WO2012108631A2

WO2012108631A2 - Pharmaceutical compositions comprising revaprazan-containing nanoparticles and processes for the preparation thereof

Info

Publication number: WO2012108631A2
Application number: PCT/KR2012/000600
Authority: WO
Inventors: Min-Soo Kim; Young-Hun Kim; Myung-Young Park
Original assignee: Yuhan Corporation
Priority date: 2011-02-11
Filing date: 2012-02-03
Publication date: 2012-08-16
Also published as: KR101730865B1; KR20120094178A; WO2012108631A3

Abstract

The present invention provides a pharmaceutical composition for oral administration comprising revaprazan-containing nanoparticles, wherein the revaprazan-containing nanoparticles comprise revaprazan or its pharmaceutically acceptable salt, a certain cationic polymer, and an organic or inorganic acid; and a process for the preparation thereof.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING REVAPRAZAN-CONTAINING NANOPARTICLES AND PROCESSES FOR THE PREPARATION THEREOF

The present invention relates to a pharmaceutical composition comprising revaprazan-containing nanoparticles and a process for the preparation thereof. More specifically, the present invention relates to a pharmaceutical composition for oral administration comprising revaprazan-containing nanoparticles having an average particle size of 1000 nm or less, wherein the revaprazan-containing nanoparticles comprise revaprazan or its pharmaceutically acceptable salt, a certain cationic polymer, and an organic or inorganic acid; and a process for the preparation thereof.

Revaprazan, whose chemical name is 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine, is represented by the following Formula 1. Revaprazan can be used in a form of an acid addition salt, including e.g., HCl salt (see International Publication No. WO1996/05177, WO1997/042186, and WO1998/018784).

Formula 1

Revaprazan or its salt is reversibly bound to a H⁺/K⁺ exchange site of a proton pump (H⁺/K⁺ ATPase) existing in a gastric parietal cell so that secretion of H⁺into the gastric lumen is competitively inhibited. Revaprazan or its salt is also bound to a specific site of H⁺/K⁺ ATPase, thereby inhibiting transport of H⁺ and suppressing an acid secretion to the gastric lumen, which results in increasing the intragastric pH. Unlike irreversible proton pump inhibitors, e.g., omeprazole, revaprazan or its salt is not dependent upon acid activation of a drug in a stomach or secretion status of a proton pump. Therefore, based on the mechanism different from irreversible proton pump inhibitors, such as omeprazole, revaprazan or its salt is classified into an acid pump antagonist (APA).

Revaprazan has very low water-solubility, i.e. less than 0.2 mg/mL, and even lower solubility in a buffer solution having pH 1 to 12. And also, revaprazan has very low intrinsic dissolution rate, i.e., about 0.0086 mg/min/cm². Due to such a low solubility and intrinsic dissolution rate, its dissolution in the gastrointestinal tract is also very low. Therefore, when revaprazan is orally administered, its absorption rate is relatively low. Revaprazan also has strong adhesion and agglutination properties, and thus, when revaprazan is formulated into a capsule or a tablet, it may be stuck to a punch or a die, thereby showing low formulation processability. In order to address these problems, WO 2008/078922 has disclosed a pharmaceutical composition for oral administration comprising a solid dispersion in which revaprazan particles are surface-modified with a water-soluble polymer, a water-soluble saccharide, a surfactant, or a mixture thereof.

The present invention provides a pharmaceutical composition for oral administration which is formulated into nanoparticles by using revaprazan or its pharmaceutically acceptable salt; a certain cationic polymer; and an organic or inorganic acid, thereby remarkably improving low formulation processability, solubility, dissolution rate, and bioavailability of the revaprazan or its salt, and a process for the preparation thereof.

Therefore, it is an object of the present invention to provide a pharmaceutical composition for oral administration comprising revaprazan-containing nanoparticles.

It is another object of the present invention to provide a process for preparing the pharmaceutical composition.

In accordance with an aspect of the present invention, there is provided a pharmaceutical composition for oral administration comprising revaprazan-containing nanoparticles having an average particle size of 1000 nm or less, wherein the revaprazan-containing nanoparticles comprise (i) revaprazan or its pharmaceutically acceptable salt; (ii) a polymer selected from the group consisting of a copolymer of butyl methacrylate, (2-dimethylaminoethyl)methacrylate, and methyl methacrylate, polyvinylacetal diethylamino acetate, and a mixture thereof; and (iii) an organic or inorganic acid.

In the pharmaceutical composition for oral administration of the present invention, the polymer may be present in an amount ranging from 5 to 50 parts by weight, based on 100 parts by weight of revaprazan or its pharmaceutically acceptable salt. And also, the organic or inorganic acid may be one or more selected from the group consisting of citric acid, oleic acid, formic acid, succinic acid, fumaric acid, acetic acid, phosphoric acid, sulfuric acid, and hydrochloric acid; and the organic or inorganic acid may be present in an amount ranging from 10 to 250 parts by weight, based on 100 parts by weight of revaprazan or its pharmaceutically acceptable salt.

The revaprazan-containing nanoparticles may further comprise one or more surfactants selected from the group consisting of sucrose fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene glycolated natural or hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyethylene glycol, polyoxyethylene stearate, polyoxyethylene-polyoxypropylene copolymer, a mixture of sucrose stearate and sucrose distearate, pegylated phospholipid, pegylated cholesterol, pegylated vitamin A, and alpha-tocopheryl polyethylene glycol succinate. And, the surfactant may be present in an amount ranging from 1 to 25 parts by weight, based on 100 parts by weight of revaprazan or its pharmaceutically acceptable salt.

The revaprazan-containing nanoparticles may further comprise one or more binders selected from the group consisting of carrageenan, gelatin, agar, starch, casein, cyclodextrin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, alginic acid, and sodium alginate.

In accordance with another aspect of the present invention, there is provided a process for preparing a pharmaceutical composition for oral administration in a granular or powder form comprising revaprazan-containing nanoparticles having an average particle size of 1000 nm or less, the process comprising (a) dispersing (i) revaprazan or its pharmaceutically acceptable salt; (ii) a polymer selected from the group consisting of a copolymer of butyl methacrylate, (2-dimethylaminoethyl)methacrylate, and methyl methacrylate, polyvinylacetal diethylamino acetate, and a mixture thereof; (iii) an organic or inorganic acid; and optionally (iv) a surfactant in water, (b) wet-grinding the dispersion obtained in the step (a); or a dispersion obtained by dissolving a pharmaceutically acceptable binder in the dispersion obtained in the step (a), and (c) drying the wet-ground dispersion obtained in the step (b), optionally along with a pharmaceutically acceptable binder, diluent, disintegrating agent, or a mixture thereof.

