Sustained-release multi-layer tablet containing rebamipide or a pharmaceutically acceptable salt thereof as an active ingredient and method for manufacturing the same

Abstract

The present invention relates to a sustained-release multilayer tablet comprising rebamipide or a pharmaceutically acceptable salt thereof as an active ingredient and a method for manufacturing the same, wherein the release and absorption of rebamipide or a pharmaceutically acceptable salt thereof into the body is possible for 24 hours with once-daily oral administration, thereby increasing convenience of administration. In addition, after oral administration, the drug is not affected by pH or the amount of gastrointestinal fluid within the gastrointestinal tract, and by increasing the dissolution rate to enable absorption throughout the entire gastrointestinal tract, the drug concentration can be maintained above a certain level for a long period of time.

Description

Technology Field

[0001] The present invention relates to a sustained-release multilayer tablet comprising rebamipide or a pharmaceutically acceptable salt thereof as an active ingredient and a method for manufacturing the same. Background Technology

[0002] Rebamipide is a substance that acts by promoting the production of prostaglandins to expand the mucosa protecting the stomach wall and increase blood flow to the gastric mucosa; it is used for gastric mucosal protection and the treatment of gastric ulcers and gastritis. The above-mentioned rebamipide is contained in Mucosta tablets containing 100 mg. TM Jeong (Mucosta TM It is sold under the brand name Tablets (Otsuka Pharmaceutical) and must be administered orally three times a day.

[0003] The above-mentioned rebamipide is a very poorly soluble drug, and its solubility in an aqueous environment is about 0.0001% (w / v) at pH 3 and about 0.013% (w / v) at pH 7, meaning its solubility is even lower under acidic conditions. Rebamipide has the problem of low solubility in the gastrointestinal environment and low absorption rate in the body after oral administration.

[0004] In addition, the above-mentioned rebamipide has an absorption site located in the upper GI tract, and absorption is limited in other digestive organs and the therapeutic effect is also limited to the local area and has low solubility in the upper GI tract, so oral administration of the drug had to be done several times a day.

[0005] Accordingly, there is a need to develop a once-daily dosage form to improve patient convenience and compliance. Prior art literature

[0006] (Patent Document 0001) KR 10-2012-0075029 A1 The problem to be solved

[0007] The object of the present invention is to provide a sustained-release multilayer tablet comprising rebamipide or a pharmaceutically acceptable salt thereof as an active ingredient and a method for manufacturing the same.

[0008] Another objective of the present invention is to provide a sustained-release multilayer tablet that allows for the continuous release and absorption of rebamipide or its pharmaceutically acceptable salt into the body over a 24-hour period with once-daily oral administration, thereby increasing convenience of administration.

[0009] Another objective of the present invention is to provide a method for manufacturing a sustained-release multilayer tablet that, after oral administration, is not affected by the amount of gastrointestinal fluid in the gastrointestinal tract, increases the dissolution rate to enable absorption throughout the entire gastrointestinal tract, and thereby maintains the concentration of the drug above a certain level for a long period of time. means of solving the problem

[0010] To achieve the above objective, the present invention provides a sustained-release multilayer tablet comprising rebamipide or a pharmaceutically acceptable salt thereof as an active ingredient, comprising a first sustained-release layer; a separation layer; and a second sustained-release layer, wherein the first sustained-release layer, the separation layer, and the second sustained-release layer comprise rebamipide and a pharmaceutically acceptable salt thereof as active ingredients, and the first sustained-release layer and the second sustained-release layer may have a gelation index of 30 to 100 according to Formula 1 below:

[0011] [Equation 1]

[0012]

[0013] Here,

[0014] The above gelation index is obtained by adding the first sustained-release layer or the second sustained-release layer, respectively, to 45 mL of purified water, and measuring the degree of gelation of the sustained-release layer after 30 minutes in a water shaking bath set at 37°C and 25 rpm.

[0015] TS int It is the initial weight of the western layer, and

[0016] TS a is the weight of the western layer that has not been penetrated by moisture.

[0017] The first sustained layer may have a gelation index of 100 according to Formula 1.

[0018] The second sustained layer may have a gelation index of 30 to 70 according to Formula 1.

[0019] The first sustained-release layer and the second sustained-release layer may comprise rebamipide and a pharmaceutically acceptable salt thereof; a sustained-release agent; an excipient; and a lubricant.

