[DESCRIPTION] [Invention Tide]

GASTRORETENTIVE SYSTEM CONTAINING SOLUBILIZED DRUG FOR MAXIMIZING ITS THERAPEUTIC EFFECT FOR GASTRITIS

[Technical Field]

The present invention relates to a gastroretentive system containing a solubilized drug having a therapeutic effect on gastritis, a pharmaceutical formulation using the same, and a method for preparing the pharmaceutical formulation, and more particularly, to a gastroretentive system containing a solubilized compound, represented by the following Formula 1, having a therapeutic effect on gastritis, a pharmaceutical formulation using the same, and a method for preparing the pharmaceutical formulation.

According to the present invention, the compound represented by the Formula 1 includes its pharmaceutically available salts and hydrates or solvates.

<Formula 1>

wherein, A is selected from the group consisting of alkyloxycarboalkyloxy, carboxylalkyloxy, N- alkylamidoalkyloxy, hydroxyalkyloxy and cycloalkyloxy, B and C are each independently selected from the group consisting of hydrogen, hydroxy, substituted or unsubstituted alkyloxy and cycloalkyloxy, and D and E are each independently selected from the group consisting of hydrogen, hydroxy, and linear or branched lower alkyloxy having 1 to 6 carbon atoms, provided that linkage between 2- and 3-positions is a single or double bond.

[Background Art]

Gastritis has been known as one of the topical inflammatory diseases caused in the stomach walls and very often occurs in modern persons that suffer from irregular eating habits and stresses, and its major symptoms includes cardialgia, etc.

The treatments of gastritis are widely divided into two categories: suppression of aggressive factors and reinforcement of defensive factors. In this case, the suppression of aggressive factors is carried out using an antiacid agent, an H ₂ blocker, a proton pump inhibitor, etc, and the reinforcement of defensive factors is carried out using cytoprotectives, etc.

Meanwhile, it has been known that naturally occurring flavonoid compounds have their highly various antioxidant effects, and, among the naturally occurring flavonoids, some flavonoid compounds such as hypolaetin-8-glucoside, apigenine-7,4'-dimethylether), kampferol, quercetin, naringenin and hesperidine have their antiulcer effects (IPharm Pharmacol. 1984, 36, 820 ; Ind. J. Pharm. ScL, 1981, 43, 159 ; Ind. J. Exp. Biol., 1988, 26, 121 ; Phytotherapy Res, 1992, 6,168).

Korean Patent Application No. 1996-30494 discloses a compound represented by the Formula 1. Here, it is known that the compound has a gastrointestinal protection effect on gastritis and ulcer and an antiinflammatory effect on colitis. Among the compound represented by the Formula 1, it has been particularly reported that T-carboxymethyloxy-S'^'^-trimethoxyflavone represented by the following Formula 2 has very excellent effects on gastritis and ulcer in the gastrointestine, as well as Mammatory bowel diseases such as Crohn's disease or ulcerative colitis

<Formula2>

Also, Korean Patent Application No. 1999-41205 discloses a method for preparing 7- carboxymethyloxy-3',4',5-trirnethoxyflavone and pharmaceutically available salts and solvates thereof. In the case of the preparation method, the compounds are obtained at a high yield due to the moderate reaction conditions and the short reaction time, compared to the conventional preparation methods.

However, the 7-carboxymethyloxy-3',4',5-trimethoxyf[avone itself of the Formula 2 has a hygroscopic property since it is an anhydrous compound, and therefore the problem is that it is difficult to prepare, handle and manage its formulations in a quantitative manner.

Accordingly, Korean Patent Application No.2005-7016164 discloses 7-carboxymethyloxy-3',4',5- trimethoxyflavone monohydrates or solvates, represented by the following Formula 3, which does not have the hygroscopic property, a method for preparing the same, and uses of gastritis- and inflammatory bowel diseases-treating agents.

<Formula 3>

The compound represented by the Formula 1, pharmaceutically available salts and hydrates or solvates thereof has an anti-inflammatory effect by topically suppressing expression of inflammatory mediators such as 5-lipooxygenase and cytokines in intestinal mucous membrane. In particular, it was proven through the preclinical trials that the 7-carboxymethyloxy-3',4',5-trimethoxyflavone monohydrates have an excellent drug-tolerable effect in treating the inflammatory bowel diseases. Therefore, clinical trials are under way to evaluate the stability and effectiveness of the monohydrates on the basis of the results from the preclinical trials. In particular, it has been known that the evaluation results on the pharmacokinetics as the preclinical trials in rats indicates that bioavailability of the orally administered compound is shown to be 0.1%, but the orally administered compound has anti-ulcer or anti-inflammatory effects by its direct reaction with mucous membrane in digestive tract since the orally administered compound is distributed at a high concentration in the digestive tract.

However, the compound represented by the Formula I ₅ and pharmaceutically available salts and hydrates or solvates thereof have sufficient solubility to be formulated at a concentration of 10 mg/ml or more under neutral and basic conditions, but have extremely low solubility at a concentration of 1 g/ml or less under an acidic condition of pH 1~4. As a result, the compound is difficult to develop as the gastritis- treating agent by the conventional designs of formulations regardless of the anti-gastritis and anti-ulcer effects in the gastric mucous membrane (see Experimental example 1 of this patent application).

Accordingly, as the formulation designs for developing the gastritis-treating agent containing the compound represented by the Formula 1 and pharmaceutically available salts and hydrates or solvates thereof, there is a required a gastroretentive system containing a solubilized drug which may maximize the topical anti-inflammatory effect in the gastric mucous membrane to improve the solubility under the acidic condition in the stomach and sustain retention of formulations in the stomach.

Meanwhile, the gastroretentive system refers to an oral delivery system in which the retention of the formulations in the stomach is enhanced for the purpose of maximizing the topical anti-inflammatory

effect of the drugs in the stomach or improving the bioavailability of the drugs using an absorption window through which the drugs are limitedly absorbed in the upper small intestine. The gastroretentive system is divided into a high density system, a floating system, a gas generating system, a raft forming system, a low density system, an expendable system, a superporous hydrogel system, a bioadhesive/mucoadhesive system, a magnetic system, etc., depending on the gastroretentive mechanisms.

Through the evaluation of treatment and prevention of gastritis using rats, the present inventors have found that the compound represented by Formula 1 and pharmaceutically available salts and hydrates or solvates thereof have a more excellent therapeutic effect when the compound is administered in the form of solution since the minimum concentration of the compound to prevent and heal a gastric ulcer is administered at a lower concentration as much as 30 times or more at a minimum concentration when the compound is dissolved in a 0.1 N NaOH solution and administered in the form of solution than when the compound is suspended in water and administered in the form of suspension. From these results, it was revealed that the compound does not have a problem regarding the solubility to exert drug efficiency in digestive tracts below the small intestine, but has an extreme importance in enhancing the therapeutic effect on gastritis by the improved solubility of drugs in order to enhance the therapeutic effect under an acidic condition of the stomach (see Experimental example 2 of this patent application).

Accordingly, the present inventors have ardent attempts to improve the elution of the compound represented by Formula 1 and pharmaceutically available salts and hydrates or solvates thereof under the acidic condition, and developed a gastroretentive system matrix formulation containing a solubilized drug for maximizing a therapeutic effect on gastritis. Therefore, the present invention was completed on the basis of the above facts.

