CORE TABLET COMPOSITE PREPARATION COMPRISING MOSAPRIDE AND RABEPRAZOLE

Abstract

The present invention relates to a composite preparation in a core tablet form, composed of an inner core containing rabeprazole as an effective ingredient; an outer layer portion including the bilayer structure of a sustained release layer and an immediate release layer and containing mosapride as an effective ingredient. The core tablet composite preparation according to the present invention is characterized by exerting sufficient pharmacological activity of rabeprazole and mosapride even upon administration of one tablet once a day.

Claims

1. A mosapride- and rabeprazole-containing tablet-in-tablet combined preparation for oral administration, the tablet-in-tablet combined preparation composed of: an inner core containing rabeprazole or a pharmaceutically acceptable salt thereof as an active ingredient; and an outer layer part containing mosapride or a pharmaceutically acceptable salt thereof as an active ingredient, wherein an entire surface of the inner core is surrounded by the outer layer part, and the outer layer part has a bilayer structure of an immediate-release layer containing an active ingredient, a filler, a disintegrant, and an additive and a sustained-release layer containing an active ingredient, a filler, a disintegrant, a release-modifying agent, and an additive.

2. The tablet-in-tablet combined preparation of claim 1, wherein a weight ratio of the sustained-release layer and the immediate-release layer of the outer layer part ranges from 1:1.5 to 1:2.5.

3. The tablet-in-tablet combined preparation of claim 1, wherein an area of the inner core surface surrounded by the immediate-release layer of the outer layer part is larger than an area of the inner core surface surrounded by the sustained-release layer of the outer layer part.

4. The tablet-in-tablet combined preparation of claim 1, wherein, as the release-modifying agent, a mixture of hydroxypropyl methylcellulose having a viscosity of 75,000 to 140,000 mPa.Math.s and hydroxypropyl methylcellulose having a viscosity of 3,000 to 5,600 mPa.Math.s is used, and, with respect to a total weight of the release-modifying agent, 60 to 70 wt % of the hydroxypropyl methylcellulose having a viscosity of 75,000 to 140,000 mPa.Math.s and 30 to 40 wt % of the hydroxypropyl methylcellulose having a viscosity of 3,000 to 5,600 mPa.Math.s are included.

5. The tablet-in-tablet combined preparation of claim 1, wherein the immediate-release layer of the outer layer part contains 4 to 6 mg of the active ingredient, and the sustained-release layer contains 9 to 12 mg of the active ingredient.

6. The tablet-in-tablet combined preparation of claim 1, wherein the sustained-release layer of the outer layer part contains, with respect to a total weight of the sustained-release layer, 12 to 16 wt % of mosapride citrate and 20 to 40 wt % of the release-modifying agent.

7. The tablet-in-tablet combined preparation of claim 1, wherein a total weight of the inner core ranges from 30 to 70 mg.

8. The tablet-in-tablet combined preparation of claim 1, wherein the inner core is coated with an enteric coating agent, and a total weight of the inner core ranges from 40 to 60 mg.

9. The tablet-in-tablet combined preparation of claim 1, wherein a total weight of the tablet-in-tablet combined preparation ranges from 250 to 350 mg.

10. A method of preparing a mosapride- and rabeprazole-containing tablet-in-tablet combined preparation for oral administration, the method comprising: preparing an inner core containing rabeprazole or a pharmaceutically acceptable salt thereof as an active ingredient; preparing immediate-release layer granules containing mosapride or a pharmaceutically acceptable salt thereof as an active ingredient, a filler, a disintegrant, and an additive and sustained-release layer granules containing mosapride or a pharmaceutically acceptable salt thereof as an active ingredient, a filler, a disintegrant, a release-modifying agent, and an additive; feeding the immediate-release layer granules into a punch die of a tablet press machine; adding the inner core to the punch die into which the immediate-release layer granules have been fed; applying pre-pressure to the punch die to which the inner core has been added; feeding the sustained-release layer granules into the punch die to which pre-pressure has been applied; and performing tableting while applying main pressure to the punch die into which the sustained-release layer granules have been fed.

11. The method of claim 10, wherein the pre-pressure ranges from 0.5 to 2 kgf/cm.sup.2, and the main pressure ranges from 3 to 20 kgf/cm.sup.2.

Description

DESCRIPTION OF DRAWINGS

[0034] FIG. 1 is a schematic diagram of a tablet-in-tablet preparation according to the present invention.

[0035] FIG. 2 is an image of the cross-section obtained by longitudinally cutting an outer layer part of a tablet-in-tablet preparation prepared according to the present invention.

[0036] FIG. 3 is a graph illustrating the active ingredient mosapride dissolution rates of bilayer tablets of Examples 1 to 3 and Comparative Examples 1 to 3 which are prepared to specify the composition of an outer layer part of the present invention and a conventional mosapride bilayer tablet which is a control, as measured in a pH 4.0 dissolution solution.

