KR102274448B1 - A controlled release pharmaceutical composition in a monolithic matrix tablet form comprising rebamipide and a process for preparing the same - Google Patents

Abstract

The present invention as an active ingredient rebamipide; And it provides a controlled-release pharmaceutical composition in the form of a single matrix tablet for oral administration twice a day containing a combination of a water-soluble saccharide and hypromellose as a release-controlling agent, and a method for preparing the same. The controlled-release pharmaceutical composition of the present invention can be easily prepared through a commonly used tablet manufacturing process, and thus can be easily applied in production. In addition, the controlled-release pharmaceutical composition of the present invention can be formulated to have a size suitable for taking even by elderly patients, thereby increasing patient compliance with the drug.

Description

A controlled release pharmaceutical composition in a monolithic matrix tablet form comprising rebamipide and a process for preparing the same

The present invention relates to a controlled-release pharmaceutical composition comprising rebamipide as an active ingredient and a method for preparing the same. More specifically, rebamipide as an active ingredient; And it relates to a controlled-release pharmaceutical composition in the form of a single matrix tablet for oral administration twice a day, comprising a combination of a water-soluble saccharide and hypromellose as a release-controlling agent, and a method for preparing the same.

Rebamipide is an amino acid derivative of 2-(1H)-quinolinone, and has the structure of Formula 1 below. Rebamipide is used for the protection of mucous membranes, the healing of gastroduodenal ulcers and the treatment of gastritis. Rebamipide works by enhancing mucosal defense, scavenging free radicals, and transiently activating the gene encoding cyclooxygenase-2.

<Formula 1>

It is known that rebamipide is mainly absorbed in the upper small intestine when administered orally, its absorption is limited in other digestive organs, and its therapeutic effect is also limited locally. In addition, since rebamipide has low solubility in the upper small intestine (ie, an environment of about pH 6.8), it is necessary to administer the drug several times. Thus, commercially marketed rebamipide-containing agents in no-Costa positive ^TM 100 mg ^(TM Mucosta Tab 100 mg, Korea Otsuka Pharmaceutical) is administered 100 mg orally once three times a day.

In order to increase the convenience and compliance of patients with rebamipide-containing formulations such as Mucosta ^{TM 100 mg, various studies on sustained-release formulations have been conducted.} For example, in consideration of the properties of rebamipide absorbed in the upper small intestine, various sustained-release formulations using a gastric retention drug delivery system have been reported. Korean Patent Registration No. 10-2112701 discloses a gastroretentive controlled release formulation comprising two or more sections separated from each other, and Korean Patent Registration No. 10-1277021 discloses a sustained release portion and a portion formed on the sustained release portion. A gastroretentive controlled release formulation having the form of a double layer formulation including an immediate release portion has been disclosed. However, since these preparations have two or more sections or have the form of a double-layer preparation, the manufacturing process is complicated, so there is a limit to application in actual production sites. In addition, when manufactured in the form of a double-layer tablet, etc., there is a problem in that the size of the tablet increases, making it difficult to administer orally to elderly patients.

In general, as the number of doses of a drug decreases, the patient's convenience increases, and thus the patient's adherence to the drug also increases. On the other hand, Eisen et al., in a paper on the effect of patient compliance according to the frequency of drug intake, found that the twice-daily dosage group (75%) had a higher adherence rate (75%) compared to the three-times-a-day group (59%). It has been reported (Eisen et al., The effect of prescribed daily dose frequency on patient medication compliance, Arch Intern Med , 1990 Sep;150(9):1881-4). However, a pharmaceutical composition suitable for taking rebamipide twice a day has not yet been reported. Moreover, to avoid the disadvantages of formulations having a plurality of compartments that are difficult to apply at the production site due to the complicated manufacturing process (for example, Korean Patent Registration Nos. 10-2112701, 10-1277021, etc.) For this, it is required to formulate in the form of a monolithic matrix. That is, it is required to formulate rebamipide in the form of a monolithic matrix suitable for administration twice a day through a commonly used formulation process, for example, a conventional tablet manufacturing process. However, until now, a formulation in a single matrix form suitable for twice daily administration containing rebamipide has not been developed, and a single matrix form suitable for twice daily administration having a size suitable for administration by elderly patients as well. formulations have not yet been developed.