[Disclosure]

[Technical Problem]

Accordingly, the present invention is designed to solve such drawbacks of the prior art, and therefore an object of the present invention is to provide a soluble gastroretentive system matrix formulation capable of showing a therapeutic effect on gastritis at a low concentration of the drugs by increasing a topical concentration of the drug in lesion regions to maximize the therapeutic effect when the compound represented by the Formula 1 and pharmaceutically available salts and hydrates or solvates thereof are administered into the stomach. In this case, this is achieved by designing the drug so that the drug having improved solubility in the stomach under an acidic condition and improved solubility is sustainably released while remaining in lesions of gastric mucous membrane for an extended period in the administration of the drug. Also, another object of the present invention is to provide a method for preparing the same.

[Technical Solution]

According to an aspect of the present invention, there is provided a soluble gastroretentive system matrix formulation containing an expandable floating matrix including a compound represented by the following Formula 1 and pharmaceutically available salts and hydrates or solvates thereof, which are used in a single form or in the form of a solid dispersant: <Formula 1>

wherein, A is selected from the group consisting of alkyloxycarboalkyloxy, carboxylalkyloxy, N- alkylamidoalkyloxy, hydroxyalkyloxy and cycloalkyloxy, B and C are each independently selected from the group consisting of hydrogen, hydroxy, substituted or unsubstituted alkyloxy and cycloalkyloxy, and D and E are each independently selected from the group consisting of hydrogen, hydroxy, and linear or

branched lower alkyloxy having 1 to 6 carbon atoms, provided that linkage between 2- and 3-positions is a single or double bond.

For the present invention, the solid dispersant may include a hydrophilic polymer or a porous excipient, and also include an alkalizer in order to enhance the solubility of the drug to solvents, and further include a solubilizer in the use of the solid dispersant including the hydrophilic polymer.

The hydrophilic polymer used herein may be selected from the group consisting of semi-synthetic cellulose derivatives such as hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, cyclodextrin or hydroxypropyl thereof, natural or synthetic polysaccharides of sulfonic acid/butyl ether substituent, and synthetic polymers of polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, and polyoxyethylene-polyoxypropylene block copolymer, and hydroxypropylmethylcellulose and polyvinylpyrrolidone are preferred. They may be used alone or in combinations thereof. A weight ratio of the drug to the hydrophilic polymer may be in a range from 1 :0.1 to 10, and preferably from 1 :0.5 to 5.

The solubilizer may include sodium lauryl sulfate, polysorbate, hydrogenated castor oil, labrasol, and the like, and they may be used alone or in combinations thereof. In this case, a weight ratio of the drug to the solubilizer may be in a range from 1 :0.1 to 10, and preferably from 1 :0.5 to 5. The solubilizer in the solid dispersant according to the present invention is used to enhance the solubilization of the solid dispersant in the manufacture of the solid dispersant.

The porous excipient may be used to prepare a solid dispersant from drugs in an absorption method using a fluid-bed granulator or a high-speed mixing machine. Also, the porous excipient includes lactose, microcrystalline cellulose, starch, mannitol, calcium silicate, light anhydrous silicic acid and the like, and they may be used alone or in combinations thereof, and also be used at a weight ratio of 1 : 1 to 10, and preferably 1 :3 to 7, based on the total weight of the drugs.

The alkalizer includes basic electrolytes such as sodium carbonate and sodium hydroxide, or basic amino acids such as arginine, and they may be used alone or in combinations thereof. In this case, the alkalizer may be used at a weight ratio of 1 :0.01 to 10, and preferably 1 :0.5 to 5, based on the total weight of the drugs. The alkalizer in the solid dispersant according to the present invention is used to enhance the solubility of the drug to solvents.

For the present invention, the expandable floating matrix essentially contains an expandable polymer, a corrosive polymer, a blowing agent and a solubilizer, and weight ratio of the expandable polymer : the corrosive polymer : the blowing agent : the solubilizer is in range of 1 — 10 : 1-10 : 1-25 : 1-10, and preferably 1-2 : 1-2 : 1-5 : 1-2. Although the matrix contains a small amount of drugs, the matrix that is swelled by the penetration of gastric acid and float on gastric juice may maximize the therapeutic effect on gastritis by sustainably releasing the solubilized drugs in the matrix to react with an inflammatory region while the matrix is being continuously corroded by the gastric juice.

The expandable polymer is a hydrophilic polymer, and includes semi-synthetic cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, sodium carboxy methylcellulose and derivatives thereof, synthetic polymers such as polyethylene oxide, polyvinylpyrrolidone and derivatives thereof, crospovidone and carbopol, and natural polysaccharides such as xanthan gum and locust bean gum, etc., and they may be used alone or in combinations thereof. Hydroxypropylmethylcellulose is preferred, and may control the swelling, floating and disintegration characteristics of the matrix and the release rate of the drugs by adjusting the kind and amount of the expandable polymer, depending on the viscosity of the expandable polymer. A weigh ratio of the drug to the expandable polymer is in a range of 1 :0.1 to 10, and preferably 1 :0.5 to 2.

The expandable polymer used in the expandable floating matrix according to the present invention is rapidly swelled and hydrated by the penetration of gastric juice in the stomach, and is allowed to float the

matrix by preventing carbon dioxide bubbles generated from a blowing agent in the matrix from flowing out from the formulation. The expandable polymer may also show a sustained-release effect by forming a hydrated gel by the penetration of gastric juice to control the release of the drugs solubilized in the gel through the diffusion of the drugs.

The corrosive polymer includes a water-insoluble polymer or an enteric polymer. Here, ethylcellulose may be used as the water-insoluble polymer, and the enteric polymer which may be used herein includes celluloseacetatephthalate, celluloseacetate trimellitate, hydroxypropylmethylcellulosephthalate, hydroxypropylmethylcelluloseacetyl succinate, polyvinylacetatephthalate, Shellac, polymethacrylate and polymers thereof, and preferably hydroxypropylmethylcellulosephthalate, hydroxypropylmethylcelluloseacetyl succinate, polymethacrylate and polymers thereof, and more preferably hydroxypropylmethylcelluloseacetyl succinate. Polymethacrylate and its polymer are methacrylic copolymers having an anionic carboxyl group, and may be used alone or in combination of Eudragjt L and S. A weight ratio of the drug to the corrosive polymer is in a range of 1 :0.1 to 10, and preferably 1 :0.5 to 2.

The corrosive polymer used in the expandable floating matrix according to the present invention is a polymer that continuously corrodes the matrix from the outside of the gel, the matrix being hydrated, swelled and floated in the stomach. When the drug of the present invention in the matrix having the floating and swelling characteristics is used alone or in combination of the hydrophilic polymer in the form of a solid dispersant, the solubilized drugs in the gel may be released by their diffusion, but it is difficult to control the release of the drugs under an acidic condition since the drugs have very low solubility (1 g/ml or less) under the acidic condition. Therefore, it is necessary to control the release of the drugs by the continuous corrosion of the gel. Since a water-insoluble or enteric corrosive polymer is included in the gel matrix that is swell and floated by the gastric juice, the water-insoluble or enteric corrosive polymer is present in the gel without being dissolved or swelled in the gastric juice. Then, when the gel matrix is swelled, the corrosive polymer

is released from the swelled gel, and therefore the matrix is continuously corroded from the hydrated gel to accelerate the release of the drugs.