[0037] FIG. 4 shows schematic diagrams of tablet-in-tablet combined preparations according to each preparation method and images obtained by photographing whether an inner core is separated in an example.

[0038] FIG. 5 is a graph of comparing the mosapride dissolution rates of a tablet-in-tablet combined preparation according to Example 6 (GSP 5) of the present invention and Gastiin CR tab, which is a control drug, in a pH 4.0 dissolution solution.

[0039] FIG. 6 is a graph of comparing the mosapride dissolution rates of a tablet-in-tablet combined preparation according to Example 6 (GSP 5) of the present invention and Gastiin CR tab, which is a control drug, in water.

[0040] FIG. 7 is a graph of comparing the mosapride dissolution rates of a tablet-in-tablet combined preparation according to Example 6 (GSP 5) of the present invention and Gastiin CR tab, which is a control drug, in a pH 6.8 dissolution solution.

[0041] FIG. 8 is a graph of comparing the mosapride dissolution rates of a tablet-in-tablet combined preparation according to Example 6 (GSP 5) of the present invention and Gastiin CR tab, which is a control drug, in a pH 1.2 dissolution solution.

[0042] FIG. 9 is a graph of comparing the rabeprazole dissolution rates of a tablet-in-tablet combined preparation according to Example 6 (GSP 5) of the present invention and Pariet tab, which is a control drug, in a pH 6.8 dissolution solution.

MODES OF THE INVENTION

[0043] A method of preparing a mosapride- and rabeprazole-containing tablet-in-tablet combined preparation for oral administration according to the present invention is as follows.

[0044] The preparation method is roughly divided into four steps as described below, but the present invention is not necessarily limited thereto. Step 1 to Step 3 which are independent processes may be performed by varying the sequence.

[0045] Step 1: Preparation of a proton pump inhibitor (PPI) portion (rabeprazole sodium) as a core tablet.

[0046] Step 2: Preparation of a digestive tract motility promoter portion (mosapride citrate dihydrate) as an immediate-release layer of an outer layer part.

[0047] Step 3: Preparation of a digestive tract motility promoter portion (mosapride citrate dihydrate) as a sustained-release layer of an outer layer part.

[0048] Step 4: Tableting of the core tablet and mixtures which are prepared in the Step 1 to Step 3 into a tablet in tablet.

[0049] Hereinafter, an embodiment of the method of preparing the mosapride- and rabeprazole-containing tablet-in-tablet combined preparation for oral administration according to the present invention will be described in detail.

[0050] Step 1: Preparation of PPI Portion (Rabeprazole Sodium) as Inner Core

[0051] With respect to the total weight of an inner core (tablet), 15 to 25 wt % of rabeprazole sodium, 5 to 10 wt % of D-mannitol, 25 to 35 wt % of magnesium oxide, and 3 to 7 wt % of low-substituted hydroxypropyl cellulose were mixed, and the mixture was kneaded with an adequate amount of ethanol, granulated, dried in a dryer at 50 to 70° C. so that loss of dry weight (LOD) became 2% or less, and then sized. Afterward, the resultant was mixed with 2 to 5 wt % of crospovidone and an adequate amount of lubricant and tableted. The tablet thus obtained was primarily coated with a film coating agent and secondarily coated with an enteric coating agent. Finally, the resultant was tertiarily coated with a film coating agent to prepare an inner core in the form of a tablet (coated tablet).

[0052] The primary film coating is intended to prevent the interaction between rabeprazole sodium which is an active ingredient and the enteric coating agent and prevent long-term moisture exposure. The secondary enteric coating is intended to achieve the effect of the drug by dissolving the inner core in the intestines while having acid resistance because rabeprazole sodium which is a PPI has a problem of stability such as drug decomposition under acidic conditions. The tertiary film coating is intended to prevent the tablet from being damaged and cracked due to tableting pressure applied to a core tablet in the preparation of a tablet in tablet.

[0053] Step 2: Preparation of Digestive Tract Motility Promoter Portion (Mosapride Citrate Dihydrate) as Immediate-Release Layer of Outer Layer Part

[0054] With respect to the total weight of an immediate-release layer of an outer layer part, 2 to 5 wt % of mosapride citrate, 20 to 40 wt % of lactose, 10 to 20 wt % of low-substituted hydroxypropyl cellulose, and an adequate amount of microcrystalline cellulose were mixed, and the mixture was kneaded with 4 to 8 wt % of povidone K-30 dissolved in ethanol as a binder solution, granulated, dried in a fluid bed dryer at 50 to 70° C. so that LOD became 4% or less, and then sized. Afterward, the resultant was mixed with an adequate amount of lubricant to prepare immediate-release layer granules.