The present inventors have found that a formulation in a monolithic matrix form suitable for twice a day administration containing rebamipide, can be easily prepared through a commonly used tablet manufacturing process, and can also be taken by elderly patients. Various studies were conducted to develop a formulation having a size suitable for The present inventors have found that when formulated in a single matrix form for twice a day administration through a commonly used tablet manufacturing process using a combination of specific ingredients as a release controlling agent, that is, a combination of water-soluble saccharide and hypromellose, conventional sustained-release It has been found that it can be easily applied at the production site compared to sexual formulations (eg, bilayer tablets, etc.), and that it can be formulated to have a size suitable for administration by elderly patients.

Accordingly, the present invention relates to rebamipide as an active ingredient; An object of the present invention is to provide a controlled-release pharmaceutical composition in the form of a single matrix tablet for oral administration twice a day, comprising a combination of a water-soluble saccharide and hypromellose as a release controlling agent.

Another object of the present invention is to provide a method for producing a controlled-release pharmaceutical composition in the form of a single matrix tablet for oral administration twice a day.

According to one aspect of the present invention, rebamipide as an active ingredient; And as a release controlling agent, a release-controlled pharmaceutical composition in the form of a single matrix tablet for oral administration twice a day comprising a combination of water-soluble saccharide and hypromellose as a release controlling agent, the disintegration test method according to the dissolution test method 2 of the Korean Pharmacopoeia. In the dissolution test performed in two solutions, the cumulative dissolution rate of rebamipide for 2 hours after the start of the test was 35 wt% or more and less than 55 wt%; A pharmaceutical composition is provided in which the cumulative dissolution rate of rebamipide for 8 hours after the start of the test is 85% or more.

According to another aspect of the present invention, the method comprising: (a) preparing wet granules using a binding solution of a mixture of rebamipide, water-soluble saccharides and hypromellose, followed by drying to prepare granules; And (b) mixing the granules obtained in step (a) with a lubricant, and then tabletting, there is provided a method for producing a controlled-release pharmaceutical composition in the form of a single matrix tablet for oral administration twice a day.

The pharmaceutical composition according to the present invention can be formulated in a single matrix form for twice a day administration through a commonly used tablet manufacturing process by using a combination of specific ingredients as a release controlling agent, that is, a combination of water-soluble saccharide and hypromellose. can That is, since the pharmaceutical composition of the present invention has a single matrix form for administration twice a day, it can be easily prepared through a generally used tablet manufacturing process, so that it can be easily applied at the production site, as well as the upper part of the small intestine. ^{It is possible to effectively secure therapeutic equivalence with a formulation administered three times a day (ie, Mucosta TM} 100 mg, Otsuka Pharmaceutical Korea)) by simultaneously exhibiting immediate-release and sustained-release dissolution patterns in the environment. In addition, the controlled-release pharmaceutical composition of the present invention can be formulated to have a size suitable for administration even by elderly patients (eg, a diameter of about 8 to 9 mm), thereby increasing patient compliance with the drug.

1 shows the blood concentration profile obtained by a single oral administration of the formulation (tablet of Formulation Example 1-6) and the control formulation ( ^{Mucosta TM} 100 mg (Otsuka Pharmaceutical Korea)) of the present invention.

The present invention as an active ingredient rebamipide; And it provides a release-controlled pharmaceutical composition in the form of a single matrix tablet for oral administration twice a day, comprising a combination of a water-soluble saccharide and hypromellose as a release controlling agent.

The controlled-release pharmaceutical composition of the present invention contains rebamipide as an active ingredient, and rebamipide may be used in an amount suitable for oral administration twice a day. For example, the controlled-release pharmaceutical composition of the present invention may contain 100 to 200 mg, preferably about 150 mg, of rebamipide per unit tablet as an active ingredient.

