KR101381999B1 - Gastroretentive system containing solubilized drug for maximizing its therapeutic effect for gastritis - Google Patents

Abstract

The present invention relates to a gastroretentive system matrix formulation having a therapeutic effect on gastritis and containing a compound represented by the formula (1) solubilized in the stomach and a preparation method thereof, wherein the solubilized gastroretentive system matrix formulation applied to the compound of the present invention is a drug In addition to improving the solubility in acidic conditions of the stomach and to increase the gastric retention through the continuous release of the solubilized drug in the stomach has the effect of maximizing the anti-inflammatory effect of the drug.

7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavones and flavanone compounds, gastroretentive systems

Description

Gastroretentive system containing solubilized drug for maximizing its therapeutic effect for gastritis

The present invention relates to a pharmaceutical preparation using a solubilizing gastric retention system of a compound represented by the following Chemical Formula 1 having a gastritis treatment effect, and a preparation method thereof.

In the present invention, the compound represented by Formula 1 includes pharmaceutically acceptable salts thereof and hydrates or solvates thereof.

≪ Formula 1 >

Wherein A is selected from the group consisting of alkyloxycarboalkyloxy, carbosylalkyloxy, N-alkylamidoalkyloxy, hydroxyalkyloxy and cycloalkyloxy, wherein B and C are each hydrogen, hydroxy, Is selected from the group consisting of unsubstituted or one substituted alkyloxy and cycloalkyloxy, and D and E are hydrogen, hydroxy and lower, which can be arranged in a straight or branched chain having 1 to 6 carbon atoms, respectively. It is selected from the group consisting of alkyloxy, wherein the bond bond between the 2- and 3-positions is a single or double bond.

Gastritis (Gastritis) is a local inflammatory disease that occurs in the stomach wall. It is a common disease among modern people who have irregular dietary habits and stress, and heartburn is the main symptom.

A method for treating gastritis is as large attack factor inhibiting and defensive factors may be classified into two kinds of growth, attack factor inhibiting method antacids, H ₂ Blocker (H ₂ Blocker) and Proton Pump Inhibitor, and the like, and protective agent enhancers include Cytoprotectives.

On the other hand, the flavonoid compounds present in nature have a wide variety of antioxidant effects, and among these flavonoids present in nature, hyporetin-8-glucoside and apigenin-7,4'-dimethyl It is known to have anti-ulcer effects such as ether (Apigenine-7,4'-dimethylether), camphorol, quercetin, naringenin, hesperidine, etc. (J. Pharm Pharmacol. 1984 , 36, 820; Ind. J. Pharm. Sci., 1981, 43, 159; Ind. J. Exp. Biol., 1988, 26, 121; Phytotherapy Res, 1992, 6,168).

Korean Patent Application No. 96-30494 discloses a compound represented by Chemical Formula 1, which has been described as useful for gastrointestinal protective action and anti-inflammatory colitis effect of anti-gastritis, anti-ulcer. Among the compounds represented by Chemical Formula 1, 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone represented by the following Chemical Formula 2 is Crohn's disease or ulcer. In addition to inflammatory bowel diseases such as colitis, antigastric and antiulcer effects in the gastrointestinal tract are reported to be very good.

(2)

In addition, Korean Patent Application No. 99-41205 discloses 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone, and a method for preparing pharmaceutically acceptable salts and solvates thereof. The reaction conditions are milder than the method and the reaction step is shorter, thereby providing a production method having a higher yield.

However, the 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone itself of the formula (2) is hygroscopic as an anhydride-type compound, and thus finds difficulty in quantitative preparation, handling and management of the formulation. It became.

Accordingly, Korean Patent Application No. 05-7016164 discloses 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate or solvate represented by the following Chemical Formula 3 having no hygroscopicity, and a method for preparing the same The use as a gastritis treatment and an inflammatory bowel disease treatment is described.

(3)

Compound represented by the formula (1), pharmaceutically acceptable salts thereof and hydrates or solvates thereof are locally inhibited inflammation mediators such as 5-lipoxygenase, Cytokine, etc. in the intestinal mucosa It has an anti-inflammatory effect, and in particular, 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate is evaluated to have excellent tolerability and effect in the treatment of inflammatory bowel disease through preclinical studies. As a basis, a clinical trial for safety and efficacy evaluation is currently in progress. In particular, as a preclinical test, the pharmacokinetic evaluation of rats showed that the bioavailability was less than 1% when administered orally, whereas the high digestive tract distribution directly acted on the gut mucosa and showed anti-ulcer or anti-inflammatory effect.

However, the compounds represented by the formula (1), their pharmaceutically acceptable salts and their hydrates or solvates have sufficient solubility to formulate at least 10 mg / ml in neutral and basic conditions while being acidic at pH 1-4. Has a very low solubility of less than 1 g / ml, despite the anti gastritis and anti-ulcer effect on the gastric mucosa, it is difficult to develop as a gastritis treatment with a conventional formulation design (see Experimental Example 1).

Therefore, as a formulation design for the development of a compound represented by the formula (1), a pharmaceutically acceptable salt thereof, and a hydrate or solvate thereof for gastritis, improving solubility in acidic gastric conditions while maintaining the intragastric retention of the formulation In order to maximize the local anti-inflammatory effect on the gastric mucosa, solubilization of the gastric retention system is urgently needed.

On the other hand, the gastroretentive system is an oral drug delivery system capable of maximizing local effect in the stomach of the drug or increasing the intragastric retention for the purpose of improving the bioavailability of the drug having an absorption window in which absorption is limited to the upper part of the small intestine. Say. According to the gastric retention mechanism, the gastric retention system is divided into a high density system, a floating system, a gas generating system, a raft forming system, a low density system, It can be classified into Expandable System, Superporous Hydrogel System, Bio, Bioadhesive, Mucoadhesive System, Magnetic System.

The inventors have shown that the compound represented by the formula (1), a pharmaceutically acceptable salt thereof, and a hydrate or solvate thereof are dissolved in 0.1 N NaOH solution in the form of a solution and administered in solution in a gastritis treatment prevention and treatment evaluation test using rats. When suspended in water and administered in the form of suspension, the lowest concentration of gastric ulcer prevention and healing effect was found to be more than 30 times higher than the solution when administered in solution form. While there is no problem in solubility in the exercise, it was found that the improvement of solubility for enhancing the therapeutic effect in acidic gastric conditions is very important for enhancing the gastritis treatment effect (see Experimental Example 2).

Therefore, the present inventors have studied to improve the dissolution of the compound represented by the formula (1), its pharmaceutically acceptable salts and their hydrates or solvates under acidic conditions, so that the solubilization of these drugs to maximize the efficacy of the gastritis therapeutic agent The present invention was completed by developing a gastroretentive system matrix formulation.