[0055] Step 3: Preparation of Digestive Tract Motility Promoter Portion (Mosapride Citrate Dihydrate) as Sustained-Release Layer of Outer Layer Part

[0056] With respect to the total weight of a sustained-release layer of an outer layer part, 12 to 16 wt % of mosapride citrate as a pharmacological active ingredient, 5 to 15 wt % of lactose, 20 to 40 wt % of a release-modifying agent including hydroxypropyl methylcellulose having a viscosity of 75,000 to 140,000 mPa.Math.s and hydroxypropyl methylcellulose having a viscosity of 3,000 to 5,600 mPa.Math.s, and an adequate amount of microcrystalline cellulose were mixed. The mixture was kneaded with 3 to 7 wt % of povidone dissolved in an adequate amount of ethanol as a binder solution, granulated, dried in a fluid bed dryer at 50 to 70° C. so that LOD became 4% or less, and then sized. Afterward, the resultant was mixed with 15 to 20 wt % of low-substituted hydroxypropyl cellulose and an adequate amount of lubricant to prepare sustained-release layer granules.

[0057] Step 4: Tableting of Core Tablet and Mixtures which are Prepared in Step 1 to Step 3 into a Tablet in Tablet

[0058] The core tablet, immediate-release layer mixture, and sustained-release layer mixture which are prepared in the Steps 1 to 3 were processed using a tablet-in-tablet press machine (PR-LT commercially available from PTK Co. Ltd.) to prepare a mosapride- and rabeprazole-containing tablet-in-tablet combined preparation for oral administration.

[0059] First, the immediate-release layer mixture prepared in the Step 2 was fed into a punch die of the tablet press machine, then the core tablet prepared in the Step 1 was added thereto, and a pre-pressure of 0.5 to 2 kgf/cm.sup.2 was applied. Subsequently, the sustained-release layer mixture prepared in the Step 3 was fed and tableted while applying a main pressure of 3 to 20 kgf/cm.sup.2, preferably, 8 to 15 kgf/cm.sup.2.

[0060] As the above-described method, the mosapride- and rabeprazole-containing tablet-in-tablet combined preparation for oral administration according to the present invention may be prepared by firstly feeding the immediate-release layer mixture of the outer layer part, adding the previously prepared inner core, applying pre-pressure, feeding the sustained-release layer mixture of the outer layer part, and performing tableting while applying main pressure.

[0061] A total weight of the tablet-in-tablet combined preparation according to the present invention ranges from 250 to 350 mg, and it is preferable that the total weight thereof is not more than 350 mg to enhance a patient's drug compliance. In addition, when the total weight thereof is less than 250 mg, the stability of the preparation may be decreased, which is not preferred.

[0062] Hereinafter, preferred embodiments of the present invention will be described in detail. The following examples describe specific components and specific factors for the implementation according to the present invention, which are provided to help the overall understanding of the present invention, and the present invention is not limited by the examples.

<Experiment 1> Design of Outer Layer Part and Selection of Optimal Composition

[0063] Based on the applicant's mosapride sustained-release technology applied to Gastiin CR tab, the research direction was established by roughly predicting the dissolution pattern and the dissolution range at a specific time, which are main quality attributes of the outer layer part of the tablet in tablet.

[0064] In the case of Gastiin CR tab (Korean Registered Patent No. 10-1612931) which is a conventional mosapride-containing sustained-release bilayer tablet, 25 to 45 wt % of the total content of the active ingredient was dissolved after 1 hour under dissolution solution conditions of pH 4.0, pH 1.2, and water, 60 to 80% was dissolved after 8 hours, and 85% or more was dissolved after 24 hours.

[0065] Based on this, the applicant has conducted studies in consideration of the characteristics, interactions with other active ingredients, and effects of the tablet-in-tablet formulation. As a result, based on the pH 4.0 dissolution solution which is a standard for commercial approval, a composition capable of stably exhibiting a 35 to 45% active ingredient dissolution after 1 hour and a 70 to 80% active ingredient dissolution after 8 hours was deduced.

[0066] Through continuous research and repeated experiments, it was possible to grasp the properties of the raw materials affecting the dissolution pattern and to select a range of the factors. In addition, the degree and relationship of the influence on the dissolution pattern of the raw materials according to the range was established.

[0067] Finally, a composition was optimized by analyzing the correlation between the properties of the raw material and the dissolution pattern, and the experimental compositions (MS3 to MS8) of the outer layer part considering the interrelationship between the components were deduced and shown in Table 1 below.