[0020] The first sustained-release layer may contain the weight of rebamipide and its pharmaceutically acceptable salt and the total weight of the sustained-release agent and excipients in a weight ratio of 1:0.1 to 1:1.

[0021] The second sustained-release layer may contain the weight of rebamipide and its pharmaceutically acceptable salt and the total weight of the sustained-release agent and excipients in a weight ratio of 1:0.5 to 1:1.5.

[0022] The above-mentioned sustained-release agent may be selected from the group consisting of polyethylene oxide (PEO), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose, carboxymethylcellulose, polyvinyl alcohol, carbomer, microcrystalline cellulose (MCC), lactose, and mixtures thereof.

[0023] The above separation layer may comprise rebamipide and a pharmaceutically acceptable salt thereof; an excipient; a disintegrant; and a lubricant.

[0024] The above sustained-release multilayer tablet enables the release and absorption of rebamipide and its pharmaceutically acceptable salts throughout the gastrointestinal tract with once-daily administration.

[0025] The above separation layer separates the first sustained-release layer and the second sustained-release layer after oral administration, and can allow the initial release and absorption of rebamipide and its pharmaceutically acceptable salt.

[0026] A method for manufacturing a sustained-release multilayer tablet comprising levamipide or a pharmaceutically acceptable salt thereof as an active ingredient according to another embodiment of the present invention may include the steps of: manufacturing a first sustained-release layer granule comprising levamipide or a pharmaceutically acceptable salt thereof; a sustaining agent, an excipient, and a lubricant; manufacturing a separation layer granule comprising levamipide or a pharmaceutically acceptable salt thereof; an excipient; a dissolving agent and a lubricant; manufacturing a second sustained-release layer granule comprising levamipide or a pharmaceutically acceptable salt thereof; a sustaining agent, an excipient, and a lubricant; and compressing the second sustained-release layer granules; the separation layer granules; and the first sustained-release layer granules in the order of the second sustained-release layer; the separation layer; and the first sustained-release layer using a three-layer tablet press.

[0027] The first sustained-release layer may contain the weight of rebamipide and its pharmaceutically acceptable salt and the total weight of the sustained-release agent and excipients in a weight ratio of 1:0.1 to 1:1.

[0028] The second sustained-release layer may contain the weight of rebamipide and its pharmaceutically acceptable salt and the total weight of the sustained-release agent and excipients in a weight ratio of 1:0.5 to 1:1.5. Effects of the invention

[0029] The present invention allows for the continuous release and absorption of rebamipide or its pharmaceutically acceptable salt into the body over a 24-hour period with a single daily dose, thereby increasing convenience of administration.

[0030] In addition, after oral administration, the drug is not affected by pH or the amount of gastrointestinal fluid within the gastrointestinal tract, and by increasing the dissolution rate to enable absorption throughout the entire gastrointestinal tract, the drug concentration can be maintained above a certain level for a long period of time. Brief explanation of the drawing

[0031] Figure 1 is the result of a rebamipide release experiment of a multilayer tablet according to one embodiment of the present invention. Specific details for implementing the invention

[0032] Hereinafter, embodiments of the present invention are described in detail so that those skilled in the art can easily implement the invention. However, the present invention may be embodied in various different forms and is not limited to the embodiments described herein.

[0033] Rebamipide is an amino derivative of 2(1H)quinoline, with the chemical name 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolone-4-yl]propionic acid, and is used for gastric mucosal protection and the treatment of gastric ulcers and gastritis. By promoting the production of prostaglandins (PG), it expands the mucosa protecting the stomach wall and increases blood flow to the gastric mucosa, thereby enhancing the stomach's defense against gastric acid to promote the healing of gastritis or gastric ulcers. Furthermore, by inhibiting the action of enzymes involved in the oxidation or reduction of NADPH or NADH, it [reduces] superoxide (O2 - It not only inhibits the production of ) but also has an indirect antioxidant effect that lowers lipid levels in the cell membrane and inhibits the activity of neutrophils and the expression of adhesion factors.

[0034] The mechanism of action of the above-mentioned rebamipide is to enhance defense factors by promoting the biosynthesis of prostaglandins, and it is the only defense factor enhancer to exhibit antioxidant activity, thereby simultaneously eliminating inflammation caused by Helicobacter pylori; thus, it possesses the two effects of enhancing defense factors and suppressing inflammation.