Accordingly, the present invention provides a gastric mucosal lesion of the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, and a drug having improved solubility while improving solubility in acidic gastric conditions upon administration of a hydrate or solvate thereof. It provides a solubilized gastroretentive system matrix formulation and a method of preparing the same to increase the local concentration of the drug at the site of the lesion and to maximize the therapeutic effect by designing it to be continuously released at the site for a long time. It aims to do it.

In order to achieve the above object, the present invention is a solubilization of the compound represented by the following formula (1), pharmaceutically acceptable salts thereof and their hydrates or solvates thereof in the foamed floating matrix in the form of a single or solid dispersion Provide a gastroretentive system matrix formulation.

≪ Formula 1 >

Wherein A is selected from the group consisting of alkyloxycarboalkyloxy, carbosylalkyloxy, N-alkylamidoalkyloxy, hydroxyalkyloxy and cycloalkyloxy, and B and C are each hydrogen, hydroxy, Is selected from the group consisting of unsubstituted or one substituted alkyloxy and cycloalkyloxy, and D and E are hydrogen, hydroxy and lower, which can be arranged in a straight or branched chain having 1 to 6 carbon atoms, respectively. It is selected from the group consisting of alkyloxy, wherein the bond bond between the 2- and 3-position is a single or double bond.

In the present invention, the solid dispersion contains a hydrophilic polymer or a porous excipient, may include an alkalizing agent for the purpose of increasing the solubility of the drug in the solvent, and in the case of a solid dispersion using a hydrophilic polymer further comprises a dissolution aid. can do.

Hydrophilic polymers include natural or synthetic polysaccharides such as semi-synthetic cellulose derivatives such as hydroxypropyl methylcellulose, hydroxyethyl cellulose and hydroxypropyl cellulose, cyclodextrin or hydroxypropyl thereof, and butyl ether sulfonate, polyvinylpyrrolidone, Synthetic polymers such as polyvinyl alcohol, polyethylene glycol, polyoxyethylene polyoxypropylene block copolymers, preferably hydroxypropyl methyl cellulose and polyvinylpyrrolidone may be used alone or in combination. The weight ratio of the drug and the hydrophilic polymer may be used in a ratio of 1: 0.1 to 10, preferably 1: 0.5 to 5.

The dissolving aid may be used alone or in combination with sodium lauryl sulfate, polysorbate, hydrogenated castor oil, labrazol, etc., and the weight ratio of the drug and the dissolving aid is 1: 0.1 to 10, preferably 1 Can be used at a ratio of 0.5 to 5. The dissolution aid contained in the solid dispersion of the present invention is used for the purpose of enhancing the solubilization effect in the preparation of the solid dispersion.

Porous excipients can be used to prepare the solid dispersion by adsorption granulation method using a fluidized bed granulator or a high speed mixer, and the drug can be used alone or in combination with lactose, microcrystalline cellulose, starch, mannitol, calcium silicate, hard silicic anhydride, etc. It may be used in a ratio of 1: 1 to 10, and preferably 1: 3 to 7, by weight.

The alkalizing agent may be used alone or in combination of basic electrolytes such as sodium hydrogencarbonate and sodium hydroxide or basic amino acids such as arginine, and the weight ratio of the alkalizing agent to the drug is 1: 0.01 to 10, preferably 1: 0.5 to Can be used at a ratio of 5. The alkalizing agent included in the solid dispersion of the present invention is used for the purpose of increasing the solubility of the drug in the solvent.

In the present invention, the foamed floating matrix essentially contains a swellable polymer, an erosive polymer, a foaming agent, and a dissolution aid, and the weight ratio of the swellable polymer: erosive polymer: foaming agent: dissolution aid is 1 to 10: 1 to 10: 1 to 25: 1-10, Preferably it is 1-2: 1-2: 1-5: '1-2'. The matrix, which is swollen by gastric acid infiltration and floated to the upper layer of gastric juice, is continuously eroded and continuously releases the solubilized drug in the matrix to act on the inflammatory site, thereby maximizing the treatment effect of gastritis with a small amount of drug.

Swellable polymers are hydrophilic polymers, semisynthetic cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, sodium carboxymethylcellulose and derivatives thereof, polyethylene oxide, polyvinylpyrrolidone and the like Derivatives, synthetic polymers such as crospovidone, carbopol, natural polysaccharides such as xanthan gum, locust bean gum, and the like may be used alone or in combination, and preferably hydroxypropylmethylcellulose is used. By adjusting the type and amount according to the viscosity, the swelling, floating and disintegrating properties of the matrix and the release rate of the drug can be controlled. The weight ratio of the drug and the swellable polymer is 1: 0.1-10, preferably 1: 0.5-2.

The swellable polymers used in the effervescent floating matrix of the present invention can suspend the matrix by preventing carbon dioxide bubbles from the formulation rapidly swelling and hydrating by the infiltration of gastric juice in the stomach and rapidly exiting the formulation. Swellable polymers can also have a sustained release effect by controlling the release of the drug solubilized in the gel through diffusion to form a hydrated gel by penetration of gastric fluid.

The erosion polymer is a water insoluble polymer or an enteric polymer, and may be used as an insoluble polymer, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetyl succinic acid, as an enteric polymer. Polyvinylacetate phthalate, shellac, polymethacrylate and polymerizers thereof, preferably hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcelluloseacetylsuccinic acid, polymethacrylate and polymers thereof, more preferably hydroxy Propylmethylcelluloseacetylsuccinic acid can be used. As polymethacrylate and polymers thereof, Eudragit L and S may be used alone or in combination as a methacrylic copolymer having an anionic carboxyl group. The weight ratio of the drug to the erosive polymer is 1: 0.1 to 10, preferably 1: 0.5 to 2.

Erodible polymers used in the foamed floating matrix of the present invention are polymers that are hydrated in the stomach to allow the swelling and suspended matrix to continuously erode from outside the gel. When the drug of the present invention is contained in the matrix having the floating and swelling properties alone or in the form of a solid dispersion with a hydrophilic polymer, the solubilized drug in the gel may be released by diffusion, Due to the very low solubility in water (below 1 g / ml), there is a limit to controlling the release of the drug, which necessitates controlled release by continuous gel erosion. Water-insoluble or enteric erosive polymers are contained in the gel matrix suspended and swelled by gastric fluid and present in the gel without dissolving or swelling in the gastric fluid to separate and separate from the swollen gel, resulting in a matrix of hydrated gel. Persistent erosion from the outside can accelerate the release of the drug.

The blowing agent is a substance capable of generating carbon dioxide gas by contact with acid in the stomach. Carbonate or bicarbonates may be used alone or in combination. Preferably, sodium bicarbonate, sodium bicarbonate, calcium carbonate, etc. May be used, more preferably sodium hydrogen carbonate. The weight ratio of drug and carbonate or bicarbonate is 1: 0.1-10, preferably 1: 1-5.