TABLE-US-00001 TABLE 1 Dose (mg/tablet) Compar- Compar- Compar- ative ative ative Exam- Exam- Exam- Exam- Exam- Exam- Purpose of ple 1 ple 2 ple 1 ple 2 ple 3 ple 3 Classification Use Raw material (MS3) (MS4) (MS5) (MS6) (MS7) (MS8) Outer Immediate- Main Mosapride 5.29 5.29 5.29 5.29 5.29 5.29 Layer release ingredient citrate dihydrate part layer Excipient Microcrystalline 31.5 31.5 31.5 31.5 31.5 31.5 cellulose 101 Excipient Lactose hydrate 32.51 32.51 32.51 32.51 32.51 32.51 Binder Povidone K30 6.7 6.7 6.7 6.7 6.7 6.7 Disintegrant Low-substituted 20.0 20.0 20.0 20.0 20.0 20.0 hydroxypropyl cellulose Lubricant Light anhydrous 2.0 2.0 2.0 2.0 2.0 2.0 silicic acid Lubricant Magnesium stearate 2.0 2.0 2.0 2.0 2.0 2.0 Total of immediate-release 100 100 100 100 100 100 layer (mg/tablet) Outer Sustained- Main Mosapride citrate 10.58 10.58 10.58 10.58 10.58 10.58 Layer release ingredient dihydrate part layer Excipient Microcrystalline 12.0 12.0 12.0 12.0 12.0 12.0 cellulose Excipient Lactose hydrate 8.8 8.8 8.8 8.8 8.8 8.8 Release- Hypromellose 2910 10.0 6.0 6.0 10.0 10.0 13.0 modifying (viscosity 4,000 agent mPa.Math.s) Release- Hypromellose modifying 2208 (viscosity 12.0 16.0 12.0 15.0 18.0 17.0 agent 100,000 mPa.Math.s) Binder Povidone K30 5.0 5.0 6.0 5.0 4.0 5.0 Disintegrant Low-substituted 14.0 14.0 14.0 14.0 14.0 14.0 hydroxypropyl cellulose Lubricant Light anhydrous 2.0 2.0 2.0 2.0 2.0 2.0 silicic acid Lubricant Magnesium stearate 0.62 0.62 0.62 0.62 0.62 0.62 Total of sustained-release 75 75 72 78 80 83 layer (mg/tablet) Total weight of bilayer tablet (mg/tablet) 175 175 172 178 180 183

[0068] Bilayer tablets were prepared according to the compositions of Examples 1 to 3 and Comparative Examples 1 to 3 (Preparation Nos. MS3 to MS8) as shown in Table 1, and dissolution rates were measured in a pH 4.0 dissolution solution. In order to specify the composition that exhibits an optimal dissolution rate, the bilayer tablets were compared with a conventional Gastiin CR tab which is a control, and results are shown in Table 2 and FIG. 3.

TABLE-US-00002 TABLE 2 Dissolution rate (%) 15 30 60 90 120 180 300 480 720 1440 Classification mins mins mins mins mins mins mins mins mins mins Comparative 32.8 38.1 41.9 46.0 50.7 56.4 67.4 76.0 84.1 88.7 Example 1 (MS3) Comparative 37.6 42.7 46.5 51.9 57.4 63.8 71.0 80.0 88.0 97.1 Example 2 (MS4) Example 19.6 24.6 32.1 34.9 40.2 47.9 58.5 70.5 81.7 100.0 1 (MSS) Example 24.2 29.1 34.8 38.5 41.8 48.8 59.1 71.1 82.6 100.0 2 (MS6) Example 19.9 31.5 39.2 44.5 46.5 51.6 61.4 72.2 81.4 101.3 3 (MS7) Comparative 15.1 25.4 36.4 43.0 46.6 54.5 66.5 81.8 91.5 103.9 Example 3 (MS8) Control drug 28.6 36.8 40.9 44.6 48.1 53.9 62.5 72.3 82.8 98.5 (Gastiin CR tab)

[0069] As shown in Table 2 and FIG. 3, Comparative Examples 1 to 3 showed problems such as excessive initial dissolution, long-term delay in dissolution, and the like, whereas Examples 1 to 3 showed preferable dissolution patterns.

[0070] Particularly, Example 3 whose dissolution pattern was very similar to that of the control drug was shown to be the most preferable.

<Experiment 2> Design of Inner Core and Selection of Optimal Composition

[0071] The mosapride- and rabeprazole-containing tablet-in-tablet combined preparation according to the present invention has a structure in which an inner core, which is a rabeprazole sodium-containing enteric-coated tablet, is surrounded by an outer layer part containing mosapride citrate dihydrate. Therefore, as the weight and size of the inner core tablet increase, the total weight and size of the tablet in tablet increase proportionally thereto, and thereby it is preferable to prepare the core tablet as small as possible in consideration of a patient's medication convenience. However, when the formulation of the core tablet becomes excessively small, cracks may occur in tableting, or stability may be decreased. Considering these conditions, the total weight of the inner core is preferably 30 to 70 mg, and more preferably, 40 to 60 mg.

[0072] According to the purpose of the present invention, rabeprazole sodium-containing enteric-coated tablets which maintain stability while having minimized weight (Preparation Nos. RB1 to RB4) were designed as the inner cores, and specific compositions are shown in Table 3 below.