In the process of the present invention, the wet-grinding may be carried out using a dispersion mill, a high speed stirrer, or a high pressure homogenizer, preferably a dispersion mill such as a ball mill, a vibrating mill, and a bead mill.

In accordance with an embodiment, the drying in the step (c) may be carried out by spray-drying the wet-ground dispersion obtained in the step (b); or a dispersion obtained by dissolving a binder in the wet-ground dispersion obtained in the step (b), in a spray-drier or a fluid bed granulator. In accordance with another embodiment, the drying in the step (c) is carried out by spray-drying the wet-ground dispersion obtained in the step (b); or a dispersion obtained by dissolving a binder in the wet-ground dispersion obtained in the step (b), while fluidizing a pharmaceutically acceptable diluent, disintegrating agent, or a mixture thereof in a fluid bed granulator.

In the process of the present invention, the binder may be one or more selected from the group consisting of carrageenan, gelatin, agar, starch, casein, cyclodextrin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, alginic acid, and sodium alginate.

In accordance with still another aspect of the present invention, there is provided a process for preparing a pharmaceutical composition for oral administration in a tablet form which comprises compressing the granules or powder obtained by the process in the above, and a pharmaceutically acceptable excipient.

In accordance with still another aspect of the present invention, there is provided a process for preparing a pharmaceutical composition for oral administration in a capsular form which comprises filing the granules or powder obtained by the process in the above, and a pharmaceutically acceptable excipient in a capsule.

It is found by the present invention that, if revaprazan or its pharmaceutically acceptable salt is formulated into nanoparticles through wet-grinding along with a certain polymer and an acid, the particle size of revaprazan can be maintained in nano-level even at the time when the resulting dispersion and/or a dry powder obtained from the dispersion is re-dispersed in an aqueous medium. Especially, the particle size of revaprazan can be stably maintained in nano-level before and after a powder-forming process even without using a dispersing agent (or a dispersion-stabilizing agent) such as saccharides, thereby being able to efficiently perform formulation processes. And also, the nanoparticles according to the present invention can remarkably increase the solubility of revaprazan or its salt and effectively improve adhesion and agglutination properties of revaprazan or its salt. In addition, the nanoparticles according to the present invention show remarkably improved dissolution rate and bioavailability. Therefore, the pharmaceutical composition of the present invention can reduce an amount of revaprazan or its salt in a unit dosage form, which makes it easy to perform a formulation process. Furthermore, the pharmaceutical composition of the present invention can reduce any side effects which may be caused by patient's misuse (e.g., intake of high amount).

FIG. 1 shows particle size distributions of revaprazan, when the dispersion comprising revaprazan-containing nanoparticles obtained in Example 8 (①); the powder obtained by spray-drying the dispersion (②); and the granules comprising revaprazan-containing nanoparticles obtained in Example 17 (③) are re-dispersed in distilled water, respectively.

FIG. 2 shows solubility in a pH 1.2 solution, according to elapse of time [■: granules of Example 17, ○: granules of Example 19, ◆: powder of Comparative Example 1 (2), ◇: powder of Comparative Example 3, ●: powder of revaprazan hydrochloride].

FIG. 3 shows dissolution rates of the tablet of Example 20 and the tablet of Revanex^TM 200 mg (Yuhan Corporation) in a pH 1.2 solution [●: the tablet of Example 20, ○: the tablet of Revanex^TM 200 mg].

FIG. 4 shows blood concentration profiles according to bioavailability test [▲: Comparative formulation (the dispersion of revaprazan hydrochloride in 0.5% methyl cellulose solution), ○: the re-dispersion of the spray-dried granules prepared in Example 8 in water].

As used herein, the term "nanoparticles" refer to particles having an average particle size of about 1000 nm or less, preferably 10 to 1000 nm, more preferably 10 to 500 nm. The term "nanoparticles in the form of dispersion in an aqueous medium" or "a dispersion containing nanoparticles in an aqueous medium" refers to a dispersion in which particles having said average particle size are dispersed in an aqueous medium, such as water, phosphate-buffered saline, etc. And also, the term "nanoparticles in the form of powder" or "nanoparticle powder" refers to a powder both (i) which stably has said average particle size in itself and (ii) which is stably dispersed as particles having said average particle size, when it is re-dispersed in an aqueous medium (e.g., water, phosphate-buffered saline, etc) or body fluid. Typically, the re-dispersing may be carried out by manually stirring an aqueous medium or body fluid or by ultrasonic treatment within about 10 minutes. The particle size may be measured with a dynamic light scattering method, a static image analysis method, or any other conventional methods.

The term "stable", "stably", or "stably dispersed" refers to (1) a state in which particles show no substantial coagulation or agglutination due to Van der Waals force and Ostwald Ripening; or the particle size is not substantially increased with the lapse of time, (2) a state in which particles show coagulation or agglutination but can be easily re-dispersed to maintain an average particle size of about 1000 nm or less, and/or (3) a state in which nanoparticles are chemically stable.

It is found by the present invention that, if revaprazan or its pharmaceutically acceptable salt is formulated into nanoparticles through wet-grinding along with a certain polymer and an acid, the particle size of revaprazan can be maintained in nano-level even at the time when the resulting dispersion and/or a dry powder obtained from the dispersion is re-dispersed in an aqueous medium. Especially, the particle size of revaprazan can be stably maintained in nano-level before and after a powder-forming process even without using a dispersing agent (or a dispersion-stabilizing agent) such as saccharides, thereby being able to efficiently perform formulation processes. And also, the nanoparticles according to the present invention can remarkably increase the solubility of revaprazan or its salt and effectively improve adhesion and agglutination properties of revaprazan or its salt. In addition, the nanoparticles according to the present invention show remarkably improved dissolution rate and bioavailability. Generally, it is common knowledge in pharmaceutics that, in the case of a drug with high adhesive and/or agglutinative property, as a particle size decreases, the adhesiveness and/or agglutination among drug particles increases and thus the dissolution of the drug decreases. Thus, very surprising is the finding that when revaprazan or its pharmaceutically acceptable salt is formulated into nanoparticles, the dissolution rate and bioavailability thereof can be remarkably increased. Therefore, the pharmaceutical composition of the present invention can reduce an amount of revaprazan or its salt in a unit dosage form, which makes it easy to perform a formulation process. Furthermore, the pharmaceutical composition of the present invention can reduce any side effects which may be caused by patient's misuse (e.g., intake of high amount).