Carbonate or bicarbonate contained in the foamed floating matrix as the blowing agent may generate carbon dioxide bubbles by the penetration of acidic gastric juice present in the stomach, wherein the matrix if necessary for the purpose of enhancing foaming power An acidifier may be added to the addition. As the acidifying agent, citric acid monohydrate, citric acid anhydride, hydrochloric acid, phosphoric acid, acetic acid, and the like may be used alone or in combination, preferably citric acid anhydride.

The dissolution aid can be used in a weight ratio of 1: 0.1 to 10, preferably in a ratio of 1: 0.5 to 2, with the drug alone or in combination with polyoxyethylene polyoxyflopropylene block copolymer, sodium lauryl sulfate, polysorbate, or the like. It is added to increase the solubilization effect in applying the drug or solid dispersion to the foam floating matrix.

In the present invention, the solubilized gastric retention system may further contain a lubricant. Glidants are used for the purpose of smoothing fluidity and tableting in the preparation of a mixture of drugs and additives constituting the matrix or their dry or wet granule compositions in the form of tablets, wherein the glidants used are stearic acid and Metal salts thereof, glyceryl behenate, hard silicic anhydride and the like can be used.

The solubilized gastric retention system according to the present invention may further contain a binder. The binder is added to the matrix mixture for the purpose of formulation into tablets or capsules to produce and grind slugs to dry granules, or to dissolve in suitable solvents such as water or ethanol, and then to the prepared matrix mixtures to associate, assemble, It can be used to prepare granules through the process of sizing and drying, polyvinylpyrrolidone, hydroxypropyl cellulose and the like can be used.

In addition, the solubilized gastroretentive system of the present invention may additionally contain a skin agent when made into a tablet. The coating agent is used for the purpose of protecting the uncoated tablet prepared by the above method from the environment such as heat, light or moisture, and the coating agent used in this case is hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethyl cellulose, Water-soluble or water-insoluble polymers such as polyvinyl alcohol, sodium carboxymethyl cellulose, and methacrylic acid copolymers may be used alone or in admixture in an appropriate composition. In addition, light-shielding agents such as titanium oxide, di As the plasticizer and colorant such as ethyl phthalate, polyethylene glycol, lecithin and the like, a tar pigment or an aluminum lake thereof, iron oxide, or the like may be additionally used.

The present invention also provides a method for preparing a solubilized gastroretentive system matrix formulation of a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, and a hydrate or solvate thereof.

Method for producing a gastric retention system matrix formulation according to the present invention

First, the solubilization step of the compound represented by the formula (1), pharmaceutically acceptable salts thereof and hydrates or solvates thereof, that is, preparing a solid dispersion; And

Second, the solubilization gastric system matrix formulation of the compound represented by the formula (1) consisting of applying the solid dispersion prepared in the first step to the foamed floating matrix, its pharmaceutically acceptable salts and hydrates or solvates thereof It relates to a manufacturing method.

Solid dispersions are prepared by dissolving drug and hydrophilic polymers and / or dissolution aids in a solvent and then powdering them directly using a spray dryer (spray drying), or by using a fluidized bed granulator or a high-speed mixer, and the drug and lactose, microcrystalline cellulose, starch and mannitol. It can be prepared by adsorbing to porous excipients such as calcium silicate and hard silicic anhydride (adsorption granulation method).

As a solvent used for preparing a solid dispersion, basic electrolytes such as sodium bicarbonate and sodium hydroxide or basic amino acids such as arginine and lysine may be used for the purpose of increasing water solubility of the drug. Dissolve these alkalizing agents in water and then dissolve the drug with a hydrophilic polymer or dissolution aid. The solid dispersion prepared as described above may be applied to the foamed floating matrix by directly including in a granule or post-mixing with the components constituting the foamed floating matrix of the present invention. In applying the solid dispersion to the foamed floating matrix, a dissolution aid may be additionally added to increase the solubilization effect, wherein the dissolution aid may be polyoxyethylene polyoxypropylene block copolymer, sodium lauryl sulfate, or polysorbent. Bait or the like can be used.

Another method according to the present invention

First, homogeneously mixing the compound represented by the formula (1), a pharmaceutically acceptable salt thereof, and a hydrate or solvate thereof with a blowing agent, a swellable polymer, an erosive polymer, a dissolution aid, a lubricant, a binder, and

Secondly, the present invention relates to a method for preparing a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, and a soluble or solvate thereof solubilizing gastric system composition comprising the steps of directly tableting the mixture of the first re-stage.

In addition, another method according to the invention

First, homogeneously mixing the compound represented by the formula (1), its pharmaceutically acceptable salts and hydrates or solvates thereof with a blowing agent, a swellable polymer, a dissolution aid;

Second, associating the first stage mixture and binder;

Third, granulating the second stage association;

Fourth, after mixing the erosion polymer in the granulation composition of the third step; And

Fifth, a method of preparing a compound represented by the formula (1), a pharmaceutically acceptable salt thereof, and a solubilized gastric solubility system matrix formulation of the hydrate or solvate thereof, comprising the step of adding a lubricant to the mixture after the fourth step. It is about.

An excipient may be added to the mixture of the first stage, and the binder of the second stage may be dissolved in alcohol or the like beforehand.

The solubilizing gastroretentive system matrix formulation of the present invention improves the solubility of the compound represented by the formula (1), its pharmaceutically acceptable salts and their hydrates or solvates, and at the same time has swelling, floating and eroding properties of the solubilized drug. Continuous release from the matrix can maximize the intragastric topical anti-inflammatory effects of the drug.

Hereinafter, the present invention will be described in detail. However, the scope of the present invention is not limited by these examples.

Example 1 Preparation of Solid Dispersion by Spray Drying and Preparation of Solubilized Gastric System Matrix Tablet Containing the Same

고체 Preparation of solid dispersion by spray drying

7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate and each of the hydrophilic polymers or dissolution aids were dissolved in water with arginine as an alkalizing agent and then sprayed in a composition as shown in Table 1 below. Using a dryer, spray-drying was carried out under the conditions of an Inlet temperature of 120 ° C., an Outlet temperature of 80 ° C., and a spray pressure of 1.5 kg / cm 2 to prepare a solid dispersion.

제조 Preparation of foamed suspended matrix tablets containing spray dried

The solid dispersion containing 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate of composition 5 was dissolved, adjuvant, foaming agent, swellable polymer, erosive polymer and glidant of the composition shown in Table 2 below. The mixture is mixed homogeneously with a tableting machine and tableted to contain 15 mg, 20 mg or 30 mg of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate in a tablet.