[0035] Therefore, it is a very effective drug that can significantly lower the recurrence rate and shorten the treatment period in patients with ulcers or gastritis. In experiments using mice in which gastric ulcers were induced by administering acetic acid, it was confirmed that the cure rate improved and both the size of the ulcer and the recurrence rate were reduced by rebamipide.

[0036] However, as previously explained, since rebamipide exhibits low solubility in water-soluble environments and has low biological solubility in the oral cavity, it is mostly prescribed and treated in IV form according to the U.S. Food and Drug Administration (FDA). Rebamipide is soluble in dimethylformamide, but only slightly soluble in methanol or ethanol, and is practically insoluble in ether or water.

[0037] Bioavailability refers to the extent to which a drug is utilized at the target site after administration. In the case of poorly water-soluble drugs, such as the aforementioned rebamipide, this can significantly affect bioavailability (whether administered orally or parenterally). For poorly water-soluble rebamipide—specifically, rebamipide with a water solubility of 10 mg / ml or less—it is difficult to develop administration formulations for parenteral (e.g., injection) administration. Furthermore, in the case of oral administration, it is difficult to achieve an appropriate therapeutic effect because the drug is eliminated and excreted within the gastrointestinal tract before entering systemic circulation.

[0038] Generally, the fewer times a drug is taken, the greater the patient's convenience, and consequently, the higher the patient's medication compliance. Meanwhile, Eisen et al. reported in a study investigating the effect of drug frequency on patient medication compliance that compliance was higher in the group taking the drug twice a day (75%) compared to the group taking it three times a day (59%) (Eisen et al., The effect of prescribed daily dose frequency on patient medication compliance, Arch Intern Med, 1990 Sep;150(9):1881-4).

[0039] As mentioned above, in order to improve convenience of administration and increase drug compliance, development has been carried out to convert rebamipide formulations, which are taken three times a day, into formulations that are taken twice a day, but formulations that can be taken once a day have not yet been developed.

[0040] The present invention relates to a sustained-release multilayer tablet comprising rebamipide or a pharmaceutically acceptable salt thereof as an active ingredient, which can be taken once a day.

[0041] Specifically, the sustained-release multilayer tablet comprises a first sustained-release layer; a separation layer; and a second sustained-release layer, wherein the first sustained-release layer, the separation layer, and the second sustained-release layer comprise rebamipide and a pharmaceutically acceptable salt thereof as active ingredients, and the first sustained-release layer and the second sustained-release layer may be characterized by having a gelation index of 30 to 100 according to Formula 1 below:

[0042] [Equation 1]

[0043]

[0044] Here,

[0045] The above gelation index is obtained by adding the first sustained-release layer or the second sustained-release layer, respectively, to 45 mL of purified water, and measuring the degree of gelation of the sustained-release layer after 30 minutes in a water shaking bath set at 37°C and 25 rpm.

[0046] TS int It is the initial weight of the western layer, and

[0047] TS a is the weight of the western layer that has not been penetrated by moisture.

[0048] More specifically, the first sustained-release layer and the second sustained-release layer are characterized by including a water-swellable polymer, a sustained-release agent, and a water-permeable excipient, thereby enabling drug absorption throughout the gastrointestinal tract through gelation and swelling in the body.

[0049] The above separation layer does not separately include a slow-release agent such as the first sustained-release layer and the second sustained-release layer, and completely separates the first sustained-release layer and the second sustained-release layer, thereby preventing the gelation and swelling of the first sustained-release layer and the second sustained-release layer from being hindered by mutual influence.

[0050] In addition, the separation layer further comprises rebamipide or a pharmaceutically acceptable salt thereof, so that after oral administration, the initial rebamipide or a pharmaceutically acceptable salt thereof can be released, thereby enabling the pharmacological effect of the rebamipide to be exerted at the beginning of administration.

[0051] In addition, the separation layer, as previously described, is not only for dissolving the initial rebamipide or its pharmaceutically acceptable salt, but can also separate the first sustained-release layer and the second sustained-release layer of the sustained-release multilayer tablet. Specifically, after oral administration of the sustained-release multilayer tablet, the separation layer is completely degraded in the body, thereby separating the first sustained-release layer and the second sustained-release layer.