The controlled-release pharmaceutical composition of the present invention is a pharmaceutical composition for oral administration twice a day, and has immediate and sustained release in the upper small intestine environment (that is, the environment of the second solution of the Korean Pharmacopoeia disintegration test method), which is the absorption site of rebamipide. By simultaneously showing the sexual dissolution pattern, it shows an immediate therapeutic effect upon administration and a continuous therapeutic effect according to the continuous release of the active ingredient. That is, the release-controlled pharmaceutical composition of the present invention has a cumulative dissolution rate of rebamipide for 2 hours after the start of the test in the dissolution test performed in the second solution of the disintegration test method according to the second method of the dissolution test method of the Korean Pharmacopoeia. greater than or equal to 55% by weight; It shows a dissolution pattern in which the cumulative dissolution rate of rebamipide for 8 hours after the start of the test is 85% or more. In one embodiment, the release-controlled pharmaceutical composition of the present invention is a dissolution test performed in the second solution of the disintegration test method according to the second method of the dissolution test method of the Korean Pharmacopoeia, the accumulation of rebamipide for 1 hour after the start of the test the dissolution rate is less than 35% by weight; The cumulative dissolution rate of rebamipide for 2 hours after the start of the test is 35% by weight or more and less than 55% by weight; The cumulative dissolution rate of rebamipide for 4 hours after the start of the test is 65% by weight or more and less than 80% by weight; It shows a dissolution pattern of 85% or more of the cumulative dissolution rate of rebamipide for 8 hours after the start of the test.

The controlled-release pharmaceutical composition of the present invention contains a combination of a specific release-controlling agent, that is, a water-soluble saccharide and hypromellose, so as to exhibit a dissolution pattern suitable for oral administration twice a day.

Hypromellose is also referred to as hydroxypropyl methylcellulose (HPMC), and as a substituent, a methoxy group (-OCH ₃ ), a hydroxypropoxy group (-OCH ₂ CH(CH ₃ )OH) or have hydrogen. Usually, numbers are attached to indicate the ratio of substituents, for example, in 'Hypromellose 2208', the first two numbers mean the percentage of methoxy groups (about ±5%) and the last two digits are hydroxypropoxyl. Percentage of time (about ±5%). In addition, hypromellose has various viscosities and exhibits different properties in the formulation depending on the viscosity of hypromellose. The viscosity of hypromellose usually means the viscosity when measured at 20° C. with a 2 wt% aqueous solution. The present inventors found that the viscosity of hypromellose had a significant effect on the initial dissolution rate of rebamipide. That is, the present inventors found that, when low-viscosity hypromellose is used, the initial dissolution rate of rebamipide (eg, the cumulative dissolution of rebamipide for 2 hours or 4 hours after the start of the test) can be effectively increased. found that Accordingly, the hypromellose is preferably low-viscosity hypromellose having a viscosity of 75 to 140 mPa·s, and particularly preferably low-viscosity hypromellose having a viscosity of about 100 mPa·s. The hypromellose may be preferably present in an amount of 5 to 23 parts by weight based on 100 parts by weight of rebamipide, and more preferably in an amount of 5 to 10 parts by weight based on 100 parts by weight of rebamipide. .

The water-soluble sugar includes both water-soluble sugars or water-soluble sugar alcohols, and for example, may be selected from the group consisting of lactose, mannitol, sorbitol, and destrin, and preferably lactose [anhydrous lactose or lactose hydrate. (including, for example, lactose monohydrate), mannitol, sorbitol, and mixtures thereof. It was found by the present invention that the water-soluble saccharide not only serves as an excipient in the single matrix tablet of the present invention, but also serves as a release controlling agent for rebamipide. Accordingly, in the present specification, 'including/using a water-soluble saccharide as a release-controlling agent' should be understood to include 'including/using a water-soluble saccharide as an excipient and a release-controlling agent'. The water-soluble saccharide may be preferably present in an amount of 12 to 33 parts by weight based on 100 parts by weight of rebamipide, and more preferably in an amount of 25 to 30 parts by weight based on 100 parts by weight of rebamipide.

The weight ratio of the water-soluble saccharide to hypromellose may be preferably in the range of 2 to 5:1, and more preferably in the range of 4 to 4.5:1.

The controlled-release pharmaceutical composition of the present invention may include additives commonly used in the pharmaceutical field. For example, the controlled-release pharmaceutical composition of the present invention may contain hydroxypropylcellulose, povidone, and Eudragit RS PO [ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride 1:2: At least one binder selected from the group consisting of a copolymer (Poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate) 1: 2: 0.1] in a molar ratio of 0.1; and colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, stearate It may further include a lubricant selected from the group consisting of acid and talc The amount of the binder and lubricant used is not particularly limited, and may be used in an amount commonly used in the pharmaceutical field.