The blowing agent is a material that is in contact with acid in the stomach to generate carbon dioxide gas, and carbonates or bicarbonates may be used alone or in combinations thereof. Preferably, sodium carbonate, sodium bicarbonate, calcium carbonate and the like may be used as the blowing agent, and sodium carbonate may more preferably be used as the blowing agent. A weight ratio of the drug to the carbonates or bicarbonates is in range of 1:0.1 to 10, and preferably 1:1 to 5.

The carbonates or bicarbonates as the blowing agent in the expandable floating matrix may generate carbon dioxide gas by the penetration of acidic gastric juice present in the stomach. In this case, an acidifier may be further added to the matrix for the purpose of enhancing its foaming capacity. The acidifier includes citric acid monohydrates, citric acid anhydride, hydrochloric acid, phosphoric acid, acetic acid, and the like, and they may be used alone or in combinations thereof, and the use of citric acid anhydride may be preferred.

The solubilizer includes polyoxyethylene/polyoxypropylene block copolymer, sodium lauryl sulfate, polysorbate, etc., and they may be used alone or in combinations thereof. In this case, a weight ratio of the drug to the solubilizer is in range of 1:0.1 to 10, and preferably 1:0.5 to 2. The expandable floating matrix is added to improve the solubilizing properties of the drug or solid dispersant when the drug or solid dispersant is used in the expandable floating matrix.

The soluble gastroretentive system according to the present invention may further include a lubricant. The lubricant is used to enhance the flow and tabletizing properties when a mixture of a drug and an additive constituting a matrix, or a dry or wet granulated composition comprising the drug and the additive is prepared in the form of tablet. In this case, the used lubricant may include stearic acid and its metallic salts, glyceryl behenate, light anhydrous silicic acid, etc.

The soluble gastroretentive system according to the present invention may further include a binder. The binder is used to formulate the mixture or the composition into a tablet or a capsule. That is to say, the binder is added to the matrix mixture to prepare, pulverize and dry a slug in the form of dry granulate, or the binder is dissolved in a suitable solvent such as water or ethanol, and added to the prepared matrix mixture, followed by undergoing the blending, organizing, formulating and drying processes to prepare a granulate. Here, polyvinylpyrrolidone, hydroxypropylcellulose and the like may be used as the binder.

Also, the soluble gastroretentive system according to the present invention may further include a tanning agent in the manufacture of the tablet. The tanning agent is used to protect the uncoated tablet prepared using the above-mentioned method from environment such as heat, light or moisture. In this case the used tanning agent includes water-soluble or water-insoluble polymers such as hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, polyvinyl alcohol, sodium carboxymethylcellulose and methacrylate copolymer, and they may be used alone or in combinations thereof. In addition, a sunscreen agent such as titanium oxide, a plasticizer such as diethylphthalate, polyethylene glycol and lecithin, and a coloring agent such as tar dye or its aluminum lake and iron oxide may be used additionally in the soluble gastroretentive system so as to facilitate the tanning.

Also, the present invention provides a method for preparing a soluble gastroretentive system matrix formulation containing the compound represented by the Formula 1 and pharmaceutically available salts and hydrates or solvates thereof.

The method for preparing a soluble gastroretentive system matrix formulation according to the present invention containing the compound represented by the Formula 1 and pharmaceutically available salts and hydrates or solvates thereof comprises: solubilizing the compound represented by the Formula 1 and pharmaceutically available salts and hydrates or solvates thereof, that is, by preparing a solid dispersant; and applying the prepared solid dispersant to an expandable floating matrix.

The solid dispersant may be prepared by dissolving a drug and a hydrophilic polymer or/and a solubilizer in a solvent and directly granulating the resulting mixture using a spray-dryer (spray-drying method), and also be prepared by absorbing a drug to a porous excipient, such as lactose, microcrystalline cellulose, starch, mannitol, calcium silicate and light anhydrous silicic acid, using a fluid-bed granulator or a high-speed mixing machine (absorption method).

Waster is used as the solvent in the preparation of the solid dispersant. In this case, a basic electrolyte such as sodium carbonate and sodium hydroxide, or a basic amino acid such as arginine and lysine may be used to enhance the solubility of the drug to water. First, these alkalizers are dissolved in water, and a drug is dissolved together with a hydrophilic polymer or a solubilizer. The solid dispersant prepared thus may be directly added to the granulate together with components constituting the expandable floating matrix according to the present invention, or be applied to the expandable floating matrix that is prepared using the post-mixing method. When the solid dispersant is directly applied to the expandable floating matrix, the solubilizer may be further added to enhance the additional solubilizing effect. In this case, the solubilizer may include polyoxyethylenepolyoxypropylene block copolymer, sodium lauryl sulfate, polysorbate, etc.

As an alternative method according to the present invention, the method for preparing a soluble gastroretentive system matrix formulation according to the present invention containing the compound represented by the Formula 1 and pharmaceutically available salts and hydrates or solvates thereof comprises: homogeneously mixing a compound represented by the Formula 1, and pharmaceutically available salts and hydrates or solvates thereof with a blowing agent, an expandable polymer, a corrosive polymer, a solubilizer, a lubricant and a binder; and directly tabletizing the mixture:

As another alternative method according to the present invention, the method for preparing a soluble gastroretentive system matrix formulation according to the present invention containing the compound represented by the Formula 1 and pharmaceutically available salts and hydrates or solvates thereof comprises: homogeneously mixing a compound represented by the Formula 1, and pharmaceutically available salts and hydrates or solvates thereof with a blowing agent, an expandable polymer and a solubilizer; blending the resulting mixture with a binder; granulating the blended mixture; post-mixing a corrosive polymer with the granulated composition; adding a lubricant to the post-mixed composition; and tabletizing the resulting mixture:

An excipient may be further added to the mixture in the homogeneously mixing step, and the binder is previously dissolved in alcohol in the blending step for its later use.

[Advantageous Effects]

As described above, the soluble gastroretentive system matrix formulation according to the present invention may be useful to improve the solubility of the compound represented by the Formula 1 and pharmaceutically available salts and hydrates or solvates thereof, and maximize a topical anti-inflammatory effect of the solubilized drug in the stomach by continuously releasing the solubilized drag from the matrix having swelling, floating and corroding properties.

[Description of Drawings] FIG. 1 shows the results obtained by evaluating the solubility of 7-carboxymethyloxy-3',4',5- trimethoxyflavone monohydrate according to pH.

FIG. 2 shows the results obtained by evaluating the effect of a dissolved state of 7- carboxymethyloxy-3',4',5-trimethoxyflavone monohydrate in gastritis-induced rat model.

FIG. 3 shows the results obtained by evaluating the solubility of a solubilized solid dispersant of 7- carboxymethyloxy-3',4',5-trimethoxyflavone monohydrate in the acidic range of pH 1.2. FIG. 4 shows the results obtained by evaluating the solubility of a solubilized solid dispersant of 7- carboxymethyloxy-3',4',5-trimethoxyflavone monohydrate in the acidic range of pH 2.

FIG. 5 shows the results obtained by evaluating the solubility of a solubilized solid dispersant of 7- carboxymethyloxy-3',4',5-trimethoxyflavone monohydrate in the acidic range of pH 3.

FIG. 6 shows the results obtained by evaluating the solubility of a solubilized solid dispersant of 7- carboxymemyloxy-3',4',5-trimethoxyflavone monohydrate in the acidic range of pH 4.