[0073] In the preparation of the inner core, a circular punch with a 4π diameter was used.

TABLE-US-00003 TABLE 3 Dose (mg/tablet) Comparative Example Comparative Example Purpose Example 4 4 Example 5 5 Classification of Use Raw material (RB1) (RB2) (RB3) (RB4) Inner core Active Rabeprazole 10.0 10.0 10.0 10.0 ingredient sodium Excipient D-mannitol 4.0 4.0 4.0 4.0 Stabilizer Magnesium 11.0 11.0 16.0 16.0 oxide Disintegrant Low-substituted 3.0 3.0 3.0 3.0 hydroxypropyl cellulose Disintegrant Crospovidone 2.0 2.0 2.0 2.0 Lubricant Light anhydrous 3.0 3.0 3.0 3.0 silicic acid Lubricant Sodium stearyl 2.0 2.0 2.0 2.0 fumarate Total of tablet 35 35 40 40 Primary Opadry 2.0 2.0 2.0 2.0 film 03K19229 coating clear agent Secondary ACRYL-EZE 5.0 10.0 5.0 10.0 enteric 93A18597 coating white agent Tertiary HPMC 2910 2.4 2.4 2.4 2.4 film coating agent Tertiary PEG 6000 0.6 0.6 0.6 0.6 film coating agent Total of enteric-coated 45 50 50 55 tablet

[0074] Each preparation shown in Table 3 was measured for the dissolution rate in pH 1.2 and pH 6.8 dissolution solutions which are gastric and intestinal fluid environments, respectively, and results are shown in the following Table 4.

TABLE-US-00004 TABLE 4 Dissolution test results (%) Dissolution under Dissolution under gastric fluid intestinal fluid Content (buffer solution, (buffer solution, test pH 1.2) pH 6.8) results condition condition Classification (%) for 2 hours for 45 minutes RB1 100.9 9.4 100.8 RB2 100.3 2.2 99.8 RB3 101.4 9.7 101.3 RB4 99.9 2.3 99.7 Control drug 100.2 2.1 100.2 (Pariet tab 10 mg)

[0075] As shown in Table 4, among the prepared rabeprazole sodium inner cores, Example 4 (RB2) and Example 5 (RB4) exhibited content and dissolution rate levels equivalent to those of 10 mg of Pariet tab which is a control drug.

[0076] Meanwhile, when the weight and size of the tablet are excessively low and small, a punch may be damaged at high tableting pressure due to low tablet thickness, and the tablet may be stuck in a perforated portion inside a coating pan during a coating process. Therefore, in consideration of both the dissolution rate and ease in tableting and coating processes, Example 5 (RB4) was shown to be the most preferable.

<Experiment 3> Preparation of Tablet in Tablet and Selection of Optimal Composition According to Weight Ratio of Each Layer of Outer Layer Part

[0077] In this experiment, based on the outer layer part composition of Example 3 and the inner core composition of Example 5 which exhibited the most preferable dissolution pattern in Experiment 1 and Experiment 2, additional experiments for ease of separation and dissolution of the inner core were performed. Based on results of the experiments for ease of separation and dissolution, the final preferable composition of the tablet-in-tablet combined preparation according to the present invention was completed.

[0078] The outer layer part of the tablet-in-tablet combined preparation according to the present invention is composed of an immediate-release layer that rapidly disintegrates after administration and a sustained-release layer that slowly disintegrates over at least 12 hours, and surrounds the inner core. Therefore, the aspect of the inner core exposed to the external environment varies depending on whether the inner core is positioned more toward the immediate-release layer side or the sustained-release layer side of the outer layer part, and accordingly, the dissolution rate of the active ingredient of the inner core and the stability of the inner core are changed.

[0079] As a result of repeated research, the applicants found that it is preferable that the inner core is positioned more toward the immediate-release layer side to ensure the stability of the inner core and achieve the effect of maintaining fast dissolution and high bioavailability.

[0080] However, since the inner core is prepared to be positioned close to the center in a conventional method of preparing a tablet in tablet, it is not easy to adjust the position of the inner core itself to be offset from the center, and the process of directly adjusting the inner core is unsuitable for application to tablet tableting equipment for mass production.

[0081] Accordingly, as a result of repeated research, the applicants designed a method of adjusting the position of the inner core relative to each layer of the outer layer part by adjusting a thickness ratio of the immediate-release layer and the sustained-release layer of the outer layer part rather than the inner core. Specifically, it was possible to adjust a relative thickness ratio by adjusting the contents of the excipients contained in the immediate-release layer and the sustained-release layer. In addition, when the amount of the excipients was adjusted to increase a weight of the immediate-release layer compared to the sustained-release layer, as shown in FIG. 1 and FIG. 2, the position of the inner core relative to the outer layer part was able to be adjusted to be more toward the immediate-release layer side.