[0052] Subsequently, the first sustained-release layer and the second sustained-release layer can sufficiently absorb body moisture to gel and swell. As described above, the first sustained-release layer and the second sustained-release layer absorb body moisture and gel and swell, thereby maximizing the dissolution rate without being affected by pH or the amount of gastrointestinal fluid in the gastrointestinal tract, allowing absorption to occur throughout the entire gastrointestinal tract, and maintaining a continuous drug concentration for a long time, thereby reducing the frequency of administration.

[0053] The above Formula 1 is a gelation index that can confirm the degree of gelation and swelling of the first sustained-release layer and the second sustained-release layer, and is characterized by being 30 to 100.

[0054] The gelation index of Equation 1 above is calculated by measuring the initial weight of the sustained-release layer and the weight of the sustained-release layer that has not been penetrated by moisture. A higher value indicates a greater degree of moisture penetration, meaning that the sustained-release layer has been sufficiently gelled and swollen.

[0055] Specifically, the first sustained-release layer may have a gelation index of 100 according to Formula 1, and the second sustained-release layer may have a gelation index of 30 to 70 according to Formula 1. As described below, due to the different gelation indices of the first sustained-release layer and the second sustained-release layer, the release timing of rebamipide or its pharmaceutically acceptable salt may be different. This difference in release timing, together with the preceding separation layer, may produce a continuous release effect of rebamipide or its pharmaceutically acceptable salt.

[0056] The above first sustained-release layer means that it is completely gelled after being placed in 45 mL of purified water and 30 minutes have elapsed in a water shaking bath set at 37°C and 25 rpm, and the above second sustained-release layer means that it is not completely gelled after being placed in 45 mL of purified water and 30 minutes have elapsed in a water shaking bath set at 37°C and 25 rpm.

[0057] This means that the first sustained-release layer completely gels and swells at a relatively faster rate compared to the second sustained-release layer due to body moisture at the beginning of administration.

[0058] As described below, the second sustained-release layer is characterized by having a gelation index of 30 to 70, a gelation index of 60 to 85 after 60 minutes, a gelation index of 90 to 100 after 90 minutes, and a gelation index that reaches 100 completely after 120 minutes.

[0059] The drug release patterns of the first and second sustained-release layers differ in drug release depending on the difference in the time at which the gelation index reaches 100. That is, the sustained-release layer at which the gelation index reaches 100 earlier completes drug release more quickly, while the sustained-release layer at which the gelation index reaches 100 later may complete drug release more slowly.

[0060] Accordingly, if the release of levamipide in the sustained-release multilayer tablet of the present invention is classified into early, middle, and late stages, the release of levamipide occurs by the separation layer during the early stage, and the continuous release effect of levamipide can be exhibited by the first sustained-release layer from the early to middle stages, and by the second sustained-release layer from the middle to late stages.

[0061] Specifically, the first sustained-release layer can exhibit a sustained-release effect of rebamipide as the separation layer is completely decomposed and the initial release of rebamipide proceeds, followed by complete gelation and swelling in the gastrointestinal tract until the middle stage.

[0062] In addition, the second sustained-release layer absorbs moisture for a longer period compared to the first sustained-release layer, so although the initial release of rebamipide is low, it can exhibit a sustained release effect of rebamipide until the middle and later stages.

[0063] However, the dissolution of rebamipide in the first sustained-release layer and the second sustained-release layer is divided into early, middle, and late stages to explain the timing, and this only means that the dissolution effect of rebamipide can be exhibited for 24 hours with a single daily dose, and does not necessarily mean that the dissolution is limited to the early, middle, and late stages.

[0064] The first sustained-release layer and the second sustained-release layer may comprise rebamipide and a pharmaceutically acceptable salt thereof; a sustained-release agent; an excipient; and a lubricant. The sustained-release agent may be selected from the group consisting of polyethylene oxide (PEO), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose, carboxymethylcellulose, polyvinyl alcohol, carbomer, microcrystalline cellulose (MCC), lactose, and mixtures thereof, but is not limited thereto.

[0065] The above excipient may be selected from the group consisting of propylene glycol, polyethyleneglycol, polypropyleneglycol, glycerol, acetic acid, citric acid, DMSO (dimethylsulfoxide), NMP (N-methylpyrrolidone), DMA (dimethylacertamide), and mixtures thereof, but is not limited thereto.