FIG. 7 shows the results obtained by evaluating a composition prepared by mixing 7- carboxymethyloxy-3',4',5-trimethoxyflavone monohydrate with a hydrophilic polymer or a solubilizer in the form of a solid dispersant using differential scanning calorimeter (DSC).

FIG. 8 shows the results obtained by evaluating 7-carboxymethyloxy-3',4',5-1rirnethoxyfiavone monohydrate using X-ray diffraction (XRD).

FIG. 9 shows the results obtained by evaluating a soluble solid dispersant of the spray-dried product prepared from the composition 5 according to the present invention.

FIG. 10 shows the results obtained by evaluating a soluble solid dispersant of the absorbed granulate according to Example 2 of the present invention, using X-ray diffraction (XRD). FIG. 11 shows the results obtained by evaluating the elution of the expandable floating matrix tablets prepared from the compositions 8 to 10 according to the present invention, and the tablet of Comparative example 1 under an acidic condition of pH 1.2.

FIG. 12 shows the results obtained by evaluating the elution of the expandable floating matrix tablets prepared from the compositions 8 to 10 according to the present invention, and the tablet of Comparative example 1 under an acidic condition of pH 2.0.

FIG. 13 shows the results obtained by evaluating the elution of the expandable floating matrix tablets prepared from the compositions 8 to 10 according to the present invention, and the tablet of Comparative example 1 under an acidic condition of pH 3.0.

FIG. 14 shows the results obtained by evaluating the elution of the expandable floating matrix tablets prepared from the compositions 8 to 10 according to the present invention, and the tablet of Comparative example 1 under an acidic condition of pH 4.0.

FIG. 15 show the photographic results illustrating the floating and disintegrating properties of the tanned tablet, which is prepared from the expandable floating matrix containing the composition 15 according to the present invention, at pH 1.2. FIG. 16 show the photographic results illustrating the floating and disintegrating properties of the tanned tablet of Comparative example 1 at pH 1.2

FIG. 17 shows the results obtained by evaluating the elution of the tanned tablet, which is prepared from the expandable floating matrix containing the composition 15 according to the present invention, and the tablet of Comparative example 1 under an acidic condition of pH 1.2. FIG. 18 shows the results obtained by evaluating the elution of the tanned tablet, which is prepared from the expandable floating matrix containing the composition 15 according to the present invention, and the tablet of Comparative example 1 under an acidic condition of pH 3.0.

FIG. 19 shows the results obtained by evaluating the elution of the tanned tablet, which is prepared from the expandable floating matrix containing the composition 15 according to the present invention, and the tablet of Comparative example 1 under an acidic condition of pH 4.0.

FIG. 20 shows an endoscopic photograph of a beagle dog to which the composition 15 according to the present invention is administered right after the induction of gastric ulcer.

FIG. 21 shows an endoscopic photograph of a beagle dog to which the composition 15 according to the present invention is administered for 4 days after the experimental induction of gastric ulcer. FIG. 22 shows an endoscopic photograph of a beagle dog to which the composition 15 according to the present invention is administered for 8 days after the experimental induction of gastric ulcer.

FIG. 23 shows an endoscopic photograph of a beagle dog to which the composition 15 according to the present invention is administered for 15 days after the experimental induction of gastric ulcer.

FIG. 24 shows an endoscopic photograph of a beagle dog to which the composition 15 according to the present invention is administered for 16 days after the experimental induction of gastric ulcer. FIG. 25 shows an endoscopic photograph of a beagle dog to which one styrene tablet is administered right after the experimental induction of gastric ulcer.

FIG. 26 shows an endoscopic photograph of a beagle dog to which one styrene tablet is administered for 4 days after the experimental induction of gastric ulcer.

FIG. 27 shows an endoscopic photograph of a beagle dog to which one styrene tablet is administered for 6 days after the experimental induction of gastric ulcer.

FIG. 28 shows an endoscopic photograph of a beagle dog to which one styrene tablet is administered for 12 days after the experimental induction of gastric ulcer.

FIG. 29 shows an endoscopic photograph of a beagle dog to which one styrene tablet is administered for 16 days after the experimental induction of gastric ulcer. FIG. 30 shows an endoscopic photograph of a beagle dog to which one soluble gastroretentive system including the composition 15 according to the present invention is administered right after the experimental induction of gastric ulcer.

FIG. 31 shows an endoscopic photograph of a beagle dog to which one soluble gastroretentive system including the composition 15 according to the present invention is administered for 4 days after the experimental induction of gastric ulcer.

FIG. 32 shows an endoscopic photograph of a beagle dog to which one soluble gastroretentive system including the composition 15 according to the present invention is administered for 8 days after the experimental induction of gastric ulcer.

FIG. 33 shows an endoscopic photograph of a beagle dog to which one soluble gastroretentive system including the composition 15 according to the present invention is administered for 12 days after the experimental induction of gastric ulcer.

FIG. 34 shows an endoscopic photograph of a beagle dog to which one soluble gastroretentive system including the composition 15 according to the present invention is administered for 16 days after the experimental induction of gastric ulcer.

FIG. 35 shows an endoscopic photograph of a beagle dog to which two soluble gastroretentive systems including the composition 15 according to the present invention are administered right after the experimental induction of gastric ulcer.

FIG. 36 shows an endoscopic photograph of a beagle dog to which two soluble gastroretentive systems including the composition 15 according to the present invention are administered for 4 days after the experimental induction of gastric ulcer. FIG. 37 shows an endoscopic photograph of a beagle dog to which two soluble gastroretentive systems including the composition 15 according to the present invention are administered for 8 days after the experimental induction of gastric ulcer.

FIG. 38 shows an endoscopic photograph of a beagle dog to which two soluble gastroretentive systems including the composition 15 according to the present invention are administered for 12 days after the experimental induction of gastric ulcer.

FIG. 39 shows an endoscopic photograph of a beagle dog to which two soluble gastroretentive systems including the composition 15 according to the present invention are administered for 16 days after the experimental induction of gastric ulcer.

FIG. 40 shows the results obtained by evaluating the elution stability of the tanned tablet prepared from the composition 15 according to the present invention under a warmed condition (at 40 ^° C , 75%).

[Best Mode]

Hereinafter, exemplary embodiment of the present invention will be described in detail. However, it should be understood that the scope of the present invention is not particularly limited to the exemplary embodiment of the present invention.

<Example 1> Preparation of solid dispersant using a spray-drying method, and preparation of soluble gastroretentive system matrix tablet containing the solid dispersant

(1) Preparation of solid dispersant using a spray-drying method 7-carboxymethyloxy-3',4',5-trirnethoxyflavone monohydrate, and a hydrophilic polymer or a solubilizer were dissolved with an alkalizer, arginine, in water, as listed in the following Table 1, and then spray-dried under conditions (an inlet temperature of 120 ^° C, an outlet temperature of 80 ⁰ C and a spraying pressure of 1.5 kg/cm2) using a spray-dryer, to prepare a solid dispersant.