[0082] In order to deduce the relative position of the inner core which achieves the most preferable dissolution rate and stability of the inner core, the applicants set various formulations and conducted tableting by varying a preparation method to apply each formulation. Specific compositions (GSP 1 to GSP 9) are shown in Table 5 below, and a circular punch with an 8π diameter was used in the preparation.

[0083] Meanwhile, each preparation method listed in Table 5 is as follows.

[0084] Preparation method 1: feeding immediate-release layer granules; adding the inner core; applying weak pre-pressure below measurable pressure; feeding sustained-release layer granules; and applying a main pressure of 8.5 kgf/cm.sup.2.

[0085] Preparation method 2: feeding immediate-release layer granules; adding the inner core; applying a pre-pressure of 1 kgf/cm.sup.2; feeding sustained-release layer granules; and applying a main pressure of 8.5 kgf/cm.sup.2.

[0086] Preparation method 3: feeding 50 wt % of the prepared immediate-release layer granules; adding the inner core; feeding another 50 wt % of the immediate-release layer granules; applying a pre-pressure of 1 kgf/cm.sup.2; feeding sustained-release layer granules; and applying a main pressure of 8.5 kgf/cm.sup.2.

TABLE-US-00005 TABLE 5 Dose (mg/tablet) Preparation method 1 Preparation method 2 Preparation method 3 Compar- Compar- Compar- Compar- Compar- Compar- ative ative ative ative Exam- Exam- ative ative Exam- Purpose Exam- Exam- Exam- Exam- ple ple Exam- Exam- ple of ple 6 ple 7 ple 8 ple 9 6 7 ple 10 ple 11 8 Classification Use Raw material (GSP1) (GSP2) (GSP3) (GSP4) (GSP5) (GSP6) (GSP7) (GSP8) (GSP9) Inner Main Rabeprazole 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 core ingredient sodium Excipient D-mannitol 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 Stabilizer Magnesium16.0 16.0 16.0 16.0 16.0 16.0 16.0 16.0 16.0 oxide Disintegrant Low-substituted 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 hydroxypropyl cellulose Disintegrant Crospovidone 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 Lubricant Light anhydrous 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 silicic acid Lubricant Sodium stearyl 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 fumarate Primary Opadry 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 film coating 03K19229 agent clear Secondary ACRYL-EZE 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 enteric 93A18597 coating white agent Tertiary HPMC 2910 2.4 2.4 2.4 2.4 2.4 2.4 2.4 2.4 2.4 film coating agent Tertiary PEG 6000 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 film coating agent Total of inner core 55 55 55 55 55 55 55 55 55 (mg/tablet) Outer Immediate- Main Mosapride 5.29 5.29 5.29 5.29 5.29 5.29 5.29 5.29 5.29 layer release ingredient citrate dihydrate part layer Excipient Microcrystalline 13.1 48.1 63.1 13.1 48.1 63.1 13.1 48.1 63.1 cellulose 101 Excipient Lactose hydrate 43.31 43.31 43.31 43.31 43.31 43.31 43.31 43.31 43.31 Binder Povidone K30 8.3 8.3 8.3 8.3 8.3 8.3 8.3 8.3 8.3 Disintegrant Low-substituted 25.0 25.0 25.0 25.0 25.0 25.0 25.0 25.0 25.0 hydroxypropyl cellulose Lubricant Light anhydrous 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 silicic acid Lubricant Magnesium 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 stearate Total of immediate-release 100 135 150 100 135 150 100 135 150 layer (mg/tablet) Outer Sustained- Main Mosapride 10.58 10.58 10.58 10.58 10.58 10.58 10.58 10.58 10.58 layer release ingredient citrate dihydrate part layer Excipient Microcrystalline 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 cellulose Excipient Lactose hydrate 8.8 8.8 8.8 8.8 8.8 8.8 8.8 8.8 8.8 Release- Hypromellose 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 modifying 2910 agent (viscosity 4,000 mPa.Math.s) Release- Hypromellose 18.0 18.0 18.0 18.0 18.0 18.0 18.0 18.0 18.0 modifying 2208 agent (viscosity 100,000 mPa.Math.s) Binder Povidone K30 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 Disintegrant Low-substituted 14.0 14.0 14.0 14.0 14.0 14.0 14.0 14.0 14.0 hydroxypropyl cellulose Lubricant Light anhydrous 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 silicic acid Lubricant Magnesium 0.62 0.62 0.62 0.62 0.62 0.62 0.62 0.62 0.62 stearate Total of sustained-release 75 75 75 75 75 75 75 75 75 layer (mg/tablet) Coating Film Opadry 5 5 5 5 5 5 5 5 5 coating 03B28796 agent white Total weight of tablet in tablet (mg/tablet) 235 270 285 235 270 285 235 270 285

[0087] Observation of Presence or Absence of Separation and Disintegration Stability of Inner Core

[0088] 20 tablets of each of Examples and Comparative Examples prepared according to the compositions and preparation methods shown in Table 5 were prepared, and a paddle was allowed to revolve at 50 rpm/min in a dissolution tester under a pH 1.2 dissolution test solution condition. After 30 minutes of the revolution, the number of tablet in tablets whose core tablet was separated from the mosapride immediate-release layer of the outer layer part and whether the core tablet was cracked were confirmed through visual observation, and results are shown in the following Table 6.