[0066] The above lubricant improves the fluidity of the powder, thereby increasing the filling capacity of the die, reducing friction between the powders and between the die and the punch, and facilitating the compression of the tablet and ejection from the die. It also prevents the powder from adhering to the die and the punch during compression molding. Consequently, it can prevent sticking, where powder adheres to the surface of the tablet punch and causes scratches on the tablet surface; capping, where the top of the tablet peels off in a cap shape during compression; and laminating, where the tablet peels off in layers. The lubricant may be selected from the group consisting of hard anhydrous silica, magnesium stearate, and mixtures thereof. Even when included in a small amount relative to the total weight, the above lubricant exhibits excellent lubrication performance and helps improve the fluidity of the mixture.

[0067] The first sustained-release layer may contain the weight of rebamipide and its pharmaceutically acceptable salt and the total weight of the sustained-release agent and excipients in a weight ratio of 1:0.1 to 1:1, in a weight ratio of 1:0.2 to 1:0.9, and in a weight ratio of 1:0.3 to 1:0.8. Within the above range, when the weight of rebamipide and the total weight of the sustained-release agent and excipients are included, a continuous release effect of rebamipide can be exhibited even after the release of rebamipide by the separation layer is completed in a sufficiently swollen state after sufficient water penetration in the body, and the gelled tablet can maintain sufficient mechanical strength despite strong contraction of the gastrointestinal tract, thereby exhibiting an effect of controlling the release of the drug throughout the gastrointestinal tract.

[0068] The second sustained-release layer may contain the weight of rebamipide and its pharmaceutically acceptable salt and the total weight of the sustained-release agent and excipients in a weight ratio of 1:0.5 to 1:1.5, 1:0.6 to 1:1.3, or 1:0.7 to 1:1.2. It is characterized by containing a larger weight of the sustained-release agent and excipients compared to the first sustained-release layer, so that it takes longer to reach a gelation index of 100 as previously described. This means that the second sustained-release layer takes more time to reach complete gelation and swelling, which implies that it can exhibit a longer dissolution effect of rebamipide compared to the separation layer and the first sustained-release layer, and that the gelled tablet can maintain sufficient mechanical strength despite strong contractions of the gastrointestinal tract, thereby exhibiting an effect of controlling drug release throughout the gastrointestinal tract.

[0069] A method for manufacturing a sustained-release multilayer tablet comprising levamipide or a pharmaceutically acceptable salt thereof as an active ingredient according to another embodiment of the present invention may include the steps of: manufacturing a first sustained-release layer granule comprising levamipide or a pharmaceutically acceptable salt thereof; a sustaining agent, an excipient, and a lubricant; manufacturing a separation layer granule comprising levamipide or a pharmaceutically acceptable salt thereof; an excipient; a dissolving agent and a lubricant; manufacturing a second sustained-release layer granule comprising levamipide or a pharmaceutically acceptable salt thereof; a sustaining agent, an excipient, and a lubricant; and compressing the second sustained-release layer granules; the separation layer granules; and the first sustained-release layer granules in the order of the second sustained-release layer; the separation layer; and the first sustained-release layer using a three-layer tablet press.

[0070] Specifically, rebamipide or a pharmaceutically acceptable salt thereof; a sustained-release agent, an excipient, and a lubricant were each sieved using a sieve and mixed to prepare a first sustained-release layer mixture; the first sustained-release layer mixture was wet-granulated using ethanol as a solvent to produce granules, then sieved to produce a dry product, and mixed with a lubricant to produce the first sustained-release layer granules.

[0071] Rebamipide or a pharmaceutically acceptable salt thereof; an excipient; a disintegrant; and ethanol as a solvent were sieved and mixed using a sieve to prepare a separation layer mixture, and a lubricant was mixed to prepare a separation layer granule.

[0072] The above second sustained-release layer granules were manufactured in the same manner as the manufacturing method of the preceding first sustained-release layer granules.

[0073] The first sustained-release layer granules, the separation layer granules, and the second sustained-release layer granules prepared in the above steps can be manufactured into a sustained-release multilayer tablet by compressing them in the order of the second sustained-release layer; the separation layer; and the first sustained-release layer using a three-layer tablet press.