[Table 1]

(2) Preparation of expandable floating matrix tablet containing a spray-dried product A solid dispersant containing 7-carboxymethyloxy-3',4',5-trimethoxyflavone monohydrate of the composition 5 was homogeneously mixed with a solubilizer, a blowing agent, an expandable polymer, a corrosive polymer and a lubricant, as listed in the following Table 2, and the resulting composition was

tabletized, using a tabletizing machine, so that 7-carboxymethyloxy-3',4',5-trimethoxyflavone monohydrate can be included in the composition at a content of 15 mg, 20 mg or 30 mg per tablet

[Table 2]

<Example 2> Preparation of solid dispersant using an absorption method and Preparation of soluble gastroretentive system tablet containing the solid dispersant

7-carboxymethyloxy-3',4',5-trimethoxyflavone monohydrate was dissolved with an alkalizer, arginine, in water, as listed in the following Table 3, and the resulting mixture solution was inject into a high-speed stirrer including a porous excipient mixture of microcrystalline cellulose, calcium silicate and light anhydrous silicic acid, while stirring the high-speed stirrer at 500 rpm for 2 minutes, thus to prepare an absorbed solid dispersant containing 7-carboxymethyloxy-3',4',5-trimethoxyflavone monohydrate. The prepared 7-carboxvme1hyloxy-3 ^l ,4',5-trimethoxyfiavone monohydrate-containing absorbed solid dispersant was homogeneously mixed with a solubilizer, a blowing agent, an expandable polymer, a corrosive polymer and a lubricant, and tabletized, using a tabletizing machine, so that 7-carboxymethyloxy-3',4',5- trimethoxyflavone monohydrate can be included in the composition at a content of 15 mg, 20 mg or 30 mg per tablet.

[Table 3]

<Example 3> Preparation of soluble gastroretentive system matrix tablet using a direct compression method y-carboxymethyloxy-S'^'jS-trimethoxyflavone monohydrate having a content as listed in the following Table 4 was directly homogeneously mixed with a solubilizer, an excipient, a blowing agent, an expandable polymer, a corrosive polymer and a lubricant without the pre-treatment for solubilizing them, as listed in the following Table 4, and then tabletized, using a tabletizing machine, so that 7- carboxymethyloxy-3',4',5-trirnethoxyflavone monohydrate can be included in the composition at a content of 15 mg, 20 mg or 30 mg per tablet.

[Table 4]

<Example 4> Preparation of soluble gastroretentive system tablet using a wet granulation method

7-carboxymethyloxy-3',4',5-trimethoxyflavone monohydrate was homogeneously mixed with a solubilizer, an excipient, a blowing agent and an expandable polymer, as listed in the following Table 5. Then, the resulting mixture solution is blended with hydroxypropylcellulose that was previously dissolved as a binder in ethanol while being stirred in a high-speed mixing machine, and the resulting mixture solution was then formulated using a 18M sieve, dried at 40 ^° C , and formulated again using a 18M sieve to prepare a granulate. A corrosive polymer and a lubricant were post-mixed with the prepared granulated composition, and the resulting composition was tabletized, using a tabletizing machine, so that 7-carboxymethyloxy- 3',4',5-trimethoxyflavone monohydrate can be included in the compositions 11, 1 and 14 at a content of 30 mg per tablet and in the composition 12 at a content of 15 mg per tablet.

[Table 5]

<Example 5> Preparation of tanned tablet from soluble gastroretentive system (1) Preparation of coating solution

0.69 kg of Opadry OY-C-7000A (Colorcon) was completely dispersed in 6.9 kg of ethanol and 1.73 kg of water, as listed in the following Table 6, which was used later as a primary coating solution. Also, 0.88 kg of Opadry 80W41039 (Colorcon) was completely dispersed in 3.64 kg of water, which was used later as a secondary coating solution, and 0.18 kg of Opadry 97W19196 (Colorcon) was completely dispersed in 2.82 kg of water, which was used later as a tertiary coating solution.

[Table 6]

(2) Coating of matrix tablet The uncoated matrix tablets of the compositions 11 to 14 were sequentially coated with the primary, secondary and tertiary coating solutions prepared in the step (1), and tanned in a coating machine to prepare compositions 15 to 18. In this case, each of the uncoated matrix tablets was tanned at tanning ratios of approximately 3% in the case of the primary coating process, approximately 3.8 % in the case of the secondary coating process, and approximately 0.8 % in the case of the tertiary coating process, based on the total weight of the uncoated tablet.

[Table 7]

<Comparative example 1> Preparation of tablet using a conventional method other than a solubilizing gastroretentive system technology

7-carboxyme1hyloxy-3V^5-trimethoxyflavone monohydrate was mixed with an excipient, as listed in the following Table 8, and mixed with polyvinylpyrrolidone, which was previously dissolved as a binder in ethanol, in a high-speed stirrer. Then, the resulting mixture solution was then formulated using a 18M sieve, dried at 40 ^° C, and formulated again using a 18M sieve to prepare a granulate. A disintegrating agent and a lubricant were post-mixed with the prepared granulated composition, and the resulting composition was tabletized, using a tabletizdng machine, so that 7-carboxymethyloxy-3',4',5- trimethoxyflavone monohydrate can be included in the composition at a content of 30 mg per tablet. The tabletized uncoated tablet was tanned with a tanning agent, a plasticizer, a lubricant and a dye, as listed in the following Table 8.

[Table 8]

<Comparative example 2> Preparation of placebo for solubilized drug-free gastroretentive system

A matrix tablet was prepared in the same manner as the composition 11 of Example 4, and then tanned in the same manner as the composition 15 of Example 5 to prepare a gastroretentive system composition. In this case, the gastroretentive system composition was prepared in Comparative example 2 except for the main component 7-carboxymethyloxy -3',4',5-trimethoxyflavone monohydrate.

<Experimental example 1> Evaluation of solubility of 7-carboxymethyloxy-3',4',5- trimethoxyflavone monohydrate

The solubility characteristics of T-carboxymethyloxy-S'^'jS-trimethoxyflavone monohydrate was evaluated according to the pH of the composition, as follows. The results are shown in FIG. 1.

(1) Conditions for solubility test - Equipment: Dialysis Tester (rotary speed: 40 rpm)

- Test solution for solubility: 20 ml of buffers having pH 1.2, 2, 3, 4, 4.5, 5, 6, 6.8 and 7.4, respectively

- Temperature of test solution for solubility: 37± 0.5 ^° C

(2) Handling for solubility test

200 mg of 7-carboxymethyloxy-3^4',5-trimethoxyfiavone monohydrate was taken into conical tubes containing 20 ml of test solution for solubility according to the pH, respectively, and stirred for 24 hours at a rotary speed of 40 rpm in a dialysis tester to obtain supernatants, and the obtained supernatants were analyzed.

(3) Analysis of test solution for solubility

- Standard solution: 20 mg of the standard compound '7-carboxymethyloxy-3',4',5- trimethoxyflavone monohydrate' was exactly taken into alOO-ml flask, and suspended in 50 ml of methanol, dissolved in USP buffer (pH 7.4), and then quantitified into 100 ml of the mixture solution, which is referred to as a standard solution. - Extract solution: supernatants were taken after the start of the solubility test according to the hour, and centrifuged at a rotary speed of 13,000 rpm for 5 minutes. The resulting solutions were referred to as extract solutions, which are diluted with a mobile-phase solvent, if necessary.

- Conditions of liquid chromatography: The standard solution and the extract solution were analyzed for under the following conditions to measure the solubility of 7-carboxymethyloxy-3',4',5- trimethoxyfiavone monohydrate in the test solution for solubility.