TABLE-US-00006 TABLE 6 Number of tablets whose Number Weight of Weight of Weight of core of core immediate- sustained- immediate- tablet is tablets release release release separated cracked layer layer layer after 30 after 30 Classification (mg) (mg) (%) minutes minutes Prepa- Compar- 100 75 57.1 11 1 ration ative method Exam- 1 ple 6 (GSP 1) Compar- 135 75 64.2 13 0 ative Exam- ple 7 (GSP 2) Compar- 150 75 66.6 12 0 ative Exam- ple 8 (GSP 3) Prepa- Compar- ration ative method Exam- 100 75 57.1 20 2 2 ple 9 (GSP 4) Exam- 135 75 64.2 20 0 ple 6 (GSP 5) Exam- 150 75 66.6 20 0 ple 7 (GSP 6) Prepa- Compar- 100 75 57.1 20 3 ration ative method Exam- 3 ple 10 (GSP 7) Compar- 135 75 64.2 20 2 ative Exam- ple 11 (GSP 8) Exam- 150 75 66.6 20 0 ple 8 (GSP 9)

[0089] Discussion

[0090] Schematic diagrams of preparation examples and images of separation results according to a preparation method are shown in FIG. 4. In the case of GSP 1 to GSP 3 which were prepared by Preparation Method 1, 100% separation and disintegration of the core tablet did not occur after 30 minutes, and thus it was difficult to exhibit the dissolution pattern expected for the rabeprazole sodium enteric-coated tablet. In the case of GSP 4 to GSP 6 which were prepared by Preparation Method 2, all of the tested 20 tablets showed that the core tablet was separated from the immediate-release layer of the outer layer part and disintegrated. In the case of GSP 7 to GSP 9 which were prepared by Preparation Method 3, all of the tested 20 tablets showed that the core tablet was separated from the immediate-release layer of the outer layer part and disintegrated.

[0091] In addition, in the case of GSP 7 and GSP 8 which were prepared by Preparation Method 3 and GSP 1 and GSP 4 which included a low proportion of the immediate-release layer relative to the outer layer part, it is judged that the core tablet is cracked due to the pressure applied during tableting of the tablet in tablet. Since the occurrence of cracks weakens acid resistance of the core tablet, they are unsuitable.

[0092] Taken together, GSP 5 (Example 6) prepared by Preparation Method 2 is shown to have the most preferable separability, disintegrability and inner core stability.

<Experiment 4> Experiment for Comparing Active Ingredient Mosapride Dissolution of Outer Layer Part and Control

[0093] An experiment for comparing dissolution was performed to confirm whether the mosapride-containing outer layer part of the GSP 5 (Example 6) formulation exhibits the same dissolution pattern as a conventional sustained-release tablet.

[0094] In-Vitro Dissolution Test for Active Ingredient Mosapride

[0095] Under dissolution test solution conditions in the Korean Pharmacopoeia, an active ingredient mosapride citrate dissolution rate of the mosapride- and rabeprazole-containing tablet-in-tablet combined preparation for oral administration according to GSP 5 (Example 6) was measured over time, and a dissolution pattern was confirmed.

[0096] Detailed conditions used in the dissolution test are as follows.

[0097] Subject: GSP 5 (mosapride- and rabeprazole-containing tablet-in-tablet combined preparation for oral administration)

[0098] Dissolution test solution: pH 1.2, pH 4.0, pH 6.8, and water according to the dissolution test method in the Korean Pharmacopoeia

[0099] Volume of dissolution solution: 900 ml, Test temperature: 37±0.5° C.

[0100] Test method: The dissolution test method II (paddle method) in the Korean Pharmacopoeia (50 revolutions/min)

[0101] Sample collection: 10 mL of a dissolution solution was taken and filtered through a 0.45-μm filter to obtain a test liquid at each sampling time, and, after taking the dissolution solution, the same amount of a fresh dissolution solution was added.

[0102] Analysis equipment: HPLC

[0103] Test Results

[0104] The in-vitro dissolution test results are shown in the following Tables 7 to 10 and FIGS. 5 to 8.