In one embodiment, the controlled-release pharmaceutical composition of the present invention comprises 150 mg of rebamipide; 35-45 mg of lactose, mannitol or sorbitol; about 10 mg of hypromellose; about 6.5 mg of binder; and about 7.3 mg of a lubricant. In another embodiment, the controlled-release pharmaceutical composition of the present invention comprises 150 mg of rebamipide; lactose 42 mg; about 10 mg of low-viscosity hypromellose having a viscosity of 100 mPa·s; about 6.5 mg of binder; and about 7.3 mg of a lubricant.

The present invention includes a method for preparing the controlled-release pharmaceutical composition of the present invention as described above. The controlled-release pharmaceutical composition of the present invention can be prepared through a tablet manufacturing process commonly used in the pharmaceutical field.

For example, the present invention comprises the steps of (a) preparing wet granules using a binding solution of a mixture of rebamipide, water-soluble saccharides and hypromellose, followed by drying to prepare granules; and (b) mixing the granules obtained in step (a) with a lubricant, and then tableting, providing a method for producing a controlled-release pharmaceutical composition in the form of a single matrix tablet for oral administration twice a day.

In the preparation method of the present invention comprising steps (a) and (b), rebamipide, water-soluble saccharide, and hypromellose are the same as those mentioned in relation to the controlled-release pharmaceutical composition of the present invention.

The binding solution used in step (a) contains hydroxypropylcellulose, povidone, and Eudragit RS PO [ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride in a 1: 2: 0.1 molar ratio. of a copolymer (Poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate) 1: 2: 0.1] obtained by dissolving one or more binders selected from the group consisting of ethanol or water. The amount of the binder used is particularly It is not limited, and it can be used in an amount commonly used in the pharmaceutical field.In the preparation of wet granules in step (a), the mixture (a mixture of rebamipide, water-soluble saccharide and hypromellose) is usually used as a binding solution. According to a conventional method used in the pharmaceutical field, the drying of step (a), that is, the drying of the obtained wet granules, is, for example, about 50 to It may be carried out by drying at 70° C. for 2 to 5 hours, but is not limited thereto. If necessary, a process of sieving the obtained dried granules to have a uniform size may be additionally performed.

The lubricant used in step (b) may be selected from the group consisting of colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, stearic acid, and talc. The amount of the lubricant used is not particularly limited, and may be used in an amount commonly used in the pharmaceutical field. The mixing and tableting of step (b) may be performed according to a method commonly used in the pharmaceutical field. For example, in consideration of the drug compliance of the elderly patient, the tableting may be performed to have a diameter in the range of about 8 to 9 mm.

Hereinafter, the present invention will be described in more detail through examples. However, these examples are for illustrating the present invention, and the scope of the present invention is not limited to these examples.

Example 1 Preparation and Evaluation of Single Matrix Tablets

(1) Preparation of single matrix tablets

A single matrix tablet containing rebamipide was prepared according to the ingredients and contents shown in Table 1 below. The contents shown in Table 1 represent the weight (mg) per unit tablet. Specifically, rebamipide and a release controlling agent (hypromellose 4000 mPa·s, hypromellose 100 mPa·s, microcrystalline cellulose, and/or lactose were uniformly mixed. Hydroxypropyl cellulose was dissolved in ethanol to Prepare binding solution.The mixture is kneaded using the binding solution and using a high shear mixer (Sejong), and then wet granules are prepared.After drying the obtained wet granules, a lubricant (colloidal After uniformly mixed with silicon dioxide and magnesium stearate), it was compressed to have a diameter of about 9 mm with a tablet press (Sejong) to prepare a single matrix tablet.

ingredient Formulation example (mg) 1-1 1-2 1-3 1-4 1-5 1-6 active ingredient rebamipid 150.0 150.0 150.0 150.0 150.0 150.0 release control agent Hypromellose 4000 mPa s 30.0 30.0 - - - - Hypromellose 100 mPa s - - 30.0 10.0 30.0 10.0 Microcrystalline Cellulose 22.0 - 22.0 42.0 - - lactose - 22.0 - - 22.0 42.0 binder Hydroxypropyl Cellulose 6.5 6.5 6.5 6.5 6.5 6.5 lubricant colloidal silicon dioxide 3.0 3.0 3.0 3.0 3.0 3.0 magnesium stearate 4.3 4.3 4.3 4.3 4.3 4.3 gross weight 215.8 215.8 215.8 215.8 215.8 215.8