[0074] The first sustained-release layer may comprise the weight of rebamipide and its pharmaceutically acceptable salt and the total weight of the sustained-release agent and excipients in a weight ratio of 1:0.1 to 1:1, in a weight ratio of 1:0.2 to 1:0.9, and in a weight ratio of 1:0.3 to 1:0.8. More specifically, the first sustained-release layer may comprise 50% to 80% by weight of rebamipide and its pharmaceutically acceptable salt, 10% to 20% by weight of the sustained-release agent, 5% to 15% by weight of the excipient, and 1% to 7% by weight of the lubricant. When included within the above range, sufficient moisture penetrates the body, and even after the release of rebamipide by the separation layer is completed in a sufficiently swollen state, a continuous release effect of rebamipide can be exhibited, and despite strong contraction of the digestive tract, the gelled tablet can maintain sufficient mechanical strength, thereby exhibiting an effect of controlling the release of the drug throughout the digestive tract.

[0075] The above separation layer may comprise 10% to 35% by weight of rebamipide and a pharmaceutically acceptable salt thereof, 40% to 80% by weight of excipients, 1% to 10% by weight of disintegrant, and 1% to 7% by weight of lubricant. When included within the above range, the initial rebamipide or a pharmaceutically acceptable salt thereof may be released after oral administration, thereby allowing the pharmacological effect of the rebamipide to be exerted at the beginning of administration. In addition, as previously described, the separation layer may separate the first sustained-release layer and the second sustained-release layer so that the swelling of each sustained-release layer by body moisture does not affect each other, allowing the time to be fully swollen to be different, and thereby allowing different times of complete dissolution to be indicated.

[0076] The second sustained-release layer may comprise the weight of rebamipide and its pharmaceutically acceptable salt and the total weight of the sustained-release agent and excipients in a weight ratio of 1:0.5 to 1:1.5, in a weight ratio of 1:0.6 to 1:1.3, and in a weight ratio of 1:0.7 to 1:1.2. More specifically, the second sustained-release layer may comprise 40% to 60% by weight of rebamipide and its pharmaceutically acceptable salt, 10% to 30% by weight of the sustained-release agent, 15% to 35% by weight of the excipient, and 1% to 5% by weight of the lubricant. When included within the above range, compared to the first sustained-release layer, it takes more time to reach complete gelation and swelling, so a long-term dissolution effect of rebamipide can be exhibited compared to the separation layer and the first sustained-release layer, and the gelled tablet can maintain sufficient mechanical strength despite strong contraction of the gastrointestinal tract, thereby exhibiting an effect of controlling the release of the drug throughout the gastrointestinal tract.

[0077] Preparation Example

[0078] Preparation of sustained-release multilayer tablets containing ticagrelor

[0079] 1) Granule manufacturing

[0080] ① Preparation of the first sustained-release layer granules

[0081] Levamipide, polyethylene oxide (molecular weight (MW) 5 million), polyethylene glycol 6000, and hard anhydrous silica were mixed by sieving through a 30-mesh sieve. The first sustained-release layer mixture and the solvent ethanol were wet-grained using a speed mixer to produce granules, and then sieved using a sieve to produce a dry product. The first sustained-release layer granules were then prepared by mixing with hard anhydrous silica and magnesium stearate.

[0082] ② Preparation of separated layer granules

[0083] Rebamipide, microcrystalline cellulose, hydroxypropylcellulose, and ethanol as a solvent were mixed after sieving through a 30-mesh sieve. Hard anhydrous silica and magnesium stearate were mixed with the above separation layer mixture to prepare separation layer granules.

[0084] ③ Preparation of second sustained-release layer granules

[0085] Levamipide, polyethylene oxide (molecular weight (MW) 5 million), polyethylene glycol 6000, and hard anhydrous silica were mixed by sieving through a 30-mesh sieve. The above second sustained-release layer mixture and the solvent ethanol were wet-grained using a speed mixer to produce granules, and then sieved to produce a dry product, which was then mixed with magnesium stearate to produce the above second sustained-release layer granules.

[0086] 2) Tablets

[0087] The first sustained-release layer granules, the separation layer granules, and the second sustained-release layer granules manufactured above were compressed using a three-layer tablet press in the order of the second sustained-release layer, the separation layer, and the first sustained-release layer.

[0088] The weights of the components for the manufacture of sustained-release multilayer tablets are as shown in Table 1 below.

[0089]

[0090] (Unit mg)

[0091] Here, the intermediate layer 1) contains the components as shown in Table 2 below, and the intermediate layer 2) contains the components as shown in Table 3 below.

