 - - - 33.3 10 Hydroxypropyl methylcellulose 2208 (100 cps) 55 82.2 - - - - 40 Hydroxypropyl Methylcellulose 2208 (15000cps) - - - - - 33.3 - Hydroxypropyl methylcellulose 2910 (4000cps) - - - - 30 - - Carrageenan - - - 15 - - - Polyethylene oxide 303 - - 15 - - - - Magnesium aluminate metasilicate 4 8.9 - - - 4 4 Sodium carbonate 30 64.4 50 50 50 75 45 Isomalt 45 100 - - - 75 45 Mannitol - - 75 75 75 - - Polyvinylpinolidone (PVP K90) 3 6.7 5 5 5 5 3 Meglumine 15 33.3 25 25 25 - - Magnesium stearate 3 6.7 5 5 5 5 3 Tablet weight per tablet (mg) 300 666.7 500 500 500 500 300

ingredient Example (mg/tablet) 10 11 12 13 14 15 16 Rebamifeed 100 100 100 100 100 100 100 Chitosan 10 40 96 - 70 150 50 Amino-methacrylate copolymer
(Eudragit E PO) 10 40 - 40 20 - - Hydroxypropyl methylcellulose 2208 (100 cps) 80 40 - 80 40 - Hydroxypropyl methylcellulose 2910 (4000cps) - - 24 - - 40 - Polyethylene oxide 301 - - - - - 40 Sodium carbonate 80 100 100 80 - 50 40 Isomalt 60 44.4 44.4 40 40 50 Mannitol - - - - - 55 - Polyvinyl pinolidone (PVP K90) 5 - - - - 3 Meglumine - - - - 80 10 Magnesium stearate 5 5.6 5.6 5 5 5 3 Tablet weight per tablet (mg) 350 350 350 350 330 400 300

Examples 17-20.

A two-layer tablet containing rebamipide was prepared according to the components and contents of Table 5 below. The content of each component in Table 5 represents the content per tablet (mg).

Rebamipide, chitosan, isomalt, sodium carbonate, amino-methacrylate copolymer (Examples 17 and 18), magnesium aluminate metasilicate, sustained-release polymer (hydroxypropyl methylcellulose 2208 and/or 2910, or carrageenan) And polyvinyl pinolidone were each apologized through a 20 mesh sieve, and then put into a high-speed rotating granulator and mixed for about 3 minutes. To the obtained mixture, 0.06 mL of ethanol was added per tablet as a binding solution and kneaded for 5 minutes. The combined product was dried in a fluid bed granulator for 2 hours, applesed through a 16 mesh sieve, and then meglumine (Examples 17, 19, and 20) appled through a 20 mesh sieve was added and mixed for 10 minutes. Magnesium stearate was added to the finally obtained mixture and mixed for 5 minutes to prepare a mixture A.

Rebamipide, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose (about 1/2 of the contents in Table 5) were each apologized through a 20 mesh sieve, and then put into a high-speed rotary granulator and mixed for about 3 minutes. In a high-speed rotary granulator, a solution obtained by dissolving low-viscosity hydroxypropyl cellulose (about 1/2 of the content in Table 5) in purified water was used as a binding solution, and the obtained mixture was kneaded for 10 minutes. The combined product was dried in a fluidized bed granulator for 2 hours and then apologized with a 16 mesh sieve, and then apologized with a 20 mesh sieve. ) And mixed for 10 minutes. To the finally obtained mixture, magnesium stearate was added as a lubricant and mixed for 5 minutes to prepare a mixture B.