<Example 2> Preparation of Solid Dispersion by Adsorption Granulation and Purification of Solubilized Gastric Retention System Containing the Same

As shown in Table 3, 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate was dissolved in water with arginine as an alkalizing agent, and then the solution was microcrystalline cellulose, calcium silicate and hard anhydride. A high-speed stirrer containing a mixture of porous excipients consisting of silicic acid was injected with stirring at 500 rpm for 2 minutes, thereby adsorbing granular solid dispersion containing 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate. Manufacture. The prepared 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate-containing adsorbent granules are mixed homogeneously with a dissolution aid, foaming agent, swellable polymer, erosive polymer and glidant, and then using a tableting machine. Tablets to contain 15 mg, 20 mg or 30 mg of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate in one tablet.

&Lt; Example 3 > Preparation of Solubilized Gastric Retention System Matrix Tablets by Direct Method

7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate is homogeneous with direct dissolution aids, excipients, foaming agents, swellable polymers, erosive polymers and glidants as shown in Table 4, without a solubilization pretreatment step. Then mix with a tableting machine to tablet 15 mg, 20 mg or 30 mg of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate in 1 tablet.

<Example 4> Preparation of Solubilized Gastric Retention System Tablets by Wet Granulation

As shown in Table 5, 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate was homogeneously mixed with a dissolution aid, excipient, foaming agent, and swellable polymer, and then ethanol was previously added as a binder. The hydroxypropyl cellulose dissolved in the mixture was combined with stirring in a high speed mixer, and then granulated using an 18 M sieve, dried at 40 ° C., and then granulated in an 18 M sieve to prepare granules. After mixing the erosive polymer and the lubricant with the prepared granule composition and using the tableting machine, the compositions 11, 13, and 14 are 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone in 1 tablet. Composition 12 is tableted to contain 15 mg of 7-carboxymethyloxy-3 ', 4', 5-trimethoxy flavone monohydrate in one tablet.

< Example  5> Solubilization Residence  system Zephyr  Manufacture of tablets

⑴ Preparation of coating liquid

As shown in Table 6, 0.69 kg of Opadry OY-C-7000A (Colorcon) was completely dispersed in 6.9 kg of ethanol and 1.73 kg of water to use this solution as the primary coating solution, and Opadry 80W41039 (Colorcon) 0.88 kg was used. Completely disperse in 3.64 kg of water and use this solution as the secondary coating solution. 0.18 kg of Opadry 97W19196 (Colorcon) is completely dispersed in 2.82 kg of water and use this solution as the third coating solution.

⑵ coating of matrix tablets

Using the coating solution prepared in and applying the matrix uncoated tablets of compositions 11-14 in order of primary coating solution, secondary coating solution, and tertiary coating solution, respectively, compositions 15-18 were prepared by coating them in the coating machine. The coating rate is about 3% of the uncoated weight for the primary coating, about 3.8% for the secondary coating, and about 0.8% for the tertiary coating, so that the total coating rate is about 7.6% of the uncoated weight.

< Comparative Example  1> Solubilization Residence  Preparation of tablets using conventional methods without applying system technology

7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate was mixed with an excipient and a polyvinylpyrrolidone dissolved in ethanol as a binder using a composition as shown in Table 8 below. After associating with and then assembled using an 18 M sieve, dried at 40 ° C conditions, and then granules are prepared using the 18 M sieve again. The dispersing agent and the glidant were post-mixed to the prepared granule composition, and the composition was compressed into tablets to contain 30 mg of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate in a tablet. do. The uncoated tablets are coated using a skin coating agent, a plasticizer, a lubricant and a pigment as in the above composition.

< Comparative Example  2> Drug-free Solubilization Residence  Placebo Manufacturing of System

A matrix tablet having the same composition as in composition 11 of Example 4 was prepared and then, as in composition 15 of Example 5, a gastric retention system composition was prepared, but the main component was 7-carboxymethyloxy-3 ′, 4 ′, 5. -Trimethoxyflavone monohydrate was prepared except for Comparative Example 2.

< Experimental Example  1> 7- Carboxymethyloxy -3 ', 4', 5- Trimethoxy flavone Monohydrate  Solubility assessment

In order to determine the dissolution characteristics of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate according to pH, the solubility was evaluated by the following method and the results are shown in FIG.

⑴ solubility test conditions

- Instrument: Dialysis Tester (rotation speed: 40 rpm)

Solubility test solution: 20 ml of pH 1.2, 2, 3, 4, 4.5, 5, 6, 6.8 and 7.4 buffer (USP HCl Buffer)

- Solubility Test liquid temperature: 37 ± 0.5 ℃

⑵ solubility test operation

200 mg of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate was added to a conical tube containing 20 ml of the solubility test solution for each pH, followed by dialysis tester at 40 rpm. Stir at speed for about 24 hours, then take supernatant and analyze.

⑶ Solubility test solution analysis method

-Standard solution: Accurately take 20 mg of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate standard, put it into a 100 ml volumetric flask, suspend in 50 ml of methanol, and dissolve in pH 7.4 USP buffer to 100 ml. Use this solution as the standard solution.

-Sample solution: After the solubility test, the supernatant taken at each time period is 13,000 rpm, and the solution is centrifuged for 5 minutes as a test solution. If necessary, dilute with a mobile phase solvent.

-Liquid chromatograph conditions: Measure the solubility of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate in the solubility test solution by analyzing the standard solution and the sample solution under the following conditions.

Column: Inertsil ODS II (C18, 5m, 4.6 x 150 mm) or similar column

Calam temperature: 30 ° C

Detector: UV Absorbance Spectrometer (334 nm)

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

Flow rate: 1 ml / min

Solubility of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate (g / ml) = (peak area of sample solution / peak area of standard solution) Dilution factor of standard solution concentration (g / ml )

결과 Results of solubility evaluation by pH of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate

7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate exhibits a relatively high solubility of at least about 10 mg / ml above neutral pH of 6.8 and above, while 1 g at acidic pH of 1-4. Very low solubility of less than / ml, which results in a very low dissolution rate under acidic conditions of the stomach when 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate is formulated in a conventional manner. When administered to the human body is expected to be distributed in suspension form in the lesion of the gastric mucosa (Fig. 1).

< Experimental Example  2> 7- Carboxymethyloxy -3 ', 4', 5- Trimethoxy flavone Monohydrate  Gastric ulcer induced by dissolution Rat  Evaluation of effectiveness in model

To investigate the correlation between the solubility of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate and the therapeutic effect of gastritis and gastric ulcer, 7-carboxymethyloxy-3 was tested in gastric ulcer induced rat model. ', 4', 5-trimethoxyflavone monohydrate was administered in the form of solution and suspension, respectively, to compare the effects in the following manner, and the results are shown in FIG. 2.