(2) Evaluation of single matrix tablets

Rebamipide is absorbed mainly in the upper small intestine, and the Tmax is known to be 1 to 2 hours. Therefore, a dissolution test was performed while stirring at 75 rpm according to the second method of the dissolution test method of the Korean Pharmacopoeia using a dissolution medium of pH 6.8 as the dissolution medium, that is, the second solution of the disintegration test method, and a single matrix tablet was evaluated. . While performing a dissolution test in the second solution of the disintegration test method according to the Korean Pharmacopoeia dissolution test method 2, the dissolution solution was taken at 1, 2, 4, and 8 hours, and the high-performance liquid chromatography (HPLC) was performed under the following conditions. The dissolution rate of mipid was measured.

<HPLC conditions>

- Detector: UV absorbance spectrometer (measurement wavelength: 254 nm)

- Column: 5μm C18-L, 4.6X150 mm or similar column

- Mobile phase: prepared by mixing water, acetonitrile, and acetic acid in a weight ratio of 70:30:1

- Flow rate: 1.5 mL/min

- Temperature: about 25℃

The results of the dissolution test performed as described above are shown in Table 2 below.

Dissolution rate (wt%) 1-1 1-2 1-3 1-4 1-5 1-6 1 hours 5.25 15.8 14.27 14.09 12.02 27.81 2 hours 10.43 33.88 31.95 28.96 27.36 47.45 4 hours 21.92 64.69 62.15 58.61 27.36 72.67 8 hours 47.9 103.84 99.69 97.64 94.01 98.80

As can be seen in Table 2, as a result of confirming the dissolution pattern for tablets prepared using medium-strength hypromellose and different excipients, the tablet of Formulation Example 1-1 showed complete drug release within 8 hours. and the initial drug release rate was also low. In contrast, the tablet of Formulation Example 1-2 improved the initial drug release rate compared to Formulation Example 1-1, and the final dissolution rate was also increased. However, from the above results, it can be seen that the initial dissolution pattern is changed depending on the type of excipient contained together with the sustained-release agent, and the overall dissolution pattern is low when medium-strength hypromellose is used.

From the results of Formulation Examples 1-1 and 1-2, dissolution patterns for tablets prepared by changing the type and content of excipients using low-viscosity hypromellose, that is, tablets of Formulation Examples 1-3 to 1-6 was evaluated. As a result of evaluating the dissolution patterns of the tablets of Formulation Examples 1-3 and 1-4, there was no significant difference in the initial drug release rate according to the content change of microcrystalline cellulose and low-viscosity hypromellose. However, as can be seen from the dissolution patterns of the tablets of Formulation Examples 1-5 and 1-6, when the lactose content is high and the hypromellose content is low, that is, the weight ratio of lactose to hypromellose is about 4.2. : When it was 1, the initial drug release rate was increased, showed a sustained release drug release form, and complete drug release was achieved within 12 hours. From these results, it can be confirmed that lactose not only serves as an excipient in the single matrix tablet of the present invention, but also plays a role as a release controlling agent of rebamipide. Considering that Tmax is short, it can be seen that Formulation Examples 1-6 in which rapid initial drug release and sustained release are simultaneously performed are most suitable.

Example 2: Preparation of single matrix tablets

(1) Preparation of single matrix tablets

From the results of Example 1, a single matrix tablet containing rebamipide was prepared according to the ingredients and contents shown in Table 3 below. The contents shown in Table 3 represent the weight (mg) per unit tablet. Specifically, rebamipide, hypromellose 100 mPa·s, and lactose/mannitol/or sorbitol were uniformly mixed. A binding solution was prepared by dissolving hydroxypropyl cellulose in ethanol. The mixture was kneaded using the binder solution using a high shear mixer (Sejong), and then wet granules were prepared. The obtained wet granules were dried, uniformly mixed with a lubricant (colloidal silicon dioxide and magnesium stearate), and then compressed to have a diameter of about 9 mm with a tablet press (Sejong) to prepare a single matrix tablet.