The present invention provides a pharmaceutical composition for oral administration comprising revaprazan-containing nanoparticles having an average particle size of 1000 nm or less, wherein the revaprazan-containing nanoparticles comprise (i) revaprazan or its pharmaceutically acceptable salt; (ii) a polymer selected from the group consisting of a copolymer of butyl methacrylate, (2-dimethylaminoethyl)methacrylate, and methyl methacrylate, polyvinylacetal diethylamino acetate, and a mixture thereof; and (iii) an organic or inorganic acid.

In the pharmaceutical composition for oral administration of the present invention, revaprazan or its pharmaceutically acceptable salt may be used in a therapeutically effect amount, for example in range of 10 to 500 mg in a unit dosage form such as tablet, capsules, etc, but not limited thereto. The pharmaceutically acceptable salt of revaprazan may be an acid addition salt, including revaprazan hydrochloride, revaprazan sulfate, revaprazan phosphate, revaprazan nitrate, revaprazan camphorsulfonate (i.e., revaprazan camsylate), revaprazan thiocyanate, and the like. Preferably, the salt of revaprazan is revaprazan hydrochloride.

The nanoparticles in the pharmaceutical composition of the present invention include a certain cationic polymer, which allows the nanoparticles being stably re-dispersed in nano-level in an aqueous medium. Especially, it is found by the present invention that a certain cationic polymer can minimize any possibility of precipitation which may be caused by chemical reaction between revaprazan with other components. The cationic polymer includes a copolymer of butyl methacrylate, (2-dimethylaminoethyl)methacrylate, and methyl methacrylate (preferably a copolymer of 1 part by weight of butyl methacrylate, 2 parts by weight of (2-dimethylaminoethyl)methacrylate, and 1 part by weight of methyl methacrylate [for example, Eudragit E]), polyvinylacetal diethylamino acetate, and a mixture thereof. The cationic polymer may be present in an amount ranging from 5 to 50 parts by weight, preferably from 6 to 40 parts by weight, based on 100 parts by weight of revaprazan or its pharmaceutically acceptable salt.

The organic or inorganic acid helps the polymer dissolving or dispersing in an aqueous medium. And also, the organic or inorganic acid helps the revaprazan particles stably being re-dispersed in nano-level. The organic or inorganic acid may be one or more selected from the group consisting of citric acid (including anhydrous citric acid and/or citric acid monohydrate), oleic acid, formic acid, succinic acid, fumaric acid, acetic acid, phosphoric acid, sulfuric acid, and hydrochloric acid; preferably acetic acid, hydrochloric acid, or citric acid. The organic or inorganic acid may be present in an amount ranging from 10 to 250 parts by weight, preferably from 15 to 250 parts by weight, based on 100 parts by weight of revaprazan or its pharmaceutically acceptable salt.

The revaprazan-containing nanoparticles may further comprise a surfactant, which helps revaprazan and the polymer dispersing in an aqueous medium. And also, the surfactant helps the revaprazan particles stably being re-dispersed in nano-level after preparing a solid powder. The surfactant may be one or more selected from the group consisting of sucrose fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene glycolated natural or hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester (for example Tweens etc), polyethylene glycol, polyoxyethylene stearate, polyoxyethylene-polyoxypropylene copolymer (for example, Poloxamer, Poloxamine, etc), a mixture of sucrose stearate and sucrose distearate (for example Crodestas F-110, etc), pegylated phospholipid, pegylated cholesterol, pegylated vitamin A, and alpha-tocopheryl polyethylene glycol succinate; preferably polyoxyethylene sorbitan fatty acid ester, sucrose fatty acid ester, alpha-tocopheryl polyethylene glycol succinate, and/or polyoxyethylene-polyoxypropylene copolymer. The surfactant may be present in an amount ranging from 1 to 25 parts by weight, preferably 1.5 to 25 parts by weight, based on 100 parts by weight of revaprazan or its pharmaceutically acceptable salt.

And also, the revaprazan-containing nanoparticles may further comprise a binder conventionally used in the pharmaceutics. For example, the binder may be one or more selected from the group consisting of carrageenan, gelatin, agar, starch, casein, cyclodextrin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, alginic acid, and sodium alginate; preferably polyvinylpyrrolidone, hydroxypropyl cellulose, or a mixture thereof. It is also found by the present invention that, even when performing a granulation process (for example, a granulation process through spray-drying with a fluid bed granulator) using the binder, revaprazan or its salt in the resulting granules can be still maintained as nanoparticles. Therefore, the revaprazan-containing nanoparticles may be directly prepared in a granular form, without preparing a powder form.

The present invention also provides a process for preparing a pharmaceutical composition for oral administration in a granular or powder form comprising revaprazan-containing nanoparticles having an average particle size of 1000 nm or less, the process comprising (a) dispersing (i) revaprazan or its pharmaceutically acceptable salt; (ii) a polymer selected from the group consisting of a copolymer of butyl methacrylate, (2-dimethylaminoethyl)methacrylate, and methyl methacrylate, polyvinylacetal diethylamino acetate, and a mixture thereof; (iii) an organic or inorganic acid; and optionally (iv) a surfactant in water, (b) wet-grinding the dispersion obtained in the step (a); or a dispersion obtained by dissolving a pharmaceutically acceptable binder in the dispersion obtained in the step (a), and (c) drying the wet-ground dispersion obtained in the step (b), optionally along with a pharmaceutically acceptable binder, diluent, disintegrating agent, or a mixture thereof.

In the step (a), (i) revaprazan or its pharmaceutically acceptable salt, (ii) the polymer, (iii) the organic or inorganic acid, and (iv) the surfactant are described as in the above. The dispersing the components (i) to (iii) or (i) to (iv) may be carried out by dissolving or dispersing the components in water (preferably, in distilled water). The dispersing may be carried out with a conventional mechanical stirrer. Water may be used in an amount suitable to perform the subsequent wet-grinding process. For example, water may be used in an amount of 30 to 70 times of weight, based on the weight of revaprazan or its pharmaceutically acceptable salt, but not limited thereto.

The process of the present invention includes wet-grinding the dispersion obtained in the step (a); or a dispersion obtained by dissolving a pharmaceutically acceptable binder in the dispersion obtained in the step (a) [i.e., step (b)].

The wet-grinding may be carried out using a dispersion mill, a high speed stirrer, or a high pressure homogenizer; preferably a dispersion mill such as a ball mill, a vibrating mill, and a bead mill. The wet-grinding using a high pressure homogenizer may be performed by passing high pressure of 10000 to 50000 psi through a reaction chamber having a uniform inner diameter. As a high pressure homogenizer, Microfludizer^®(Microfludics), MicroDebee^®(Bee International), APV Micron Lab 40^®(APV Deutschland GmbH), etc may be used. Time for wet-grinding is not limited. Typically, as the time increases, revaprazan particles having more fine and uniform particle size may be obtained. The wet-ground dispersion maintains a stable dispersion form without any agglutination or precipitation, even when being stored for more than 24 hours.