⑴ Dosing

7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate was dissolved in 0.1% NaOH aqueous solution to prepare a solution or suspended in 1% aqueous hydroxypropylmethylcellulose solution, and each was negative control (0.1 Rats are administered once per dose, as shown in Table 9, below, in an aqueous solution of% NaOH and 1% aqueous hydroxypropylmethylcellulose solution.

비교 Comparison of ulcer induction and prevention

After 1 hour of drug administration, 5 ml / kg of alcohol (60%) diluted with aqueous 150 mM hydrochloric acid solution was administered to rats as an ulcer causing substance, and then opened 1 hour later. The area was measured and compared.

효력 Results of efficacy evaluation in ulcer-induced rats according to the dissolved state of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate

When 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate was dissolved in 0.1% NaOH aqueous solution and administered in solution, ulcer area reduction was shown at a dose of 10 mg / kg, whereas 1 Suspension in an aqueous solution of% hydroxypropylmethylcellulose resulted in a reduction in ulcer area at a dose of 300 mg / kg, resulting in 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate. Silver has been found to be much better at treating and preventing ulcers when acting on the mucosa in a dissolved state. As a result, in order to maximize the efficacy of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate as a gastritis therapeutic agent, solubilization in acidic conditions in the stomach is required, and more preferably solubilized drug in the design of the formulation. It can be seen that it is necessary to continuously release the drug while staying at the mucosal lesion for a longer time (FIG. 2).

< Experimental Example  3> 7- Carboxymethyloxy -3 ', 4', 5- Trimethoxy flavone Monohydrate Of the solid dispersion  Physicochemical Evaluation

Solid dispersion and 7-carboxymethyloxy-3 ', 4' containing 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate of Compositions 1-7 prepared in Example 1 Solubility evaluation of, 5-trimethoxyflavone monohydrate was carried out in the following manner and the test results are shown in FIGS. 3A to 3D. In addition, DSC and XRD of the spray-dried solid dispersion of composition 5, the adsorbent granules of Example 2, and 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate were measured. The results are shown in 5a to 5c.

⑴ Solubility Assessment

end. Solubility Test Condition

-Device: Dialysis Tester (Rotation Speed: 40 rpm)

Solubility Test Solution: 150 ml each of pH 1.2, 2, 3, and 4 buffers (USP HCl Buffer)

- Solubility Test liquid temperature: 37 ± 0.5 ℃

I. Solubility test operation

7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone having a solid dispersion of the compositions 1-7 and 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate, respectively Take 20 mg of monohydrate and place it into a clear plastic bottle containing 150 ml of the solubility test solution for each pH. Then, use a Dialysis Tester to stir at a speed of 40 rpm. After that, take supernatant and analyze.

All. Solubility Test Solution Analysis Method

-Standard solution: Accurately take 20 mg of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate standard, put it into a 100 ml volumetric flask, suspend in 50 ml of methanol, and dissolve in pH 7.4 USP buffer to 100 ml. Use this solution as the standard solution.

-Sample solution: After the solubility test, the supernatant taken at each time period is 13,000 rpm, and the solution is centrifuged for 5 minutes.

- Liquid chromatographic conditions: The solubility of 7-carboxymethyloxy-3 ', 4', 5-trimethoxy flavone monohydrate in the solubility test liquid is determined by analyzing the standard solution and the sample solution under the following conditions.

Column: Inertsil ODS II (C18, 5m, 4.6 x 150 mm) or similar column

Calam temperature: 30 ° C

Detector: Ultraviolet absorptiometer (334 nm)

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

Flow rate: 1 ml / min

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

la. 7- carboxymethyloxy- 3 ', 4', 5 -trimethoxyflavone Monohydrate Solubility Evaluation Result of Solid Dispersion

The solid dispersion of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate has a pH of 1.2 to -7 compared to 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate. Solubility was improved under acidic condition of 4, especially the improvement effect at pH 3, 4 was noticeable.

Hydrophilic polymers such as hydroxypropylmethylcellulose and polyvinyl pyrrolidone as additives for the preparation of solid dispersions have excellent solubility improvement, and most preferably, when hydroxypropylmethylcellulose viscosity of 50 cp is used, It was confirmed that the effect of preventing recrystallization is excellent (FIGS. 3A to 3D).

DSC and XRD evaluation of solid dispersion of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate

end. Evaluation condition

DSC evaluation: Take 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone sample and increase the temperature at 10oC / min from 40 ℃ to 300 ℃ under nitrogen gas filling Analyzed. The instrument used was DSC 2010 from TA instrument.

XRD evaluation: Take 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone sample and measure X-ray diffraction pattern with 2θ value from 4 to 40 using Cu-K radiation to measure X-ray diffraction pattern Analysis was performed. The instrument used DMAX-IIIA manufactured by Japan Rigaku.

I. DSC and XRD evaluation results

7-carboxymethyloxy-3 for the spray dried composition of composition 5, which is a spray-dried solid dispersion of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate, and the adsorption granule solid dispersion of Example 2 It was confirmed that the peak indicating the melting point of the ', 4', 5-trimethoxyflavone monohydrate was present in amorphous form (FIG. 4).

In addition, the diffraction peaks due to the crystal form of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate in the case of the spray-dried solid dispersion and the adsorbed granular solid dispersion were also measured by the X-ray diffractometer. It was confirmed that is present in the amorphous by disappearing (Figs. 5a to 5c).

< Experimental Example  4> 7- Carboxymethyloxy -3 ', 4', 5- Trimethoxy flavone Monohydrate  Alone or Of the solid dispersion  Containing in form Solubilization Residence  Dissolution Assessment of the System

Elution, dissolution, and dissolution characteristics of solubilized gastroretentive system tablets containing 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate alone or in the form of solid dispersions Evaluated. The dissolution test results according to the pH of the compositions 8 to 10 and Comparative Example 1 are shown in Figures 6a to 6d, the dissolution test results of the composition 15 and Comparative Example 1 and after the start of the dissolution test, and the time of suspension and disintegration pictures of Figure 7a, respectively. 7b and 8a to 8c.

Elution test conditions

-Equipment: Paddle type dissolution tester (rotation speed: 50 rpm)

Solubility test solution: 900 ml each of pH 1.2, 2, 3 and 4 buffer (USP HCl Buffer)

- Solubility Test liquid temperature: 37 ± 0.5 ℃

Elution test operation

-Dissolution test 1

A solubilized gastric suspension system containing 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate of Compositions 8-10 alone or in the form of a solid dispersion was prepared in the conventional manner of Comparative Example 1. The dissolution test was carried out in accordance with the above conditions with the prepared tablets.

Dissolution test 2

A solubilized gastroretentive system epidermal tablet containing 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate of composition 15 was prepared according to the above conditions together with the tablets prepared by the conventional method of Comparative Example 1. A dissolution test was performed and at the same time a picture showing the floating and disintegrating properties was taken.