The mixture A was compressed using a two-layer tablet press, and the mixture B was compressed thereon to prepare a two-layer tablet having a hardness of 6 to 15 kp.

ingredient Example (mg/tablet) 17 18 19 20 Immediate release Rebamifeed 60 60 50 52.5 Microcrystalline Cellulose PH101 18 18 18 25.5 Low Substitution Hydroxypropyl Cellulose 27 27 27 27 Low viscosity hydroxypropyl cellulose 4 4 4 4 Magnesium stearate One One One Western Rebamifeed 90 90 100 97.5 Chitosan 70 60 40 92.8 Amino-methacrylate copolymer
(Eudragit E PO) 20 10 - - Hydroxypropyl methylcellulose 2208 20 40 10 18.6 Hydroxypropyl methylcellulose 2910 - - - 18.6 Carrageenan - - 40 - Magnesium aluminate metasilicate 4 4 4 4.6 Sodium carbonate 30 45 30 35.2 Isomalt 45 45 50 79.8 Polyvinyl pinolidone K90 3 3 3 7.4 Meglumine 15 - 10 18.6 Magnesium stearate 3 3 3 5.7 Tablet weight per tablet (mg) 410 410 400 488.8

Comparative Example 1

According to the components and contents of Table 6 below, in the same manner as in Example 2, a sustained-release tablet containing rebamipide (containing hydroxypropyl methylcellulose 2208 (100 cps) as a sustained-release polymer) was prepared. The content of each component in Table 6 represents the content per tablet (mg).

ingredient mg/tablet Rebamifeed 150 Hydroxypropyl methylcellulose 2208 (100 cps) 183.3 Magnesium aluminate metasilicate 6.7 Sodium carbonate 50 Isomalt 75 Polyvinyl pinolidone (PVP K90) 5 Meglumine 25 Magnesium stearate 5 Tablet weight per tablet (mg) 500

Test Example 1

The dissolution test for the sustained-release tablets prepared in Example 2 and Comparative Example 1 was performed under conditions similar to the low pH conditions in the body. Specifically, using 900 mL of a pH 4.0 dissolution test solution (a buffer solution containing acetic acid and sodium acetate), a dissolution test was performed while rotating the paddle at 37°C at 50 rpm according to the second method of dissolution test method of the Korean Pharmacopoeia. After 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, and 8 hours after the start of the test, each 5 mL was taken as a sample solution, and analyzed as follows.

<Preparation of standard stock solution>

166.7 mg of rebamipide standard was dissolved in 100 mL of N,N-dimethylformamide to prepare a standard stock solution (concentration: 1.667 mg/mL).

<Preparation of standard solution>

Standard solution 1: Standard solution 1 was prepared by mixing 1 mL of standard stock solution and 49 mL of elution test solution.

Standard solution 2: Standard solution 2 was prepared by mixing 3 mL of standard stock solution and 47 mL of elution test solution.

Standard solution 3: Standard solution 3 was prepared by mixing 5 mL of standard stock solution and 45 mL of elution test solution.

Standard Solution 4: Standard Solution 4 was prepared by mixing 6 mL of standard stock solution and 44 mL of elution test solution.

<Analysis method>

For the standard solution and the sample solution, the absorbance was measured at 326 nm with an ultraviolet absorbance photometer (UV-vis absorbance photometer), and the elution rate (%) was calculated from the calibration curve obtained using the standard solution by the following equation.

A _T : absorbance of the sample solution

I: Intercept of the calibration curve

S: slope of calibration curve

D: Theoretical content of rebamipide (mg)

The results of performing the dissolution test as described above are shown in FIG. 1. As can be seen from the results of FIG. 1, the tablet of Comparative Example 1 containing no anti-gelling agent retained the elution of rebamipide within 20%, whereas the tablet obtained according to the present invention contained rebamipide continuously. It is being released.

Test Example 2.

For the sustained-release tablet prepared in Example 4, a urine release test was performed in the same manner as in Test Example 1, and the results are shown in FIG. 2. From the results of FIG. 2, the tablets obtained according to the present invention showed continuous dissolution without showing a phenomenon in which the degree of dissolution was not refined, and showed about 50% level of dissolution up to 12 hours, so that continuous dissolution is possible for up to 24 hours. Able to know.

Test Example 3.