Column: Inertsil ODS II (Cl 8, 5m, 4.6 x 150 mm) or its equivalent column Column temperature: 30 ^° C Detector: UV spectorophotometer (334 nm)

Mobile phase: 20 mM potassium dihydrogen phosphate : acetonitrile = 78 : 22 (v/v) Flow rate: 1 rnl/min

Solubility (g/ml) of 7-carboxymethyloxy-3 ^l ,4',5-trimethoxyflavone monohydrate = (Peak area of extract solution / Peak area of standard solution) concentration (g/ml) of serially diluted standard solution of extract solution

(4) Evaluation of solubility of 7-carboxyme1hyloxy-3 ^l ,4 ^l ,5-trimethoxyflavone monohydrate according to the pH

7-carboxymethyloxy-3',4',5-trimethoxyflavone monohydrate showed relatively high solubility of approximately 10 mg/ml or more at pH 6.8 (neutral pH) or more, but very low solubility of 1 g/ml or less at an acidic condition of pH 1 to 4. In this case, when the compound '7-carboxymefhyloxy-3',4',5- trimethoxyfiavone monohydrate' was formulated using the conventional methods, the compound showed very low elution rate at the acidic condition in the stomach, and therefore it was expected that the compound

is distributed in lesions of mucous membrane in the stomach when the compound is administered into human (FIG. 1).

<Experimental example 2> Evaluation of effects of 7-earboxymethyloxy-3',4',5- trimethoxyflavone monohydrate in a gastric ulcer-induced rat model according to the dissolved state

In order to determine the correlation between the solubility of 7-carboxymethyloxy-3',4',5- trimethoxyflavone monohydrate and the therapeutic effects on gastritis and gastric ulcer, the gastric ulcer- induced rat model was used to compare the effects, as follows, when the 7-carboxymethyloxy-3',4',5- trimethoxyflavone monohydrate was administered to rats in the form of solution and suspension, respectively. The results are shown in FIG.2.

(1) Administration

7-carboxymethyloxy-3',4 ^l ,5-trimethoxyflavone monohydrate was dissolved in an aqueous 0.1%

NaOH solution (in the form of solution), or suspended in an aqueous 1% hydroxypropylmethylcellulose solution (in the form of suspension). The aqueous solution and the suspension were once administered, respectively, with a negative control (aqueous 0.1% NaOH solution and aqueous 1% hydroxypropylmethylcellulose solution) to rats, as listed in the following Table 9.

[Table 9]

(2) Comparison of Induction of ulcer to protection of ulcer

1 hour after the drug was administered to the rats as described above, 5 ml/kg of alcohol (60%) diluted with a 150 mM aqueous hydrochloric acid solution as the ulcer-inducing material was administered respectively to the rats. 1 hour after the administration of the drug, the rat abdomens were cut open to measure areas of ulcer generated in the stomachs of the rat groups and compare the ulcer areas.

(3) Evaluation of effects of y-carboxymethyloxy-S'^'^-trimethoxyflavone monohydrate in an ulcer-induced rat model according to the dissolved state When 7-carboxymethyloxy-3',4',5-trimethoxyflavone monohydrate was dissolved in an aqueous

0.1% NaOH solution and administered to the rats in the form of solution, the areas of ulcer were reduced in the rats to which 10 mg/kg of the drug was administered, and when 7-carboxymethyloxy-3',4',5- trimethoxyflavone monohydrate was suspended in an aqueous 1% hydroxypropylmethylcellulose solution and administered to the rats in the form of suspension, the areas of ulcer were reduced in the rats to which 300 mg/kg of the drug was administered. Therefore, it was revealed that the compound 7- carboxymethyloxy-3V^5-trime1hoxyflavone monohydrate showed more excellent therapeutic effects and protective effects on the ulcer when the compound was administered in the form of solution. Accordingly, it was seen that it is necessary to design a formulation so that the 7-carboxymethyloxy-3 ^l ,4' _s 5- trimethoxyflavone monohydrate can be solubilized under the acidic condition in the stomach so as to maximize the effect of the compound as the gastritis-treating agent, and more preferred to continuously release the drug while the solubilized drug remained in lesion regions of mucous membrane for an extended period (FIG. 2).

<ExperimentaI example 3> Physieoehemical evaluation of solid dispersant '7- carboxymethyloxy-3',4',5-trimethoxyflavone monohydrate'

The solid dispersants containing 7-carboxymethyloxy-3',4',5-trimethoxyflavone monohydrate (compositions 1 to 7 prepared in Example 1) and the 7-carboxymethyloxy-3',4 ^l ,5-trimethoxyflavone

monohydrate were evaluated for solubility, as follows. Then, the test results are shown in FIG. 3 to FIG. 6, respectively. Also, the spray-dried solid dispersant of the composition 5, the absorbed composition of Example 2 and the T-carboxymethyloxy-S'^'^-trimethoxyflavone monohydrate were measured using differential scanning calorimeter (DSC) and X-ray diffraction (XRD). Then, the test results are shown in FIG. 7 and FIG. 8 to FIG. 10, respectively.

(1) Solubility evaluation

A. Condition for solubility test

- Equipment: Dialysis Tester (rotary speed: 40 rpm) - Test solution for solubility: 20 ml of buffers (USP HCl buffers) having pH 1.2, 2, 3, and 4, respectively

- Temperature of test solution for solubility: 37± 0.5 ^° C

B. Handling of solubility test The solid dispersants of the compositions 1 to 7 and the 7-carboxymethyloxy-3',4',5- trimethoxyflavone monohydrate were taken at an amount corresponding to 20 mg of the 7- carboxymethyloxy-3',4',5-trimethoxyfiavone monohydrate and added respectively to transparent flask containing 150 ml of the test solution for solubility according to the pH. Then, the solid dispersants and the 7-carboxymethyloxy-3',4',5-trimethoxyflavone monohydrate were stirred for 10, 20, 30 and 60 minutes at a rotary speed of 40 rpm in a dialysis tester to obtain supernatants, and the obtained supernatants were analyzed.

C. Analysis of test solution for solubility

- Standard solution: 20 mg of the standard compound '7-carboxymethyloxy-3',4',5- trimethoxyflavone monohydrate' was exactly taken into al00-ml flask, and suspended in 50 ml of methanol, dissolved in USP buffer (pH 7.4), and then quantitified into 100 ml of the mixture solution, which is referred to as a standard solution.

- Extract solution: supematants were taken after the start of the solubility test according to the hour, and centrifuged at a rotary speed of 13,000 rpm for 5 minutes. The resulting solutions were referred to as extract solutions.

- Conditions of liquid chromatography: The standard solution and the extract solution were analyzed for under the following conditions to measure the solubility of 7-carboxymethyloxy-3',4',5- trimethoxyflavone monohydrate in the test solution for solubility.

Column: Inertsil ODS II (C 18, 5m, 4.6 x 150 mm) or its equivalent column

Column temperature: 30 ^° C

Detector: UV spectorophotometer(334 nm) Mobile phase: 20 mM potassium dihydrogen phosphate : acetonitrile = 78 : 22 (v/v)

Flow rate: 1 ml/min

Solubility (g/ml) of 7-carboxymethyloxy-3',4',5-trimethoxyflavone monohydrate = (Peak area of extract solution / Peak area of standard solution) concentration (g/ml) of standard solution

D. Evaluation of solubility of solid dispersant of 7-carboxymethyloxy-3^4\5-trimethoxyflavone monohydrate

It was revealed that the solid dispersant of 7-carboxymethyloxy-3',4',5-trimethoxyflavone monohydrate showed the improved solubility at the acidic condition of pH 1.2 to 4, compared to the 7- carboxymethyloxy-3',4',5-tr^ethoxyfiavone monohydrate, and particularly improved solubility at pH 3 and 4.