[0092] In addition, the intermediate layer* is based on the weight of all components including rebamipide and excipients; disintegrants; and lubricants.

[0093] Ingredient Name 1 tablet dose (mg) Levamipid 60 Sodium lauryl sulfate 0.6 Chitosan 30 Yudrajit L100 12 POLYOX WSR COAGULANT 48 Macrogol6000 12 Colloidal silicon dioxide 2 Magnesium stearate 2 total 166

[0094] The middle layer of RBPD025 contained only half of the content of all the components in Table 2 above.

[0095] Ingredient Name 1 tablet dose (mg) Levamipid 30 Microcrystalline cellulose 58 hydroxypropyl cellulose 3 Low-substituted hydroxypropyl cellulose 5 Colloidal silicon dioxide 3 Magnesium stearate 1 total 100

[0096] Experimental Example 1

[0097] Swelling test

[0098] The tablets of Table 1 above were placed in 45 mL of purified water as upper and lower layer tablets, respectively, in a water shaking bath set at 37°C and 25 rpm, and the weight of the tablets was measured at 30-minute intervals.

[0099] The gelation index was calculated using the following Equation 1.

[0100] [Equation 1]

[0101]

[0102] Here,

[0103] TS int It is the initial weight of the western layer, and

[0104] TS a is the weight of the western layer that has not been penetrated by moisture.

[0105] The experimental results for the upper layer are as shown in Table 4 below:

[0106]

[0107] The experimental results for the lower well are as shown in Table 5 below:

[0108]

[0109] As shown in the experimental results above, it was confirmed that the upper layer tablets all showed a gelation index of 100 within 30 minutes, and the lower layer tablets showed a gelation index of 100 after 1.5 hours.

[0110] Based on the above experimental results, it was confirmed that the upper layer tablet absorbs moisture and swells faster than the lower layer tablet, causing the release of rebamipide in the body, while the lower layer tablet swells later than the upper layer tablet, exhibiting the release effect of rebamipide for a longer period of time.

[0112] Experimental Example 2

[0113] Rebamipide dissolution experiment

[0114] A dissolution experiment of levamipide was conducted on the above RBPD024 to RBPD032.

[0115] A buffer solution with a pH of 6.8 was used as the eluent, and the degree of elution of rebamipide was checked every hour while stirring at 75 rpm using a water shaking bath.

[0116] The experimental results are as shown in Figure 1 and Table 6 below:

[0117] division 0 1 2 4 8 12 16 RBPD024 0 5.9 10.1 19.3 37.6 64.5 76.2 RBPD025 0 5.1 9.0 17.5 34.4 61.7 74.1 RBPD026 0 20.0 33.3 60.8 73.8 87.4 90.2 RBPD027 0 19.8 31.6 54.7 68.5 82.6 90.2 RBPD028 0 13.8 19.9 39.2 72.5 87.5 98.8 RBPD029 0 11.6 17.5 30.6 58.5 89.9 99.8 RBPD030 0 11.9 23.0 44.4 56.9 69.3 80.3 RBPD031 0 12.8 18.1 33.6 61.6 73.8 86.3 RBPD032 0 16.0 25.0 44.8 73.7 86.6 95.5

[0118] (unit %)

[0119] According to the above experimental results, RBPD024 and RBPD025 have an intermediate layer that is composed differently from other multilayer tablets and contains chitosan, etc., so the initial release of levamipide is too low, and even in the case of the upper and lower layers, the release of levamipide is too insignificant, so there is a problem that the effect of levamipide is not easily manifested.

[0120] In contrast, in the case of other multilayer tablets, the separation layer is easily degraded, resulting in the initial release of rebamipide and subsequent continuous release of rebamipide. Furthermore, it was confirmed that more than 85% of rebamipide is released after 16 hours, confirming that it can be utilized as a sustained-release formulation for once-daily intake.

[0121] Although preferred embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and various modifications and improvements by those skilled in the art using the basic concept of the present invention as defined in the following claims also fall within the scope of the present invention.