After oral administration of the tablet (bilayer tablet) prepared in Example 17 and the non-costa tablet (containing 100 mg of rebamipide) as a control preparation to a beagle dog, the concentration profile of rebamipide in the blood was measured to evaluate the in vivo kinetics. . Each tablet was orally administered with 25 mL of water to beagle dogs weighing about 10 kg. The tablet of Example 17 was administered at 12 hour intervals, and the control agent was administered 3 times at 6 hour intervals. At 12.5, 13, 13.5, 14, 14.5, 15, 16, 17, 18, 20, and 24 hours from 12 hours after the start of the test, take 2 mL of blood from the jugular vein of the beagle dog and immediately take 10 ul (5 units) of blood. It was placed in a heparin-treated Eppendorf tube, and the blood sample obtained at each time was centrifuged at 4° C. for 10 minutes at 4,000 rpm. Dispense the separated supernatant into 1 set of 400 ul into a 1.5 ml Eppendorf tube, and put the remaining plasma in another 1 set to make a total of 2 sets per blood collection point. It was used to analyze the amount of rebamipide in blood under the following conditions.

<LC/MS/MS analysis conditions>

(1) HPLC conditions

(2) LC/MS/MS analysis conditions

<3> Preparation of calibration curve

A stock solution (1 mg/mL) was prepared by dissolving 10.00 mg of rebamipide in 10 mL of acetonitrile. After diluting the stock solution with acetonitrile, 50 μL of donor plasma and 50 μL of a previously prepared working solution were added to a micro tube, and a standard concentration of 5, 10, 50, 100, 500, and 1000 ng/mL Plasma samples were prepared. To 50 μL of the prepared standard plasma sample, 50 μL of an internal standard standard solution (Rebamipide-D4, 500 ng/mL) dissolved in acetonitrile and 350 μL of acetonitrile as a precipitation solvent were added, followed by vortexing for 3 minutes to precipitate proteins. After centrifuging this solution at 20000 g for 15 minutes, 100 μL of the supernatant was added to 100 μL of distilled water, vortexed for 3 minutes, and 5 μL was injected into LC-MS/MS. The calibration curve was prepared by applying weighted regression (1/x) to the ratio of the peak area of the drug to the peak area of the internal standard in the plasma drug concentration range.

The blood concentration profile obtained by analyzing as described above is shown in FIG. 3. From the results of FIG. 3, it can be seen that the sustained-release tablet obtained according to the present invention gradually absorbs rebamipide and continuously maintains the drug concentration.

Claims (21)