The wet-grinding may be performed by wet-grinding the dispersion obtained in the step (a) according to the method described in the above; or by wet-grinding a dispersion obtained by dissolving a pharmaceutically acceptable binder in the dispersion obtained in the step (a). As described in the above, even when performing a granulation process (for example, a granulation process through spray-drying with a fluid bed granulator) using the binder, revaprazan or its salt in the resulting granules can be still maintained as nanoparticles. The binder may be added in the step (b) and/or the subsequent step (c). The binder may be one or more selected from the group consisting of carrageenan, gelatin, agar, starch, casein, cyclodextrin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, alginic acid, and sodium alginate.

The process of the present invention includes drying the wet-ground dispersion obtained in the step (b), optionally along with a pharmaceutically acceptable binder, diluent, disintegrating agent, or a mixture thereof [i.e., step (b)].

The drying may be carried out using a conventional drying method, such as drying under reduced pressure, lyophilization, spray-drying, etc. If necessary, filtration or centrifugation may be performed before the drying process. The drying may be performed preferably by lyophilization or spray-drying, more preferably by spray-drying. The spray-drying may be carried out using a spray-drier, a fluid bed granulator, a cylindrical granulator, a high speed rotary granulator, etc. The resulting product may have a powder or granular form.

In an embodiment, the drying may be carried out by spray-drying the wet-ground dispersion obtained in the step (b); or a dispersion obtained by dissolving a binder in the wet-ground dispersion obtained in the step (b), in a spray-drier or a fluid bed granulator. The binder is the same as described in the above.

In another embodiment, the drying may be carried out by spray-drying the wet-ground dispersion obtained in the step (b); or a dispersion obtained by dissolving a binder in the wet-ground dispersion obtained in the step (b), while fluidizing a pharmaceutically acceptable diluent, disintegrating agent, or a mixture thereof in a fluid bed granulator.

The diluent may be one or more selected from the group consisting of calcium carbonate, cyclodextrin, calcium sulfate, calcium silicate, magnesium carbonate, microcrystalline cellulose, cellulose, maltodextrin, lactose, L-hydroxypropyl cellulose, starch, gelatinized starch, mannitol, sucrose, and sorbitol. Preferably, the diluent may be microcrystalline cellulose and/or lactose. And also, the disintegrating agent may be one or more selected from the group consisting of low-substituted hydroxypropyl cellulose (L-HPC), chitin, chitosan, polymerized agar acrylamide, xylan, smecta, alginic acid or its salt, hydroxypropyl cellulose, cellulose derivatives, polacralin potassium, croscarmellose sodium (Ac-Di-Sol, CLD-2), starch, gelatinized starch, carboxymethyl starch, gellan gum, sodium starch glycolate (e.g., Primojel^TM, Explotab^TM, etc), and crospovidone (Polyplasdone-X1R, Polyplasdone-XL 10R, or Kollidon CL, etc); preferably, crospovidon and/or sodium starch glycolate. The binder is the same as described in the above.

The present invention also provides a process for preparing a pharmaceutical composition for oral administration in the form of solid formulation such as tablet or capsule, using the granules or powder obtained according to the process in the above. Specifically, the present invention provides a process for preparing a pharmaceutical composition for oral administration in a tablet form which comprises compressing the granules or powder obtained by the process described in the above, and a pharmaceutically acceptable excipient. And also, the present invention provides a process for preparing a pharmaceutical composition for oral administration in a capsular form which comprises filing the granules or powder obtained by the process described in the above, and a pharmaceutically acceptable excipient in a capsule. The pharmaceutically acceptable excipient used for preparing the tablet or capsule includes a diluent such as calcium carbonate, cyclodextrin, calcium sulfate, calcium silicate, magnesium carbonate, cellulose, maltodextrin, lactose, L-hydroxypropyl cellulose, starch, gelatinized starch, mannitol, sucrose, and sorbitol; a disintegrating agent such as low-substituted hydroxypropyl cellulose (L-HPC), chitin, chitosan, polymerized agar acrylamide, xylan, smecta, alginic acid or its salt, hydroxypropyl cellulose, cellulose derivatives, polacralin potassium, croscarmellose sodium (Ac-Di-Sol, CLD-2), starch, gelatinized starch, carboxymethyl starch, gellan gum, sodium starch glycolate (e.g., Primojel^TM, Explotab^TM, etc), and crospovidone (Polyplasdone-X1R, Polyplasdone-XL 10R, or Kollidon CL, etc); a lubricant such as Aerosil^TM, magnesium stearate, etc. The compressing and filling may be carried out according to conventional pharmaceutical processes.

The present invention will be described in further detail with reference to the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Revaprazan hydrochloride was prepared according to the method described in WO97/42186, and it has an average particle size of about 2 to 4 ㎛. Unless otherwise specified, the revaprazan hydrochloride used in the following examples and experimental examples has an average particle size of about 2 to 4 ㎛.

Example 1. Preparation of nanoparticles

Eudragit E (3 g), 1N HCl (15 g), and revaprazan hydrochloride (10 g) were dissolved or dispersed in distilled water (178 g) using a mechanical stirrer. Zirconia beads having an average particle size of 0.3 mm were added to the resulting dispersion, which was then wet-ground at room temperature (about 25 ℃) and at 2700 rpm for 2 hours using Netzch Mill (Netzsch Inc). After discarding the beads, the resulting wet-ground dispersion was spray-dried with a spray drier (Mini spray dryer, Buchi 190) to obtain a powder. Conditions for the spray-drying are as follows; Inlet air temperature: 135 to 145 ℃, Spray rate: 4 to 8 ml/min, and Outlet air temperature: 70 to 78 ℃.

In the above processes, a portion of the wet-ground dispersion (0.3 ml) was re-dispersed in distilled water (10 ml) to obtain a test-dispersion (Test Dispersion-1). And, the spray-dried powder (0.03 g) was re-dispersed in distilled water (10 ml) to obtain another test-dispersion (Test Dispersion -2). The particle sizes of revaprazan in Test Dispersion-1 and Test Dispersion-2 were respectively measured, according to a Dynamic Light Scattering method, using Zetasizer nanoZS (Malvern Inc.). The re-dispersing was performed by manually stirring. The average particle sizes of revaprazan in Test Solution-1 and Test Solution-2 were 205 ± 4.5 nm and 255 ± 7.3 nm, respectively. From these results, it can be seen that, when not only a dispersion obtained through wet-grinding process but also a dry powder obtained from the dispersion is re-dispersed in an aqueous medium, the particle size of revaprazan is maintained in nano-level.