ingredient Formulation example (mg) 2-1 2-2 2-3 2-4 active ingredient rebamipid 150.0 150.0 150.0 150.0 release control agent Hypromellose 100 mPa s 10.0 10.0 10.0 10.0 lactose 32.0 22.0 - - mannitol - - 42.0 - sorbitol - - - 42.0 binder Hydroxypropyl Cellulose 6.5 6.5 6.5 6.5 lubricant colloidal silicon dioxide 3.0 3.0 3.0 3.0 magnesium stearate 4.3 4.3 4.3 4.3 gross weight 205.8 195.8 215.8 215.8

(2) Evaluation of single matrix tablets

In the same manner as in Example 1 (2), a dissolution test was performed on the tablets of Examples 2-1 to 2-4, and the results are shown in Table 4 below.

Dissolution rate (wt%) 2-1 2-2 2-3 2-4 1 hours 24.21 21.38 26.26 25.98 2 hours 42.45 39.77 49.22 47.14 4 hours 69.26 68.41 72.18 71.23 8 hours 93.80 90.52 94.21 96.27

As can be seen in Table 4, the tablets of Examples 2-1 and 2-2 were comparatively evaluated for dissolution patterns by reducing the weight of lactose in the tablets of Examples 1-6. The weight ratio of lactose to hypromellose was 2.2 to 3.2: 1, and the dissolution pattern was similar even when the lactose content was decreased. The tablets of Examples 2-3 and 2-4 used mannitol and sorbitol as water-soluble sugars, respectively, and as can be seen from the results in Table 4, the initial drug release pattern and the sustained release drug release pattern of Example 1 using lactose It appeared similar to the purification of -6. Therefore, it can be seen that the weight ratio of the water-soluble saccharide and hypromellose is preferably in the range of 2 to 5:1.

Example 3: Pharmacokinetic test using beagle dogs

Pharmacokinetic studies using beagle dogs on the tablets prepared in Formulation Examples 1-6 of Example 1 and Mucosta Tablet ^TM 100 mg (Otsuka Pharmaceutical Korea) were performed as follows.

(1) Test animals

Male beagle dogs were selected as test animals, separated into 2 groups, and 4 beagle dogs were tested in each group. Animals used in the test were fasted for 12 hours before drug administration, and fed from 4 hours after administration.

(2) Experimental method

^{After oral administration of 100 mg of Mucosta TM} 100 mg (Otsuka Pharmaceutical Korea) and the tablets prepared in Formulation Examples 1-6 of Example 1 to Beagle dogs in Group 1 and Group 2, respectively, blood was collected and blood rebamipide was collected. was measured.

(3) Test results

The blood concentration profile of each group obtained from the beagle dogs of each group is shown in FIG. 1 , and the pharmacokinetic parameters obtained from FIG. 1 are shown in Table 5 below.

C _max (ng/ml) T _max (h) AUC _Δ (ng hr/ml) AUC _(0-12) (ng hr/ml) 1st Army
(contrast preparation) 284.29±62.39 0.88±0.48 531.01±120.70 514.29±30.66 2nd Army
(Test formulation, formulation example 1-6) 264.39±86.61 1.25±0.65 679.53±261.43 697.31±261.43

As can be seen from the results of Figures 1 and 5, the T _max of the tablet of Formulation Example 1-6 was delayed due to sustained release compared to the control formulation, and the C _max of the tablet of Formulation Example 1-6 and the control formulation had a significant difference. there was no The area under the blood concentration time curve (AUC _(0-12) ) of the tablet of Formulation Example 1-6 was significantly increased compared to that of the control formulation, and thus a lasting effect can be expected.