Rebamipide or a pharmaceutically acceptable salt thereof; And a sustained-release pharmaceutical composition for oral administration once a day or twice a day, comprising chitosan as an anti-gelling agent and a sustained-release polymer. Rebamipide or a pharmaceutically acceptable salt thereof; At least one anti-gelling agent selected from the group consisting of chitosan and amino-methacrylate copolymers; And a sustained-release pharmaceutical composition for administration once a day or twice a day, comprising a sustained-release polymer. The pharmaceutical composition according to claim 1 or 2, wherein the chitosan is chitosan having a degree of deacylation of 70% or more. The pharmaceutical composition according to claim 1, wherein the chitosan is present in a range of 20 to 200 parts by weight based on 100 parts by weight of rebamipide. The pharmaceutical composition according to claim 2, wherein the anti-gelling agent is present in the range of 20 to 200 parts by weight based on 100 parts by weight of rebamipide. The pharmaceutical composition according to claim 2, wherein the anti-gelling agent is an amino-methacrylate copolymer and chitosan, and the weight ratio of the amino-methacrylate copolymer and chitosan is 1-10. The method of claim 2, wherein the amino-methacrylate copolymer is a copolymer in which butyl methacrylate, (2-dimethylaminoethyl) methacrylate, and methyl methacrylate are copolymerized in a molar ratio of 1:2:1. A pharmaceutical composition, characterized in that. The pharmaceutical composition according to claim 2, wherein the sustained-release polymer is present in a range of 10 to 100 parts by weight based on 100 parts by weight of rebamipide. The method of claim 2, wherein the sustained-release polymer is hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, polyethylene oxide, polyvinyl alcohol, polyvinylpyrrolidone , Xanthan gum, guar gum, carbomer, carrageenan, sodium alginate, polymethacrylate copolymer, glyceryl bihinate, glyceryl monostearate, cetyl alcohol, and stearyl alcohol. A pharmaceutical composition, characterized in that. The pharmaceutical composition according to claim 9, wherein the sustained-release polymer is hydroxypropyl methylcellulose, carrageenan, or polyethylene oxide. The method according to any one of claims 1 to 10, further comprising at least one additive selected from the group consisting of a diluent, an alkalizing agent, a lubricant, a binder, a surfactant, a complexing agent, and a colorant. Pharmaceutical composition. The method of claim 11, wherein the diluent is lactose, glucose, microcrystalline cellulose, crystalline cellulose, calcium dihydrogen phosphate or a hydrate thereof, mannitol, isomalt, sorbitol, pregelatinized starch, sucrose, starch, lactitol, xylitol, dextrose, Dextran, beta cyclodextrin, a mixture of lactose and cellulose, a mixture of silica and microcrystalline cellulose, maltitol, and a pharmaceutical composition, characterized in that at least one selected from the group consisting of low-substituted hydroxypropyl cellulose. The method of claim 11, wherein the alkalizing agent is from the group consisting of meglumine, potassium hydrogen phosphate, sodium hydrogen phosphate, magnesium oxide, calcium carbonate, calcium hydrogen carbonate, sodium hydrogen carbonate, sodium carbonate, magnesium hydroxide, sodium hydroxide, and potassium hydroxide. Pharmaceutical composition, characterized in that at least one is selected. The pharmaceutical composition according to claim 11, wherein the binder is selected from the group consisting of polyvinylpyrrolidone, gelatin, copovidone, hydroxymethyl cellulose, corn starch, and sucrose. The pharmaceutical composition according to claim 11, wherein the surfactant is selected from the group consisting of sodium lauryl sulfate, polysorbate, sucrose fatty acid ester, and hydrogenated castor oil. The method of claim 11, wherein the lubricant is stearic acid or its salt, metasilicate aluminic acid or its salt, stearyl fumaric acid or its salt, light anhydrous silicic acid, palmitic acid, talc, carnauba wax, hydrogenated vegetable oil, mineral oil, And a pharmaceutical composition, characterized in that at least one selected from the group consisting of polyethylene glycol. The pharmaceutical composition according to any one of claims 1 to 10, which has a formulation of tablets, compressed granules, or pellets. The pharmaceutical composition according to claim 17, wherein the formulation is prepared by a dry granulation method or a wet granulation method. Rebamipide or a pharmaceutically acceptable salt thereof; And chitosan as an anti-gelling agent and a sustained-release polymer; Or rebamipide or a pharmaceutically acceptable salt thereof; Chitosan or amino-methacrylate copolymers as anti-gelling agents; And a sustained-release first layer comprising a sustained-release polymer; And
Immediate-release second layer comprising rebamipide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive
Multilayer tablet showing a multiple emission pattern of rebamipide comprising a. Rebamipide or a pharmaceutically acceptable salt thereof; And chitosan as an anti-gelling agent and a sustained-release polymer; Or rebamipide or a pharmaceutically acceptable salt thereof; Chitosan or amino-methacrylate copolymers as anti-gelling agents; And sustained-release pellets or granules containing a sustained-release polymer; And
Immediate-release pellets or granules containing rebamipide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive
Capsules showing a multiple release pattern of rebamipide comprising a. Rebamipide or a pharmaceutically acceptable salt thereof; And chitosan as an anti-gelling agent and a sustained-release polymer; Or rebamipide or a pharmaceutically acceptable salt thereof; Chitosan or amino-methacrylate copolymers as anti-gelling agents; And a sustained-release core comprising a sustained-release polymer; And
Rebamipide or a pharmaceutically acceptable salt thereof and an immediate-release shell comprising a pharmaceutically acceptable additive
A nucleated tablet showing a multiple release pattern of rebamipide comprising a.

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