⑶ Method of dissolution test solution

-Standard solution: Accurately take 20 mg of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate standard, put it into a 100 ml volumetric flask, suspend in 50 ml of methanol, and dissolve in pH 7.4 USP buffer to 100 ml. Use this solution as the standard solution.

-Test solution: After the solubility test, the supernatant taken at each time period is 13,000 rpm and the solution is centrifuged for 5 minutes.

-Liquid chromatograph conditions: Measure the solubility of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate in the solubility test solution by analyzing the standard solution and the sample solution under the following conditions.

Column: Inertsil ODS II (C18, 5m, 4.6 x 150 mm) or similar column

Calam temperature: 30 ° C

Detector: Ultraviolet absorptiometer (334 nm)

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

Flow rate: 1 ml / min

Concentration of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate in the dissolution test solution (g / ml) = (peak area of the sample solution / peak area of the standard solution) concentration of the standard solution (g / ml)

Dissolution rate of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate (%)

= (Elution test solution concentration (g / ml) / concentration corresponding to 100% dissolution rate (g / ml)) × 100

⑷ Dissolution test result

-Dissolution test 1

The solubilized gastric body system tablets containing 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate in compositions 8 to 10 alone or in the form of a solid dispersion were prepared at acidic conditions of pH 1.2-4. During the dissolution test, the samples were suspended with swelling within 5 minutes and continuously eroded for 1 hour, whereas Comparative Example 1 prepared by the conventional method disintegrated within 5 minutes after the dissolution test and then did not dissolve. And excipients sink to the bottom of the dissolution tester.

As a result of measuring the dissolution rate according to the time slot, Comparative Example 1 showed a dissolution rate of less than about 5% at pH 1.2 to 3 and a dissolution rate of less than about 20% at pH 4 after 10 minutes from the start of dissolution test. Compositions 8, 9 and 10 In the case of elution test, the elution was increased up to about 20% at pH 1.2, up to 60% at pH 2, up to 80% at pH 3, and up to 90 to 100% at pH 4 after starting the dissolution test (Fig. 6A to Fig. 6). 6d).

Thus, solubilized gastroretentive system tablets containing 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate of compositions 8-10 alone or in the form of a solid dispersion were compared using conventional methods. Compared with the tablet of Example 1, it was confirmed that the elution improvement effect was noticeable in the acidic region of pH 1.2 ~ 4.

The dissolution rates between compositions 8-10 were not significantly different, resulting in spray-dried solid dispersion (composition 8) or adsorption granule solid dispersion of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate. Not only the method of incorporating the sieve (Example 2) into the matrix but also the effect of increasing dissolution when 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate was directly contained in the matrix together with the dissolution aid. It was confirmed that there is.

Dissolution test 2

7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate, as in Composition 15, was included in the effervescent suspended matrix with a dissolution aid and then compared to solubilized gastric system tablets prepared as tablets avoided. As a result of evaluating the elution of Example 1 at pH 1.2-4, which is an acidic condition, the tablet of Composition 15 was initially swelled in an acidic region of pH 1.2-4 compared to the tablet of Comparative Example 1 prepared by a conventional method as in Elution Test 1. Release of the drug with sustained erosion for one hour after the floating phenomenon resulted in a noticeable dissolution improvement effect (FIGS. 7A, 7B, 8A-8C).

< Experimental Example  5> 7- Carboxymethyloxy -3 ', 4', 5- Trimethoxy flavone Monohydrate  Containing Solubilization Residence  Of the system Beagles  Gastric Ulcer Treatment Effect Evaluation

A placebo and commercial gastritis therapeutic comprising a solubilized gastric supernatant system containing the 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate of composition 15 and a solubilized gastric system of Comparative Example 2 9A to 12E show results of comparing the effects of the styrene tablets of Dong-A Pharmaceutical with gastric ulcer-induced beagle dogs in the following manner.

동물 Test animal

Twelve female beagle dogs with a clinically recognized body weight of 7 to 8 kg were used. All test dogs were stocked one month prior to adaptation to the breeding environment. Blood tests, serum chemistry, abdominal and chest radiographic examinations were performed. It was confirmed that a healthy state was used for the test.

분류 Classification of test substance and test group

The test group was divided into placebo administration group (Comparative Example 2), test drug 1 (styrene tablet, 1 tablet) administration group, test drug 2 (composition 15, 1 tablet) administration group, and test drug 3 (composition 15, 2 tablets) administration group. Three beagle dogs per group were used. The drug was administered three times a day after meals and 20 ml of negative water was forcibly supplied immediately after drug administration. The total administration period of the drug was 16 days.

유발 Inducing experimental gastric ulcer

Beagle dogs fasted for 12 hours were subcutaneously injected with 0.04 mg / kg of atropine sulphate, and then 30 minutes after intravenous injection of 20 μg / kg of meditomidine and 0.3 mg / kg of midazolam. After combined anesthesia by intramuscular injection, the gastric wall was examined with an endoscope to confirm that the gastric wall was normal. It was. Injury sites were selected for 3 individuals at the base of the gastric endoscopic examination.

평가 Evaluation of healing effect of gastric ulcer (gastroscopy)

An endoscope (Olympus) with a diameter of 10 mm was used, and Olympus CLV-E was used as the endoscope light source. Endoscopy was performed before, 4, 8, 12, and 16 days post-induction. Endoscopy was performed 1-2 hours after drug administration. For endoscopy, the test animals were not fed the morning feed on the day of the test. The test animals were supplied with only the test drug and drinking water. We evaluated the healing effect on gastric ulcer by adding grades from 0 to 5 to the gastric ulcer sites induced in three places. The evaluation criteria are as follows.

⑷ Endoscopic examination result

According to the date of administration of the drug, the gastric endoscopy grade is as follows.

Gastric endoscopy showed that the placebo (Comparative Example 2) administration group tended to maintain an ulcer state from 8 to 12 days after gastric ulcer induction, and was observed in the form of erosion from day 12 to the end of the experiment. Could.

However, in the group administered with test drug 1 (one tablet of styrene), the ulcer site tended to heal in the form of erosion at 8 days after gastric ulcer induction. In the test drug 2 (composition 15, 1 tablet) and test drug 3 (composition 15, 2 tablets) administration group, the ulcers were cured in the form of erosion from the 4th day after the induction of ulcers. Compared with the drug 1 (styrene tablet, 1 tablet) administration group, it was confirmed that the therapeutic effect on gastric ulcer appeared earlier (FIGS. 9A to 12E).

In addition, the placebo ulcer was applied in the form of mucous membrane at the site of lesion in both groups to which the test drug 2 (composition 15, 1 tablet) and the test drug 3 (composition 15, 2 tablet) were specifically administered. ) Or test drug 1 (styrene tablets, 1 tablet) was observed earlier, and gastric ulcer between test drug 2 (composition 15, 1 tablet) and test drug 3 (composition 15, 2 tablets). No clear difference in healing effect could be observed.