Claims (28)

rebamipide as an active ingredient; a combination of a water-soluble saccharide and a low-viscosity hypromellose having a viscosity of 75 to 140 mPa·s as a release controlling agent; binder; And as a release-controlled pharmaceutical composition in the form of a single matrix tablet for oral administration twice a day consisting of a lubricant,
The water-soluble saccharide is lactose, mannitol, sorbitol, or a mixture thereof, and the water-soluble saccharide is present in an amount of 12 to 33 parts by weight based on 100 parts by weight of rebamipide,
The hypromellose is present in an amount of 5 to 23 parts by weight based on 100 parts by weight of rebamipide,
The weight ratio of the water-soluble saccharide to hypromellose is in the range of 2 to 5: 1,
The binder is hydroxypropyl cellulose; povidone; and at least one selected from the group consisting of a copolymer of ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride in a molar ratio of 1: 2: 0.1,
The lubricant is selected from the group consisting of colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, stearic acid, and talc,
In the dissolution test performed in the second solution of the disintegration test method according to the Korean Pharmacopoeia dissolution test method 2, the cumulative dissolution rate of rebamipide for 2 hours after the start of the test was 35% by weight or more and less than 55% by weight; A pharmaceutical composition in which the cumulative dissolution rate of rebamipide for 8 hours after the start of the test is 85% or more. The method of claim 1, wherein in the dissolution test performed in the second solution of the disintegration test method according to the second method of the dissolution test method of the Korean Pharmacopoeia, the cumulative dissolution rate of rebamipide for 1 hour after the start of the test is less than 35% by weight; The cumulative dissolution rate of rebamipide for 2 hours after the start of the test is 35% by weight or more and less than 55% by weight; The cumulative dissolution rate of rebamipide for 4 hours after the start of the test is 65% by weight or more and less than 80% by weight; A pharmaceutical composition with a cumulative dissolution rate of 85% or more of rebamipide for 8 hours after the start of the test. delete The pharmaceutical composition according to claim 1, wherein the hypromellose is a low viscosity hypromellose having a viscosity of about 100 mPa·s. delete The pharmaceutical composition according to claim 1, wherein the hypromellose is present in an amount of 5 to 10 parts by weight based on 100 parts by weight of rebamipide. delete delete delete The pharmaceutical composition according to claim 1, wherein the water-soluble saccharide is present in an amount of 25 to 30 parts by weight based on 100 parts by weight of rebamipide. delete The pharmaceutical composition according to claim 1, wherein the weight ratio of the water-soluble saccharide to hypromellose is in the range of 4 to 4.5: 1. delete According to claim 1, Rebamipide 150 mg; 35-45 mg of lactose, mannitol or sorbitol; about 10 mg of hypromellose; about 6.5 mg of binder; and about 7.3 mg of a lubricant. According to claim 1, Rebamipide 150 mg; lactose 42 mg; about 10 mg of low-viscosity hypromellose having a viscosity of 100 mPa·s; about 6.5 mg of binder; and about 7.3 mg of a lubricant. (a) preparing wet granules using a binder solution for a mixture of rebamipide, water-soluble saccharides, and low-viscosity hypromellose having a viscosity of 75 to 140 mPa·s, followed by drying to prepare granules; and (b) mixing the granules obtained in step (a) with a lubricant and then tableting, as a method for producing a controlled-release pharmaceutical composition in the form of a single matrix tablet for oral administration twice a day,
The water-soluble saccharide is lactose, mannitol, sorbitol, or a mixture thereof, and the water-soluble saccharide is used in an amount of 12 to 33 parts by weight based on 100 parts by weight of rebamipide,
The hypromellose is used in an amount of 5 to 23 parts by weight based on 100 parts by weight of rebamipide,
The weight ratio of the water-soluble saccharide to hypromellose is in the range of 2 to 5: 1,
The binder solution is obtained by dissolving at least one binder selected from the group consisting of a copolymer of ethyl acrylate, methyl methacrylate, and trimethylammonioethyl methacrylate chloride in a molar ratio of 1: 2: 0.1 in ethanol or water. ,
wherein the lubricant is selected from the group consisting of colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, stearic acid, and talc. delete 17. The method of claim 16, wherein the hypromellose is a low viscosity hypromellose having a viscosity of about 100 mPa·s. delete The method according to claim 16, wherein the hypromellose is used in an amount of 5 to 10 parts by weight based on 100 parts by weight of rebamipide. delete delete delete The method according to claim 16, wherein the water-soluble saccharide is used in an amount of 25 to 30 parts by weight based on 100 parts by weight of rebamipide. delete The method according to claim 16, wherein the weight ratio of the water-soluble saccharide to hypromellose is in the range of 4 to 4.5: 1. delete delete

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