Examples 2 to 7. Preparation of nanoparticles and evaluation thereof

Wet-ground dispersions and dry powders were prepared by using the same procedures of Example 1, according to the components and amounts shown in Table 1. And also, the respective particle size of revaprazan was measured in accordance with the same method as described in Example 1. The results are shown in Table 1.

Table 1

Example	Drug*	Polymer	Acid/Base	Average particle size
Example	Drug*	Polymer	Acid/Base	Dispersion	Dry powder
2	10 g	Eudragit E (4 g)	1N HCl (25 g)	188.3 nm	203.5 nm
3	10 g	Eudragit E (2 g)	1N HCl (5 g)	214.2 nm	279.4 nm
4	10 g	Eudragit RL (4 g)	1N HCl (5 g)	Nanoparticles could not be prepared
5	10 g	Eudragit L (4 g)	1N NaOH (10 g)	Nanoparticles could not be prepared
6	10 g	Eudragit S (4 g)	1N NaOH (10 g)	Nanoparticles could not be prepared
7	10 g	AEA^** (3 g)	Citric acid (10 g)	230.4 nm	291.5 nm

* Revaprazan HCl

** Polyvinylacetal diethylamino acetate

From the results of Table 1, it can be seen that, when Eudragit E or polyvinylacetal diethylamino acetate is used, the particle size of revaprazan can be stably maintained in nano-level before and after the powder-forming process (i.e., spray-drying process), even without using a dispersing agent (or a dispersion-stabilizing agent) such as saccharides.

Example 8. Preparation of nanoparticles and evaluation thereof

Eudragit E (6 g), sucrose fatty acid ester (Roto Ester L 1695, Mitsubishi, Japan) (3 g), 1N HCl (20 g), and revaprazan hydrochloride (30 g) were dissolved or dispersed in distilled water (241 g) using a mechanical stirrer. Zirconia beads having an average particle size of 0.3 mm were added to the resulting dispersion, which was then wet-ground at room temperature (about 25 ℃) and at 2450 rpm for 3 hours using Netzch Mill (Netzsch Inc). After discarding the beads, the resulting wet-ground dispersion was spray-dried with a spray drier (Mini spray dryer, Buchi 190) to obtain a powder. Conditions for the spray-drying are as follows; Inlet air temperature: 140 to 150 ℃, Spray rate: 3 to 10 ml/min, and Outlet air temperature: 70 to 78 ℃.

In accordance with the same method described in Example 1, the wet-ground dispersion and the powder obtained by the spry-drying process were re-dispersed in distilled water and then the particle size distributions thereof were measured, respectively. The results are shown in FIG. 1. As shown in FIG. 1, the average particle size of revaprazan in the re-dispersion obtained from the wet-ground dispersion is 186.3 ± 2.5 nm; and D90% (defined as the particle sizes corresponding to the cumulative volume percentage of 90% in the particle size distribution curve) is 396 nm. The average particle size of revaprazan in the re-dispersion obtained from the spray-dried powder is 201.0 ± 5.0 nm; and D90% is 396 nm. From these results, it can be seen that both a dispersion obtained through wet-grinding process and a dry powder obtained from the dispersion stably maintain the particle size of revaprazan in nano-level before and after the powder-forming process, even without using a dispersing agent such as saccharides.

Examples 9 to 16. Preparation of nanoparticles and evaluation thereof

Wet-ground dispersions and dry powders were prepared by using the same procedures of Example 8, according to the components and amounts shown in Table 2. And also, the respective particle size of revaprazan was measured in accordance with the same method as described in Example 1. The results are shown in Table 2.

Table 2

Exam-ple	Drug*	Polymer	Acid	Surfactant	Average particle size
Exam-ple	Drug*	Polymer	Acid	Surfactant	Dispersion	Dry powder
9	30 g	Eudragit E(4 g)	1N HCl(50 g)	Tween 80(0.5 g)	205 nm	258 nm
10	80 g	Eudragit E(16 g)	1N HCl(50 g)	Sucrose fattyacid ester(8 g)	194 nm	211 nm
11	30 g	Eudragit E(6 g)	1N HCl(20 g)	TPGS^***(3 g)	210 nm	245 nm
12	30 g	Eudragit E(5 g)	Citric acid(10 g)	Sucrose fattyacid ester(6 g)	196 nm	234 nm
13	30 g	Eudragit E(2 g)	1N HCl(5 g)	Poloxamer188(2 g)	225 nm	263 nm
14	40 g	AEA^**(8 g)	1N HCl(20 g)	Sucrose fattyacid ester(6 g)	196 nm	258 nm
15	30 g	AEA^**(8 g)	1N HCl(40 g)	Sucrose fattyacid ester(5 g)	170 nm	196 nm
16	30 g	AEA^**(4 g)	Citric acid(20 g)	TPGS^***(3 g)	205 nm	276 nm

* Revaprazan HCl

** Polyvinylacetal diethylamino acetate

*** Alpha-tocopheryl polyethylene glycol succinate

Comparative Example 1. Preparation of nanoparticles and evaluation thereof

(1) Preparation of nanoparticles using a cellulose derivative (hydroxypropyl methylcellulose) and evaluation thereof

Hydroxypropyl methylcellulose (2 g), sucrose fatty acid ester (Roto Ester L 1695, Mitsubishi, Japan) (1 g), and revaprazan hydrochloride (10 g) were dissolved or dispersed in distilled water (187 g) using a mechanical stirrer. Using the resulting dispersion, a spray-dried powder was prepared in accordance with the same method as described in Example 8. And also, the particle sizes of revaprazan in the re-dispersions (obtained from the wet-ground dispersion and from the spry-dried powder, respectively) were measured in accordance with the same method as described in Example 8. As a result, the average particle size of revaprazan in the re-dispersion obtained from the wet-ground dispersion was 234.3 ± 2.9 nm; and D90% is 342 nm. In contrast, the average particle size of revaprazan in the re-dispersion obtained from the spray-dried powder was 547.3 ± 8.7 nm; and D90% is 4800 nm.