As a result, test drug 1 (styrene tablets, 1 tablet), test drug 2 (composition 15, 1 tablet), and test drug 3 (composition 15, 2 tablets) all have a healing effect on gastric ulcers. There was no significant difference in gastric ulcer healing effect between Test Drug 2 (composition 15, 1 tablet) and Test Drug 3 (composition 15, 2 tablets), but it showed superior gastric ulcer healing effect than Test Drug 1 (styrene tablet, 1 tablet). .

< Experimental Example  6> Solubilization Residence  Evaluation of stability under acceleration condition of system

The solubilized gastric system epidermal tablet containing 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate of Composition 15 was stored in HDPE material under accelerated conditions (40 ° C., 75%). The elution change over time was evaluated in the following manner, and the dissolution graph is shown in FIG. 13.

⑴ Stability test conditions

Test formulation: tablets of composition 15

-Storage condition: room temperature and 40 ℃ 75% RH, HDPE bottle packaging

-Stability Evaluation Items: Elution

Elution test conditions

- Device: paddle type dissolution tester (rotation speed: 50 rpm)

Solubility Test Solution: 900 ml of pH 4 Buffer (USP Acetate Buffer)

- Solubility Test liquid temperature: 37 ± 0.5 ℃

-The following dissolution test operation and analysis method is the same as Experimental Example 4.

⑶ Stability evaluation result

The solubilized gastric rejuvenation system of the composition 15 tablets after storage for 4 months at room temperature and 40 ℃, 75% RH conditions did not show a lower dissolution rate compared to the start-up, thereby accelerating the dissolution improvement effect of the solubilized gastric system of the present invention It was confirmed that the conditions do not change over time (Fig. 13).

Figure 1 shows the results of solubility of 7-carboxymethyloxy-3 ', 4', 5-trimethoxy flavone monohydrate according to pH.

FIG. 2 shows the results of evaluating the efficacy of 7-carboxymethyloxy-3 ', 4', 5-trimethoxy flavone monohydrate according to the dissolution state as a model of gastritis-induced rats.

Figure 3a shows the results of solubility evaluation at pH 1.2, the acidic region of the solubilized solid dispersion of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate.

Figure 3b shows the results of solubility evaluation at pH 2, the acidic region of the solubilized solid dispersion of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate.

Figure 3c shows the results of solubility evaluation at pH 3, the acidic region of the solubilized solid dispersion of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate.

Figure 3d shows the results of solubility evaluation at pH 4, which is the acidic region of the solubilized solid dispersion of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate.

Figure 4 shows the result of DSC by measuring 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate in the form of a solid dispersion with a hydrophilic polymer or a dissolution aid.

Figure 5a shows the XRD measurement results of 7-carboxymethyloxy-3 ', 4', 5-trimethoxyflavone monohydrate.

5b shows the XRD measurement results of the solubilized solid dispersion of the spray dried composition 5 according to the present invention.

Figure 5c shows the XRD measurement results of the solubilized solid dispersion of the adsorbent granules of Example 2 according to the present invention.

Figure 6a shows the results of elution evaluation in acidic conditions pH 1.2 of the foamed floating matrix tablets and Comparative Example 1 tablets of Compositions 8 to 10 according to the present invention.

Figure 6b shows the results of dissolution evaluation in acidic conditions pH 2.0 of the foamed floating matrix tablets and Comparative Example 1 tablets of Compositions 8 to 10 according to the present invention.

Figure 6c shows the results of dissolution evaluation in acidic conditions pH 3.0 of the foamed floating matrix tablets and Comparative Example 1 tablets of Compositions 8 to 10 according to the present invention.

Figure 6d shows the results of elution evaluation in acidic conditions pH 4.0 of the foamed floating matrix tablets and Comparative Example 1 tablets of Compositions 8 to 10 according to the present invention.

Figure 7a is a photograph of the floating and disintegration characteristics when evaluating the dissolution at pH 1.2 of the tablet contained in the foamed floating matrix of composition 15 according to the present invention.

7b is a photograph taken of the flotation and disintegration characteristics in the dissolution evaluation at pH 1.2 of Comparative Example 1.

FIG. 8A shows the results of elution evaluation under acidic conditions pH 1.2 of the tablets and the Comparative Example 1 tablets containing the composition 15 according to the present invention in the expanded floating matrix.

8b shows the results of elution evaluation under acidic condition pH 3.0 of the tablet and the comparative tablet of Comparative Example 1 containing the composition 15 according to the present invention in the expanded floating matrix.

FIG. 8C shows the results of elution evaluation under acidic conditions pH 4.0 of the tablets obtained by containing the composition 15 according to the present invention in a foamed floating matrix and a Comparative Example 1 tablet.

Figure 9a shows an endoscope photograph following dosing of the composition 15 according to the present invention immediately after induction of gastric ulcer in a beagle dog.

Figure 9b shows an endoscopic photograph of the fourth day of dosing of the composition 15 according to the present invention after induction of gastric ulcer experimentally in beagle dogs.

Figure 9c shows an endoscopic photograph of the eighth day of dosing of the composition 15 according to the present invention after induction of gastric ulcer experimentally in beagle dogs.

Figure 9d shows an endoscopic photograph of day 12 dosing of composition 15 according to the present invention after induction of gastric ulcer experimentally in beagle dogs.

Figure 9e shows an endoscope photograph of the 16 days of dosing of the composition 15 according to the present invention after the gastric ulcer induced experimentally beagle dog.

FIG. 10a shows an endoscopic photograph after experimentally administering one tablet of styrene tablet to the beagle dog immediately after inducing gastric ulcer.

FIG. 10B shows an endoscopic photograph of the Beagle dog experimentally on day 4 of styrene tablets immediately after induction of gastric ulceration.

Figure 10c shows an endoscopic photograph of the beagle dog experimentally on the 8th day of styrene tablets immediately after the induction of gastric ulceration.

FIG. 10D shows an endoscopic photograph of the beagle dog 12 days after the administration of one tablet of styrene tablets immediately after induction of gastric ulceration.

FIG. 10E shows an endoscopic photograph of the Beagle dog experimentally on day 16 of styrene tablets immediately after induction of gastric ulceration.

FIG. 11a shows an endoscopic photograph of a beagle dog after administration of a single solubilizing gastric retention system of composition 15 immediately after inducing gastric ulcer experimentally.

FIG. 11B shows an endoscopic photograph of the first day of solubilization of the solubilizing gastric retention system of Composition 15 according to the present invention after experimentally inducing gastric ulcer in beagle dogs.