It was also revealed that the solubility was very excellent when the hydrophilic polymers 'hydroxypropylmethylcellulose and polyvinylpyrrolidone' were added as the additive to prepare a solid dispersant, and the solubility was very excellent and the recrystallization was highly suppressed when hydroxypropylmethylcellulose viscosity 50 cp was used as the additive (FIG. 3 to FIG. 6).

(2) Evaluation of solid dispersant of 7-carboxymethyloxy-3',4',5-trimethoxyflavone monohydrate using DSC and XRD

A. Evaluation condition

DSC Evaluation: a sample of 7-carboxymethyloxy-3',4',5-trimethoxyflavone was taken and warmed from 40 °C to 300 °C at a rate of 10°C/min under a nitrogen gas environment, and the thermal changes in the sample were analyzed. DSC 2010 (commercially available from TA instrument) was used herein.

XRD Evaluation: a sample of 7-carboxymethyloxy-3',4',5-trirnethoxyflavone was taken, and its X- ray diffraction pattern was measured by irradiating the sample with Cu-K radiation at 20 values of 4 to 40. DMAX-IHA (commercially available from Japan Rigaku) was used herein.

B. Results of DSC and XRD evaluations

It was confirmed that the spray-dried product of the composition 5 that is the spray-dried solid dispersant of 7-carrjoxymethyloxy-3',4',5-trimethoxyfiavone monohydrate and the absorbed solid dispersant of Example 2 were present in the amorphous form since their peaks showing a melting point of the 7- carboxyme%loxy-3',4',5-trimethoxyflavone monohydrate were not observed around the peak (FIG.7).

Also, the X-ray diffraction (XRD) spectroscopy showed that the spray-dried solid dispersant and the absorbed solid dispersant were present in the amorphous form since their diffraction peaks showing a crystalline form of the 7-carboxymethyloxy-3',4',5-trimethoxyflavone monohydrate were not observed around the peak (FIGS. 8 to FIG. 10).

<Experimental example 4> Evaluation of elution of soluble gastroretentive system containing 7-carboxymethyloxy-3',4',5-trimethoxyflavone monohydrate in a single form or a solid- dispersant form Floating, disintegrating and elution characteristics of the soluble gastroretentive system tablet containing 7-carboxymethyloxy-3 ^l ,4 ^l ,5-trimethoxyflavone monohydrate in a single form or a solid- dispersant form were evaluated, as follows. The elution test results of the tablets of the compositions 8 to 10

and Comparative example 1 were shown in FIGS. 11 to FIG. 14, respectively. Also, the elution test results of the tablets of composition 15 and Comparative example 1, and the floating and disintegration photographs according to the hour after the elution start were shown in FIG. 15, FIG. 16, FIGS. 17 to FIG. 19, respectively.

(1) Elution test condition

- Equipment: Paddle-type elution tester (rotary speed : 50 rpm)

- Test solution for solubility: 900 ml of buffers (USP HCl buffers) having pH 1.2, 2, 3 and 4, respectively - Temperature of test solution for solubility: 37± 0.5 ⁰ C

(2) Handling of solubility test - Elution test 1

The soluble gastroretentive system tablet containing 7-carboxvmethyloxy-3',4',5- trimethoxyflavone monohydrate in a single form or a solid-dispersant form (compositions 8 to 10) were subject to the elution test under the above-mentioned conditions in addition to the tablet prepared using the conventional method of Comparative example 1.

-Elution test 2 The soluble gastroretentive system-tanned tablet containing 7-carboxymethyloxy-3',4',5- trimethoxyflavone monohydrate (composition 15) was subject to the elution test under the above-mentioned conditions in addition to the tablet prepared using the conventional method of Comparative example 1. At the same time, photographs of the floating and disintegrating characteristics of the tablets were taken.

(3) Analysis of elution test solution

- Standard solution: 20 mg of the standard compound 7-carboxymethyloxy-3',4',5- trimethoxyflavone monohydrate' was exactly taken into alOO-ml flask, and suspended in 50 ml of

methanol, dissolved in USP buffer (pH 7.4), and then quantitified into 100 ml of the mixture solution, which is referred to as a standard solution.

- Extract solution: supernatants were taken after the start of the solubility test according to the hour, and centrifuged at a rotary speed of 13,000 rpm for 5 minutes. The resulting solutions were referred to as extract solutions.

- Conditions of liquid chromatography: The standard solution and the extract solution were analyzed for under the following conditions to measure the solubility of 7-car1x)xymethyloxy-3 ^l ,4',5- trimethoxyflavone monohydrate in the test solution for solubility.

Column: Inertsil ODS II (C 18, 5m, 4.6 x 150 mm) or its equivalent column Column temperature: 30 ⁰ C

Detector: UV spectorophotometer (334 ran)

Mobile phase: 20 mM potassium dihydrogen phosphate : acetonitrile = 78 : 22 (v/v)

Flow rate: l ml/min

Concentration (g/ml) of 7-carboxymethyloxy-3',4',5-trimethoxyflavone monohydrate in elution test solution = (Peak area of extract solution / Peak area of standard solution) concentration (g/ml) of standard solution

Elution rate (%) of 7-carboxymethyloxy-3 ^l ,4',5-trimethoxyflavone monohydrate = (Concentration (g/ml) of elution test solution / Concentration(g/ml)) solution whose elution rate approaches 100%) x 100

(4) Elution test results

- Elution test 1

It was revealed that the soluble gastroretentive system tablets containing 7-carboxymethyloxy-

3',4',5-trimethoxyflavone monohydrate in a single form or a solid-dispersant form (compositions 8 to 10) were swelled and floated under the acidic condition of pH 1.2 to 4 within 5 minutes after the start of the elution test, and then continuously precipitated for 1 hour. However, it was revealed that the tablet of

Comparative example 1 prepared using the conventional method was disintegrated completely within 5

minutes of the start of the elution test but the drug and the excipient were not dissolved after that time while being precipitated to the bottom of the elution tester.

From the results of elution rates measured according to the hour, it was revealed that the tablet of Comparative example 1 showed an elution rate of up to approximately 5% or less at pH 1.2 to 3 and approximately 20% or less at pH 4 inlO minutes from the start of the elution test, but the soluble gastroretentive system tablets of the compositions 8, 9 and 10 showed an increased elution rate of an elution rate of up to approximately 20% at pH 1.2, up to approximately 60% at pH 2, approximately 80% at pH 3, and up to approximately 90 to 100% atpH 4 (FIGS. 11 to 14).

Therefore, It was revealed that the soluble gastroretentive system tablets containing 7- carboxyme1hyloxy-3Vl',5-trLmemoxyflavone monohydrate in a single form or a solid-dispersant form (compositions 8 to 10) showed highly improved elution effects at an acidic range of pH 1.2 to 4, compared to the tablet of Comparative example 1 prepared using the conventional method.

There is no big difference in the elution rates between the compositions 8 to 10, but it was confirmed that the soluble gastroretentive system tablets showed improved elution effects when the spray- dried solid dispersant of 7-carboxymethyloxy-3',4',5-trimethoxyflavone monohydrate (composition 8) or the absorbed solid dispersant (Example 2) was added to the matrix, and 7-carboxymethyloxy-3',4',5- trimethoxyflavone monohydrate was also directly added together with the solubilizer to the matrix.