(2) Preparation of Nanoparticles using a cellulose derivative (hydroxypropyl cellulose) and Evaluation thereof

Hydroxypropyl cellulose (2 g), sucrose fatty acid ester (Roto Ester L 1695, Mitsubishi, Japan) (0.1 g), and revaprazan hydrochloride (10 g) were dissolved or dispersed in distilled water (187.9 g) using a mechanical stirrer. Using the resulting dispersion, a spray-dried powder was prepared in accordance with the same method as described in Example 8. And also, the particle sizes of revaprazan in the re-dispersions (obtained from the wet-ground dispersion and from the spry-dried powder, respectively) were measured in accordance with the same method as described in Example 8. As a result, the average particle size of revaprazan in the re-dispersion obtained from the wet-ground dispersion was 233.3 ± 5.8 nm; and D90% was 396 nm. In contrast, the average particle size of revaprazan in the re-dispersion obtained from the spray-dried powder was 727.7 ± 89.9 nm; and D90% was 4150 nm.

From the results of (1) and (2), it can be seen that, when a cellulose derivative is used, revaprazan hydrochloride can exist as a nanoparticle form in the dispersion; but agglomeration or growth of revaprazan particles occurs in the spray-dried powder.

Comparative Example 2. Preparation of nanoparticles (using a dispersion-stabilizing agent) and evaluation thereof

Hydroxypropyl methylcellulose (2 g), sucrose fatty acid ester (Roto Ester L 1695, Mitsubishi, Japan) (1 g), and revaprazan hydrochloride (10 g) were dissolved or dispersed in distilled water (187 g) using a mechanical stirrer. Zirconia beads having an average particle size of 0.3 mm were added to the resulting dispersion, which was then wet-ground at room temperature (about 25 ℃) and at 2450 rpm for 3 hours using Netzch Mill (Netzsch Inc). After discarding the beads, sucrose (10 g or 20 g) was add to the resulting dispersion, which was then spray-dried with a spray drier (Mini spray dryer, Buchi 190) to obtain a powder. Conditions for the spray-drying are the same as in Example 8.

The particle sizes of revaprazan in the re-dispersions (obtained by re-dispersing the resulting spry-dried powders in water) were measured in accordance with the same method as described in Example 1. As a result, the average particle size of revaprazan in the re-dispersion obtained from the spry-dried powder (including 100 wt/wt% of sucrose based on 100 wt/wt% of revaprazan hydrochloride) was 330.0 ± 11.1 nm; and D90% was 825 nm. And, the average particle size of revaprazan in the re-dispersion obtained from the spry-dried powder (including 200 wt/wt% of sucrose based on 100 wt/wt% of revaprazan hydrochloride) was 223.7 ± 3.1 nm; and D90% was 495 nm. From these results, it can be seen that the addition of sucrose to a homogenized dispersion leads to improvement in re-dispersibility of the spray-dried powder obtained from the resulting dispersion, but that very large amounts of sucrose (about more than 200 wt/wt%, based on 100 wt/wt% of a drug, i.e., revaprazan hydrochloride) are required in order to re-disperse substantially all particles to nano level.

Comparative Example 3. Preparation of revaprazan-containing solid dispersion

A revaprazan-containing solid dispersion was prepared in accordance with the method disclosed in WO08/078922. Polyvinylpyrrolidone (10 g), sucrose fatty acid ester (20 g), Cremophor RH40 (20 g), and Poloxamer 407 (20 g) were dissolved in distilled water (2100 ml). Revaprazan hydrochloride (100 g) was suspended in the resulting solution, under stirring with a mechanical stirrer. The resulting suspension was spray-dried with a spray-drier (Mini spray dryer, Buchi 190), under the conditions of 120 to 130 ℃ of inlet temperature and 80 to 90 ℃ of outlet temperature, to obtain a solid dispersion.

Example 17. Preparation of granules and evaluation thereof

In accordance with the same method described in Example 8, wet-grinding was performed and then beads were discarded to obtain a wet-ground dispersion. While fluidizing a mixture of microcrystalline cellulose (28.5 g) and crospovidone (1.5 g) in a fluid bed granulator (Mini Glatt, Glatt), the wet-ground dispersion (200 g) was sprayed into the granulator to obtain spray-dried granules. Conditions for the spray-drying are as follows; Inlet air temperature: 60 to 75 ℃, and Spray pressure: 0.5 to 1.5 bar.

The resulting granules (about 0.09 g) were re-dispersed in distilled water (10 ml) by stirring manually. The particle size of revaprazan in the resulting re-dispersion was measured, using Zetasizer nanoZS (Malvern Inc.). The result is shown in FIG. 1. As shown in FIG. 1, the revaprazan-containing nanoparticles of the dispersion (i.e., wet-ground dispersion) did not show any agglomeration of particles or any increase of particle size due to precipitation, in preparing granules using the fluid bed granulator. Therefore, it can be seen that the particle size of revaprazan in the granules is maintained in nano level.

Example 18. Spray-drying a dispersion containing a binder and evaluation thereof

In accordance with the same method described in Example 8, wet-grinding was performed and then beads were discarded to obtain a wet-ground dispersion. A solution of polyvinylpyrrolidone (2 g) in water (98 g) (i.e., binder solution) was added to the dispersion (100 g) to obtain a binder-containing dispersion (200 g). According to the same method of Example 8, the wet-ground dispersion was spray-dried to obtain a powder, which was then re-dispersed in distilled water. As a result of measuring the particle size, the average particle size of revaprazan in the re-dispersion obtained from the spray-dried powder was 277.3 ± 4.0 nm; and D90% was less than 459 nm. From the results, it can be seen that the process for spray-drying a binder-containing dispersion does not give rise to any substantial changes in the particle size of revaprazan in the resulting powder.

Example 19. Preparation of granules and evaluation thereof

Eudragit E (6 g), sucrose fatty acid ester (Roto Ester L 1695, Mitsubishi, Japan) (3 g), 1N HCl (20 g), and revaprazan hydrochloride (30 g) were dissolved or dispersed in distilled water (241 g) using a mechanical stirrer. Hydroxypropyl cellulose (3 g) as a binder was dissolved in the dispersion. Zirconia beads having an average particle size of 0.3 mm were added to the resulting binder-containing dispersion, which was then wet-ground at room temperature (about 25 ℃) and at 2450 rpm for 3 hours using Netzch Mill (Netzsch Inc). While fluidizing a mixture of microcrystalline cellulose (78 g) and crospovidone (3.6 g) in a fluid bed granulator (Mini Glatt, Glatt), the wet-ground dispersion (200 g) was sprayed into the granulator to obtain spray-dried granules. Conditions for the spray-drying are the same as in Example 17.

According to the same method of Example 1, the spray-dried powder (0.09 g) was re-dispersed in distilled water (10 ml) and then the particle size was measured in the resulting re-suspension. As a result thereof, the average particle size of revaprazan in the re-dispersion obtained from the spray-dried powder was 255.1 ± 6.0 nm; and D90% was about 459 nm. From the results, it can be seen that the process for spray-drying a binder-containing dispersion does not give rise to any substantial changes in the particle size of revaprazan in the resulting powder.