Figure 11c shows an endoscopic image of the beagle dog 8 days after the first solubilization of the solubilizing gastric retention system of the composition 15 according to the present invention after inducing gastric ulcer experimentally.

FIG. 11D shows an endoscopic photograph of the beagle dog 12 days after solubilizing the gastric ulcer system of composition 15 according to the present invention after inducing gastric ulcer experimentally.

FIG. 11E shows an endoscopic image of a beagle dog 16 days after solubilizing the gastric ulcer system of composition 15 according to the present invention after inducing gastric ulcer experimentally.

FIG. 12a shows an endoscopic photograph of a beagle dog experimentally after administration of two tablets of the solubilizing gastric retention system of composition 15 immediately after inducing gastric ulcer.

FIG. 12B shows an endoscopic image of the second day of solubilization of the solubilizing gastric retention system of composition 15 according to the present invention after experimentally inducing gastric ulcer in beagle dogs.

Figure 12c shows the endoscopic image of the beagle dog 8 days after solubilization of the solubilizing gastric retention system of the composition 15 according to the present invention after inducing gastric ulcer experimentally.

FIG. 12D shows an endoscopic image of a beagle dog 12 days after solubilizing the gastric retention system of composition 15 according to the present invention after inducing gastric ulcer experimentally.

FIG. 12E shows an endoscopic image of a beagle dog 16 days after solubilizing the gastric ulcer system of composition 15 according to the present invention after inducing gastric ulcer experimentally.

FIG. 13 shows the results of evaluating the elution stability under the accelerated conditions (40 ° C., 75%) of the coating tablet of the composition 15 according to the present invention. FIG.

Claims (32)

A swellable polymer, an erosive polymer, a blowing agent, and a dissolution aid are swellable polymers: a compound represented by the following formula (2), a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof: swellable polymer: foaming agent: dissolving aid = 1-10: Solubilized gastroretentive system matrix formulation contained in a foamed floating matrix composed of a weight ratio of 1 to 10: 1 to 25: 1 to 10 (2)

The solubilized gastric retention system matrix formulation of claim 1, wherein the drug is contained in the foamed floating matrix alone or in solid dispersion form. The solid dispersion of claim 2, wherein the solid dispersion contains a hydrophilic polymer. Solubilized gastroretentive system matrix formulation, characterized in that the spray-dried solid dispersion. 4. The hydrophilic polymer of claim 3, wherein the hydrophilic polymer is hydroxypropylmethylcellulose, hydroxyethylcellulose, semi-synthetic cellulose derivative of hydroxypropylcellulose, cyclodextrin or hydroxypropyl thereof, natural or synthetic polysaccharides of butyl ether sulfonate substituents, polyvinyl A solubilized gastric system matrix formulation, characterized in that it is selected from the synthetic polymers of pyrrolidone, polyvinyl alcohol, polyethylene glycol, polyoxyethylene polyoxypropylene block copolymers alone or in combination thereof. The solubilized gastric system matrix formulation of claim 4, wherein the hydrophilic polymer is hydroxypropylmethylcellulose. The solubilizing body according to claim 3, wherein the solid dispersion further contains a dissolution aid selected from sodium lauryl sulfate, polysorbate, hydrogenated castor oil, and labrazol alone or in combination thereof. System matrix formulation. delete The solubilized gastric fluid matrix matrix preparation according to claim 2, wherein the solid dispersion is an adsorbent granular solid dispersion containing a porous excipient. The solubilized gastric system matrix formulation of claim 8, wherein the porous excipient is selected from lactose, microcrystalline cellulose, starch, mannitol, calcium silicate, light silicic anhydride alone or in combinations thereof. 10. The solubilized gastric retention system matrix formulation of claim 9, wherein the porous excipient combines microcrystalline cellulose, calcium silicate, and hard silicic anhydride. The solubilized gastric system matrix preparation according to claim 3 or 8, wherein the solid dispersion further contains an alkalizing agent selected from sole hydrogen carbonate, sodium hydroxide, arginine, or a combination thereof. delete The swellable polymer according to claim 1, wherein the swellable polymer is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, sodium carboxymethylcellulose and its semi-synthetic cellulose derivatives, polyethylene oxide, polyvinylpyrrolidone and A solubilized gastroretentive system matrix formulation, characterized in that it is selected from its derivatives, crospovidone, synthetic polymers of carbopol, xanthan gum, natural polysaccharides of locust bean gum, alone or in combination thereof. delete The method of claim 1, wherein the erosive polymer is water-insoluble polymer of cellulose and cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcelluloseacetylsuccinic acid, polyvinylacetate phthalate, shellac, polymetha A solubilized gastroretentive system matrix formulation, characterized in that it is selected from the enteric polymers of the acrylate and its polymerizing agent alone or in combination thereof. 16. The solubilized gastroretentive system matrix formulation of claim 15, wherein the erosive polymer is hydroxypropylmethylcelluloseacetylsuccinic acid. The solubilized gastric retention system matrix formulation according to claim 1, wherein the blowing agent is selected from sole hydrogen carbonate, sodium bicarbonate, calcium carbonate alone or a combination thereof. 18. The solubilized gastroretentive system matrix formulation of claim 17, wherein the blowing agent is sodium bicarbonate. The solubilized gastric system matrix formulation of claim 1, wherein the dissolution aid is selected solely or in combination from polyoxyethylene polyoxyflopylene block copolymer, sodium lauryl sulfate, and polysorbate. The solubilized gastric retention system matrix preparation according to claim 1, wherein the foamed floating matrix further comprises at least one composition selected from acidifying agents, glidants, excipients, binders, skin coatings. The solubilized gastric system matrix preparation according to claim 1, wherein the drug is a monohydrate of the compound represented by the following Chemical Formula 3. (3)

delete delete delete delete Preparing a solid dispersion by solubilizing a compound represented by Formula 2, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof; And The prepared solid dispersion is a swellable polymer, an erosive polymer, a foaming agent and a dissolution aid are swellable polymers: erosive polymers: foaming agents: dissolution aids = 1-10: 1-10: 1-25: 1-10: Steps to Apply to Suspended Matrix Method for producing a solubilized gastroretentive system matrix formulation consisting of. (2)

delete delete delete delete Mixing the compound represented by the following Chemical Formula 2, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof with a blowing agent, a swellable polymer, an erosive polymer, a dissolution aid, a lubricant, and a binder homogeneously; And A method for preparing a solubilized gastroretentive system matrix formulation consisting of directly compressing the mixture. (2)

Mixing the compound represented by the following Formula 2, a pharmaceutically acceptable salt thereof, a hydrate or a solvate thereof with the blowing agent, the swellable polymer, and the dissolving aid homogeneously; Associating the mixture with a binder; Granulating the union; Post-mixing the erosive polymer to the granule composition; And And then lubricating the mixture by adding a lubricating agent. (2)

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