- Elution test 2

7-carboxymethyloxy -3',4',5-trimethoxyflavone monohydrate was added together with a solubilizer to the expandable floating matrix as described in the composition 15, and the soluble gastroretentive system tablet prepared as the tanned tablet and the eluent of Comparative example 1 were measured for elution properties under an acidic condition of pH 1.2 to 4. The results indicate that the tablet of composition 15 showed the conspicuously improved elution effects since the tablet was swelled and

floated at the beginning stage, and the drug was then continuously released for 1 hour while being continuously precipitated at the acidic condition of pH 1.2 to 4, compared to the tablet of Comparative example 1 prepared in the conventional method, as described in the elution test 1 (FIG. 15, FIG. 16, and FIGS. 17 to FIG. 19).

<Experimental example 5> Therapeutic effect of soluble gastroretentive system containing 7-earboxymethyloxy-3',4'£-trimethoxyflavone monohydrate on gastric ulcer in beagle dog

The soluble gastroretentive system-tanned tablet containing 7-carboxymethyloxy-3',4',5- trimethoxyflavone monohydrate (composition 15), the placebo containing the soluble gastroretentive system (Comparative example 2), and a styrene tablet (commercially available as gastritis-treating agent,

Dong-A Pharmaceutical) were administered respectively to gastric ulcer-induced beagle dogs, and evaluated for therapeutic effects using the following method. The results are shown in FIGS.20 to 39.

(1) Test animal 12 clinically available female beagle dogs weighing 7 to 8 kg were used herein. The test dogs were all selected before one month of their birth, adapted to the breeding ground and subject to a blood test, serum chemistry, abdominal and chest X-ray test to confirm that the test dogs are all healthy. These healthy dogs were used for testing.

(2) Classification of test material and test group

The test groups were divided into a placebo-administered group (Comparative example 2), a test drug 1 -administered group (one styrene tablet), a test drug 2-administered group (one tablet of composition 15), and a test drug 3-administered group (two tablets of compositionl5), and three beagle dogs were used in each group. The drug was administered three times a day after each meal, and 20 ml of drinking water was forcibly fed to the test dogs right after the administration of the drug. The drug was administered for the total period of 16 days.

[Table 10]

(3) Experimental induction of gastric ulcer 0.04 mg/kg of atropine sulfate was subcutaneously injected to beagle dogs fasted for 12 hours, and, after 30 minutes of the subcutaneous injection, 20 μg/kg of meditomidine was intravenously injected to the beagle dogs and 0.3 mg/kg of midazolam was intramuscularly injected to the beagle dogs for the combined anesthesia Then, the stomach walls of the test dogs were thoroughly examined using an endoscope to confirm that the test dogs are all healthy. The stomach walls were injured in the same size of 3 mm x 3 mm using biopsy forceps to induce gastric ulcer. Three lesion regions were selected from the fundus of the stomach wall to facilitate the gastroscopic examination.

(4) Evaluation of effect on healing gastric ulcer (gastroscopic examination) An endoscope (Olympus) having a diameter of 10mm was used, and Olympus CLV-E was used as an endoscopic light source. The gastroscopic examination was carried out right before the induction of gastric ulcer, and in 4, 8, 12 and 16 days after the induction of gastric ulcer, respectively. The gastroscopic examination was carried out within 1 - 2 hours after the administration of the drug. The test animals that would be subject to the gastroscopic examination were not fed on the day of the gastroscopic examination, but only test drug and drinking water were fed to the test dogs. Three lesions of gastric ulcer caused in each dog were leveled from Level 0 to Level 5 to evaluate an effect on healing gastric ulcer. The Level evaluation standards are listed in the following Table 11.

[Table 11]

(5) Gastroscopic examination results

The gastroscopic examination levels were listed in the following Table 12, depending on the administration period of the drug.

[Table 12]

Form the gastroscopic examination results, it was observed that the ulcer tends to continue in 8 to 12 days after the induction of gastric ulcer in the case of the placebo-administered group (Comparative example 2), and the gastric ulcer is observed in the form of inflammation from 12 days to the closing day of the test, which indicates that the gastric ulcer is being healed for that period.

However, it was revealed that the gastric ulcer is observed in the form of inflammation in 8 days after the induction of gastric ulcer the case of the test drug 1 -administered group (one styrene tablet), which indicates that the gastric ulcer is being healed for that period. And, it was revealed that the gastric ulcer is observed in the form of inflammation in 4 days after the induction of gastric ulcer the case of the test drug 2- administered group (one tablet of composition 15) and the test drug 3-administered group (two tablets of compositionlS), which indicates that the gastric ulcer is being healed for that period. Therefore, it was confirmed that the test drug 2-administered group and the test drug 3-administered group show excellent therapeutic effects on gastric ulcer, compared to the placebo-administered group (Comparative example 2) and the drug 1 -administered group (one styrene tablet) (FIGS.20 to 39).

Also, it was confirmed that a phenomenon where the ulcers in the lesion-induced regions are virtually pasted in the form of mucous membrane more rapidly in the test drug 2-administered group (one tablet of composition 15) and the test drug 3-administered group (two tablets of compositionl5) than in the placebo-administered group (Comparative example 2) and the drug 1 -administered group (one styrene tablet), and it was also revealed that the therapeutic effects on gastric ulcer are significantly different between the test drug 2-administered group (one tablet of composition 15) and the test drug 3-administered group (two tablets of compositionl5).

From the results, it was revealed that the all of the drug 1 -administered group (one styrene tablet), the test drug 2-administered group (one tablet of composition 15) and the test drug 3-administered group (two tablets of compositionl5) have the healing effects on gastric ulcer, and there is no particular difference

in the healing effects on gastric ulcer between the test drug 2 (one tablet of composition 15) and the test drug 3 (two tablets of compositionl5), but the test drug 2 (one tablet of composition 15) and the test drug 3 (two tablets of compositionl5) show the excellent healing effects on gastric ulcer, compared to Hie drug 1 (one styrene tablet).

Experimental example 6> Stability evaluation of soluble gastroretentive system under a warmed condition

The soluble gastroretentive system-tanned tablet containing 7-carboxymethyloxy-3',4',5- trknethoxyflavone monohydrate (composition 15) was kept under a warmed condition (at 40 ^° C, 75%) while being packaged in an HDPE bottle, and the changes in the elution with time were then evaluated, as follows. The evaluation results are plotted on an elution graph and shown in FIG.40.

(1) Condition for stability test

- Test formulation: Tablet of composition 15 - Storage condition: Room temperature and 40 ^° C , 75% RH, packaged in HDPE bottle

- Stability evaluation item: Elution

(2) Condition for elution test

- Equipment: Paddle-type elution tester (rotary speed: 50 rpm) - Test solution for solubility: 900 ml of buffer (USP acetate buffer) having pH 4

- Temperature of test solution for solubility: 37± 0.5 °C

- Hereinafter, the handling and analysis of the elution test were carried out in the same manner as in Experimental example 4.

(3) Stability evaluation results

Even when the soluble gastroretentive system-tanned tablet of the composition 15 was kept at a room temperature and 40 °C and a relative humidity (RH) of 75% for 4 months, the elution rate of the soluble

gastroretentive system-tanned tablet of the composition 15 was not degraded, compared to the initial storage of the soluble gastroretentive system-tanned tablet. Therefore, it was revealed that the elution of the soluble gastroretentive system according to the present invention is not changed with time even under the warmed condition (FIG.40).