Example 20. Preparation of tablets

The granules obtained in Example 17 (22.6 g), microcrystalline cellulose (1.32 g), and sodium starch glycolate (0.6 g), crospovidone (0.6 g), Aerosil (0.6 g), and magnesium stearate (0.28 g) were mixed. The resulting mixture was compressed with a single-punch tablet-press machine to obtain tablets containing revaprazan-nanoparticles.

Examples 21 to 23. Preparation of tablets

Tablets containing revaprazan-nanoparticles were prepared by using the same procedures of Example 20, according to the components and amounts shown in Table 3. The amounts of the table 3 refer to the amounts (in mg) per 1 tablet.

Table 3

	Example 21	Example 22	Example 23
Granules of Example17	283	-	-
Granules of Example19	-	566	283
Microcrystalline cellulose	85	33	85
Polyplasdone-XL 10R	12	15	-
Sodium starch glycolate	12	15	-
Kollidon CL	-	-	24
Aerosil	4	15	4
magnesium stearate	4	7	4
Total	400	651	400

Experimental Example 1. Solubility test

The solubilities of revaprazan hydrochloride, the nanoparticle-containing granules prepared in Examples 17 and 19, and the powder prepared in Comparative Examples 1 (2) and 3 were measured in a pH 1.2 solution. Each 1 g of test samples containing revaprazan was added to each 50 ml of the pH 1.2 solution, and vigorously stirred with a magnetic stirrer in a 25℃ water bath for 2 hours. Samples were taken from the resultant solutions at 10, 30, 60, and 120 minutes and filtered with a 0.1 ㎛ syringe filter. Each filtrate was diluted with methanol and then the concentration of revaprazan was measured using UV. The results are presented in FIG. 2 and Table 4 below.

Table 4

	Solubility at 2 hours
Revaprazan hydrochloride	15.9 ㎍/ml
Granules of Example 17	956.6 ㎍/ml
Granules of Example 19	2080.7 ㎍/ml
Powder of Comparative Example 1 (2)	415.2 ㎍/ml
Powder of Comparative Example 3	282.5 ㎍/ml

As shown in FIG. 2 and Table 4, the granules containing revaprazan-nanoparticles of the present invention showed remarkably increased solubility. In particular, the granules containing revaprazan-nanoparticles of the present invention showed about 10 times higher solubility than the powders of Comparative Examples 1 (2) and 3.

Experimental Example 2. Adhesiveness and agglutination test

The compressibilities of revaprazan hydrochloride, the powder prepared in Example 8, and the nanoparticle-containing granules prepared in Examples 17 and 19 were evaluated to determine flowabilities thereof. The results are presented in Table 5 below.

Table 5

	Compressibility (%)^*	Flowability
Revaprazan hydrochloride	42.5%	Very poor
Powder of Example 8	21.5%	Good
Granules of Example 17	19.4%	Excellent
Granules of Example 19	20.1%	Good

* Compressibility (%) = (Bulk density -　Tap density ) / Bulk density X 100

As shown in Table 5, the revaprazan hydrochloride powder with very strong adhesiveness and agglutination exhibited 40% or more compressibility. Thus, it can be seen that revaprazan hydrochloride has very poor flowability. On the other hand, the nanoparticle-containing powder and granules exhibited improved flowability and increased compressibility.

Experimental Example 3: Dissolution test of nanoparticle-containing tablet

The dissolution test of the tablet prepared in Example 20 and the commercially marketed formulation [i.e., the tablet of Revanex^TM 200 mg (Yuhan Corporation)] were performed according to the 'Dissolution Test 2 (Paddle Method)' of the Korean Pharmacopeia. 900 ml of a first solution (pH 1.2) was used as a dissolution medium and the dissolution test was performed at 37 ± 0.5 ℃ and at the paddle rotation rate of 50 rpm. A 4 ml aliquot was taken from the dissolution medium at the time of 5, 10, 15, 30, 45, 60, and 120 minutes, respectively. Each aliquot was filtered with a 0.2 ㎛ syringe filter. The resulting filtrate was diluted with methanol and then analyzed with UV. The results are presented in FIG. 3.

As shown in FIG. 3, the tablet containing revaprazan-nanoparticles of the present invention exhibited remarkably higher dissolution rate than the tablet of Revanex^TM 200 mg. The tablet prepared in Example 20 showed about more than 90% of dissolution for the initial 15 minutes, while the tablet of Revanex^TM 200 mg showed only less than 30% of dissolution even after 120 minutes. These results mean that the formulation of the present invention increase both dissolution rate and solubility of revaprazan. And also, these results suggest that the tablet containing revaprazan-nanoparticles of the present invention exhibit higher bioavailability. That is, according to Han, K.S. et al.'s report (Han, K.S., Kim, Y.G., Yoo, J.K., Lee, J.W., and Lee, M.G., 1998. Pharmacokinetics of a new reversible proton pump inhibitor, YH1885, after intraveneous and oral administrations to rats and dogs: hepatic first-pass effect in rats. Biopharm. Drug Dispos., 19, 493-500) and Li, H. et al.'s report (Li, H., Chung, S.J., Kim, D.C., Kim, H.S., Lee, J.W., and Shim, C.K., 2001. The transport of a reversible proton pump antagonist, 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) pyrimidine hydrochloride (YH1885), across caco-2 cell monolayers. Drug Metab. Dispos., 29, 54-59), the low bioavailability of revaprazan is originated from low solubility and low penetration in the small intestine. Therefore, the tablet containing revaprazan-nanoparticles of the present invention exhibits remarkably high initial dissolution rate (i.e., dissolution rate for initial 15 minutes), which results in high effective concentration at absorption sites of the small intestine, thereby being able to expect high bioavailability.

Experimental Example 4: Evaluation of bioavailability

Sprague-Dawley rats (body weight: 200 to 230 g) fasted for 12 hours were divided into 3 groups, each group having 3 rats (i.e. n=3). We evaluate bioavailability of the revaprazan-containing nanoparticles according to the present invention (the spray-dried powder prepared in Example 8). For comparison, we also performed bioavailability test of the wet-ground dispersion before the spray-drying process.

The rats of Group 1 were administered with a dispersion of revaprazan hydrochloride in a 0.5% solution of methyl cellulose (MC) in a dose of 4 mg/kg. The rats of Group 2 were administered with the wet-ground dispersion prepared in Example 8 in a dose of 4 mg/kg. The rats of Group 3 were administered with a re-dispersion of the spray-dried granules prepared in Example 8 in water, in a dose of 4 mg/kg. The administration was carried out using an oral zonde. About 0.3 ml of blood was collected using a heparin-treated injector, at the time of 0.25, 0.5, 1, 1.5, 2, 3, 5, 7 hours after the administration.　