Claims

Claim 1 It comprises a first sustained-release layer; a separation layer; and a second sustained-release layer, wherein the first sustained-release layer, the separation layer, and the second sustained-release layer comprise rebamipide and a pharmaceutically acceptable salt thereof, an excipient; It comprises a lubricant, wherein the first sustained-release layer and the second sustained-release layer further comprise polyethylene oxide (PEO) and polyethylene glycol (PEG) having a molecular weight (MW) of 5 million as sustained-release agents, and the separation layer comprises microcrystalline cellulose (MCC) and hydroxypropyl cellulose (HPC), wherein the first sustained-release layer comprises the weight of rebamipide and its pharmaceutically acceptable salt and the total weight of the sustained-release agent and excipients in a weight ratio of 1:0.3 to 1:0.8, and the second sustained-release layer comprises the weight of rebamipide and its pharmaceutically acceptable salt and the total weight of the sustained-release agent and excipients in a weight ratio of 1:0.7 to 1:1.2, wherein the first sustained-release layer has a gelation index of 100 according to Formula 1 below, and the second sustained-release layer has a gelation index of 30 to 70 according to Formula 1 below, and gels after 90 minutes. A sustained-release multilayer tablet comprising rebamipide or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the index reaches 100, the separation layer separates the first sustained-release layer and the second sustained-release layer after oral administration, thereby releasing and absorbing the initial rebamipide and its pharmaceutically acceptable salt, and after oral administration once daily, continuously releases rebamipide or its pharmaceutically acceptable salt and allows absorption throughout the gastrointestinal tract for 24 hours, thereby enhancing convenience of administration: [Formula 1] Here, the gelation index is obtained by adding the first sustained-release layer or the second sustained-release layer, respectively, to 45 mL of purified water and measuring the degree of gelation of the sustained-release layer after 30 minutes in a water shaking bath set at 37°C and 25 rpm, TS int Silver is the initial weight of the western layer, and TS a is the weight of the western layer that has not been penetrated by moisture. Claim 2 delete Claim 3 delete Claim 4 delete Claim 5 delete Claim 6 delete Claim 7 delete Claim 8 delete Claim 9 delete Claim 10 delete Claim 11 A step of preparing a first sustained-release layer granule comprising rebamipide or a pharmaceutically acceptable salt thereof; a sustained-release agent, an excipient, and a lubricant; a step of preparing a separation layer granule comprising rebamipide or a pharmaceutically acceptable salt thereof; an excipient; a dissociating agent and a lubricant; a step of preparing a second sustained-release layer granule comprising rebamipide or a pharmaceutically acceptable salt thereof; a sustained-release agent, an excipient, and a lubricant; and the second sustained-release layer granules; the separation layer granules; and the first sustained-release layer granules are prepared by using a three-layer tablet press to form a second sustained-release layer; a separation layer; The method comprises the step of compressing tablets in the order of the first sustained-release layer and the second sustained-release layer, wherein the first sustained-release layer and the second sustained-release layer further comprise polyethylene oxide (PEO) and polyethylene glycol (PEG) having a molecular weight (MW) of 5 million as sustained-release agents, and the separation layer comprises microcrystalline cellulose (MCC) and hydroxypropyl cellulose (HPC) as excipients, wherein the first sustained-release layer comprises the weight of rebamipide and its pharmaceutically acceptable salt and the total weight of the sustained-release agent and excipients in a weight ratio of 1:0.3 to 1:0.8, and the second sustained-release layer comprises the weight of rebamipide and its pharmaceutically acceptable salt and the total weight of the sustained-release agent and excipients in a weight ratio of 1:0.7 to 1:1.2, and the separation layer separates the first sustained-release layer and the second sustained-release layer after oral administration, and releases and absorbs the initial rebamipide and its pharmaceutically acceptable salt. A method for manufacturing a sustained-release multilayer tablet comprising rebamipide or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the first sustained-release layer has a gelation index of 100 according to Formula 1 below, the second sustained-release layer has a gelation index of 30 to 70 according to Formula 1 below, and the gelation index reaches 100 after 90 minutes, thereby enhancing convenience of administration by allowing continuous release of rebamipide or a pharmaceutically acceptable salt thereof and absorption throughout the gastrointestinal tract for 24 hours after oral administration once a day: [Formula 1] Here, the gelation index is obtained by adding the first sustained-release layer or the second sustained-release layer to 45 mL of purified water, respectively, and measuring the degree of gelation of the sustained-release layer after 30 minutes in a water shaking bath set at 37°C and 25 rpm, where TSint is the initial weight of the sustained-release layer and TSA is the weight of the sustained-release layer before water penetration. Claim 12 delete Claim 13 delete

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