TABLE-US-00007 TABLE 7 Dissolution rate at pH 4.0 Dissolution rate (%) of mosapride citrate Classifi- 15 30 60 90 120 180 300 360 480 600 720 1440 cation mins mins mins mins mins mins mins mins mins mins mins mins Example 6 33.1 37.7 42 45.5 48.9 54.5 63.8 68 74.8 80.5 84.8 98.9 (GSP 5) Control 24.7 36.7 41.4 45.1 48.7 54.8 64.6 69.1 76.4 82 86.8 100.3 drug (Gastiin CR tab)

TABLE-US-00008 TABLE 8 Dissolution rate in water Dissolution rate (%) of mosapride citrate Classifi- 15 30 60 90 120 180 300 360 480 600 720 1440 cation mins mins mins mins mins mins mins mins mins mins mins mins Example 6 29.8 37 41.5 45.2 48.3 53.5 62.4 66.8 73.4 78.3 83 93.7 (GSP 5) Control 29.1 37.5 42.5 46.2 49.5 55 64.3 68.4 75.4 80.7 85.6 97.5 drug (Gastiin CR tab)

TABLE-US-00009 TABLE 9 Dissolution rate at pH 6.8 Dissolution rate (%) of mosapride citrate Classifi- 15 30 60 90 120 180 300 360 480 600 720 1440 cation mins mins mins mins mins mins mins mins mins mins mins mins Example 6 11.4 15.5 20.7 21.7 23.2 25.7 28.1 29.5 30.4 30.9 31.1 33.7 (GSP 5) Control drug 11 15.8 21.4 22.5 24.3 26.5 28.9 30.1 30.9 31.5 32.5 34.2 (Gastiin CR tab)

TABLE-US-00010 TABLE 10 Dissolution rate at pH 1.2 Dissolution rate (%) of mosapride citrate Classifi- 15 30 60 90 120 180 300 360 480 600 720 1440 cation mins mins mins mins mins mins mins mins mins mins mins mins Example 6 37.1 44.4 47.7 50.1 52 58.7 67.8 72.6 79.6 84.5 89.4 100.2 (GSP 5) Control drug 38.3 45.6 48.5 51.3 54.2 59.6 70.5 73.8 81.5 86.4 91.1 101.5 (Gastiin CR tab)

[0105] Discussion

[0106] As shown in Tables 7 to 10 and FIGS. 5 to 8, an active ingredient mosapride citrate dissolution rate of the GSP 5 (Example 6) exhibits the same dissolution pattern as Gastiin CR tab which is a control drug, and thus it can be seen that the GSP 5 is suitable for a preparation for oral administration once a day.

<Experiment 5> Experiment for Comparing Active Ingredient Rabeprazole Dissolution of Inner Core and Control

[0107] An experiment for comparing dissolution was performed to confirm whether the rabeprazole-containing inner core of the GSP 5 (Example 6) formulation exhibits the same dissolution pattern as a conventional rabeprazole enteric-coated tablet.

[0108] In-Vitro Dissolution Test for Active Ingredient Rabeprazole Sodium

[0109] Under a pH 6.8 dissolution test solution condition in the Korean Pharmacopoeia, an active ingredient rabeprazole sodium dissolution rate of the mosapride- and rabeprazole-containing tablet-in-tablet combined preparation for oral administration according to GSP 5 was measured over time, and a dissolution pattern was confirmed.

[0110] Detailed conditions used in the dissolution test are as follows.

[0111] Subject: GSP 5 (mosapride- and rabeprazole-containing tablet-in-tablet combined preparation for oral administration)

[0112] Dissolution test solution: pH 6.8 according to the dissolution test method in the Korean Pharmacopoeia

[0113] Volume of dissolution solution: 900 ml, Test temperature: 37±0.5° C.

[0114] Test method: The dissolution test method II (paddle method) in the Korean Pharmacopoeia (50 revolutions/min)

[0115] Sample collection: 5 mL of a dissolution solution was taken and filtered through a 0.45-μm filter to obtain a test liquid at each sampling time.

[0116] Analysis equipment: HPLC

[0117] Test Results

[0118] The in-vitro dissolution test results are shown in the following Table 11 and FIG. 9.

TABLE-US-00011 TABLE 11 Dissolution rate at pH 6.8 Dissolution rate (%) of rabeprazole sodium Classification 5 mins 10 mins 20 mins 30 mins 45 mins Example 6 0 2.4 34.2 99.8 101.2 (GSP 5) Control drug 0 0 28.4 97.1 100.1 (Pariet tab 10 mg)

[0119] Discussion

[0120] As shown in Table 11 and FIG. 9, an active ingredient rabeprazole sodium of the GSP 5 (Example 6) exhibits the same dissolution pattern as Pariet tab, which is a control drug, even though being contained in the inner core of the tablet-in-tablet formulation, and thus the GSP 5 is expected to have optimal bioavailability.

[0121] In conclusion, due to the optimal composition and formulation design, the tablet-in-tablet combined preparation according to the present invention exhibits effects of both the active ingredient of the inner core and the active ingredient of the outer layer part by only one oral administration of a single tablet a day.