The collected blood was centrifuged at a rotation speed of 3,000 rpm for 5 minutes, and then the separated serum (100 ㎕) was mixed with 200 ㎕ of an internal standard solution (500 ng/ml of oxybutynin in acetonitrile). The mixture was centrifuged at 13,000 rpm for 10 minutes. The supernatant (150 ㎕) was diluted with 350 ㎕ of a mobile phase and then analyzed with LC/MS/MS under the following conditions. The blood concentration profiles are shown in FIG. 4; and the pharmacokinetic parameters are presented in Table 6 below.

- Detector: Agilent 610 mass spectrometer (Agilent, USA)

- Column: Zorbax C18 (2.1x50 mm, 1.9 ㎛)

- Mobile phase: 10 mM ammonium formate (pH 7.4):acetonitrile = 15:85 (v/v)

- Flow rate: 0.3 ml/min

- Injection volume: 2 ㎕

- MS/MS condition

MRM mode: revaprazan (m/z 363.1 245.1) oxybutynin (m/z 358.2 142.1)

Table 6

	Group 1(0.5% Dispersion)	Group 2(Dispersion of Example 8)	Group 3(Powder of Example 8)
AUC_0-7hr(ng·hr/ml)	347.1±33.0	669.2±107.6	648.1±56.7
Cmax (ng/ml)	113.2±35.7	239.6±71.9	207.4±21.8
Tmax (hr)	0.8±0.3	1.3±0.9	0.8±0.2

As shown in FIG. 4 and Table 6, the wet-ground dispersion and the nanoparticle-containing powder of the present invention exhibited respectively about 2.1 and 1.8 times higher of Cmax and about 1.9 and 1.9 times higher of AUC_0-7hr than the dispersion of revaprazan hydrochloride in a 0.5% solution of methyl cellulose. From these results, it can be seen that the nanoparticles obtained according to the present invention remarkably increase the bioavailability of revaprazan.

Claims

A pharmaceutical composition for oral administration comprising revaprazan-containing nanoparticles having an average particle size of 1000 nm or less, wherein the revaprazan-containing nanoparticles comprise (i) revaprazan or its pharmaceutically acceptable salt; (ii) a polymer selected from the group consisting of a copolymer of butyl methacrylate, (2-dimethylaminoethyl)methacrylate, and methyl methacrylate, polyvinylacetal diethylamino acetate, and a mixture thereof; and (iii) an organic or inorganic acid.
The pharmaceutical composition for oral administration according to claim 1, wherein the polymer is present in an amount ranging from 5 to 50 parts by weight, based on 100 parts by weight of revaprazan or its pharmaceutically acceptable salt.
The pharmaceutical composition for oral administration according to claim 1, wherein the organic or inorganic acid is one or more selected from the group consisting of citric acid, oleic acid, formic acid, succinic acid, fumaric acid, acetic acid, phosphoric acid, sulfuric acid, and hydrochloric acid.
The pharmaceutical composition for oral administration according to claim 1, wherein the organic or inorganic acid is present in an amount ranging from 10 to 250 parts by weight, based on 100 parts by weight of revaprazan or its pharmaceutically acceptable salt.
The pharmaceutical composition for oral administration according to claim 1, wherein the revaprazan-containing nanoparticles further comprise one or more surfactants selected from the group consisting of sucrose fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene glycolated natural or hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyethylene glycol, polyoxyethylene stearate, polyoxyethylene-polyoxypropylene copolymer, a mixture of sucrose stearate and sucrose distearate, pegylated phospholipid, pegylated cholesterol, pegylated vitamin A, and alpha-tocopheryl polyethylene glycol succinate.
The pharmaceutical composition for oral administration according to claim 5, wherein the surfactant is present in an amount ranging from 1 to 25 parts by weight, based on 100 parts by weight of revaprazan or its pharmaceutically acceptable salt.
The pharmaceutical composition for oral administration according to any one of claims 1 to 6, wherein the revaprazan-containing nanoparticles further comprise one or more binders selected from the group consisting of carrageenan, gelatin, agar, starch, casein, cyclodextrin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, alginic acid, and sodium alginate.
A process for preparing a pharmaceutical composition for oral administration in a granular or powder form comprising revaprazan-containing nanoparticles having an average particle size of 1000 nm or less, the process comprising

(a) dispersing (i) revaprazan or its pharmaceutically acceptable salt; (ii) a polymer selected from the group consisting of a copolymer of butyl methacrylate, (2-dimethylaminoethyl)methacrylate, and methyl methacrylate, polyvinylacetal diethylamino acetate, and a mixture thereof; (iii) an organic or inorganic acid; and optionally (iv) a surfactant in water,

(b) wet-grinding the dispersion obtained in the step (a); or a dispersion obtained by dissolving a pharmaceutically acceptable binder in the dispersion obtained in the step (a), and

(c) drying the wet-ground dispersion obtained in the step (b), optionally along with a pharmaceutically acceptable binder, diluent, disintegrating agent, or a mixture thereof.
The process according to claim 8, wherein the wet-grinding is carried out using a dispersion mill, a high speed stirrer, or a high pressure homogenizer.
The process according to claim 9, wherein the wet-grinding is carried out using a dispersion mill selected from the group consisting of a ball mill, a vibrating mill, and a bead mill.
The process according to claim 8, wherein the drying in the step (c) is carried out by spray-drying the wet-ground dispersion obtained in the step (b); or a dispersion obtained by dissolving a binder in the wet-ground dispersion obtained in the step (b), in a spray-drier or a fluid bed granulator.
The process according to claim 8, wherein the drying in the step (c) is carried out by spray-drying the wet-ground dispersion obtained in the step (b); or a dispersion obtained by dissolving a binder in the wet-ground dispersion obtained in the step (b), while fluidizing a pharmaceutically acceptable diluent, disintegrating agent, or a mixture thereof in a fluid bed granulator.
The process according to claim 8, wherein the binder is one or more selected from the group consisting of carrageenan, gelatin, agar, starch, casein, cyclodextrin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, alginic acid, and sodium alginate.
A process for preparing a pharmaceutical composition for oral administration in a tablet form which comprises compressing the granules or powder obtained by the process according to any one of claims 8 to 13, and a pharmaceutically acceptable excipient.
A process for preparing a pharmaceutical composition for oral administration in a capsular form which comprises filing the granules or powder obtained by the process according to any one of claims 8 to 13, and a pharmaceutically acceptable excipient in a capsule.