Patent Publication Number: US-2021177765-A1

Title: Core tablet composite preparation comprising mosapride and rabeprazole

Description:
TECHNICAL FIELD 
     This application claims priority to and the benefit of Korean Patent Application No. 10-2017-0172473, filed on Dec. 14, 2017, the disclosure of which is incorporated herein by reference in their entirety. 
     The present invention relates to a combined preparation in a tablet-in-tablet formulation, which is composed of an inner core containing rabeprazole as an active ingredient and an outer layer part containing mosapride as an active ingredient and having a bilayer structure of a sustained-release layer and an immediate-release layer. 
     BACKGROUND ART 
     Mosapride, which is a selective serotonin 5-hydroxytryptamine 4 (hereinafter, referred to as “5-HT4”) receptor agonist, is a drug that promotes the release of acetylcholine at the nerve end by selectively stimulating only the serotonin 5-HT4 receptors present in the myenteric plexus, in which the acetylcholine contracts the smooth muscle of the digestive tract and promotes digestive tract motility, thereby showing excellent efficacy in the treatment of diabetic gastropathy, dyspepsia, gastritis, and gastroesophageal reflux disease. Mosapride is a safe drug that is free from the risk of arrhythmia or sudden cardiac death caused by the prolongation of the QT interval shown in cisapride which is a non-selective 5-HT4 receptor agonist and has no side effects such as central nervous system (CNS) side effects (extrapyramidal symptoms), hyperprolactinemia (lactation, gynecomastia), or the like without dopamine-2 (D-2) receptor antagonism. 
     Meanwhile, rabeprazole, which is a benzimidazole derivative, is a drug that inhibits gastric acid secretion and is known as a proton pump inhibitor (PPI) that inhibits gastric acid secretion by inhibiting H + /K +  ATPase on the surface of the parietal cells of the gastric mucosa for acid secretion. Furthermore, rabeprazole induces inhibition of basal acid secretion and acid secretion by stimulation and is thus attracting attention as a therapeutic agent for peptic ulcers, duodenal ulcers, and the like. 
     Although combined preparations of the two components having similar drug efficacy have advantages in that they can replace combination therapies, improve a patient&#39;s medication convenience, and can be more economical than administering each agent in combination, there is a concern that a change in dissolution pattern or side effects in the body may occur due to an interaction between drugs. 
     Meanwhile, various formulations for a mosapride and rabeprazole combined preparation are proposed in Korean Laid-open Patent Application No. 2016-0080449, but there is much to be studied on the specific and detailed composition and dosage form of a tablet-in-tablet combined preparation including rabeprazole as an inner core and a mosapride sustained-release preparation as an outer layer part for improving bioavailability. 
     DISCLOSURE 
     Technical Problem 
     The present invention is directed to providing a tablet-in-tablet combined preparation which overcomes the drawbacks of the conventional art related to rabeprazole and mosapride combined preparations and improves bioavailability and medication convenience, and the tablet-in-tablet combined preparation according to the present invention has the same effect as administering a single rabeprazole tablet once and a single mosapride immediate-release tablet three times by only one oral administration of a single tablet a day. 
     Technical Solution 
     One aspect of the present invention provides a 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. 
     In addition, 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. 
     Due to the inner core containing rabeprazole as an active ingredient and the outer layer part having a bilayer structure of an immediate-release layer and a sustained-release layer and containing mosapride as an active ingredient, the tablet-in-tablet combined preparation according to the present invention has the same effect as generally administering a single mosapride tablet three times a day and a single rabeprazole tablet once by only one oral administration of a single tablet a day. 
     In this case, a weight ratio of the sustained-release layer and the immediate-release layer of the outer layer part preferably ranges from 1:1.5 to 1:2.5, and the position of the inner core relative to each layer of the outer layer part may vary depending on the weight ratio. Specifically, the inner core is positioned relatively more toward the immediate-release layer side of the outer layer part, so that a better effect of dissolving the active ingredient of the inner core is exhibited, and the stability of the tablet is maintained. 
     As described above, as the inner core is positioned relatively more toward the immediate-release layer side of the outer layer part, the area of the inner core surface surrounded by the immediate-release layer of the outer layer part is larger than that surrounded by the sustained-release layer of the outer layer part. 
     When the proportion of the immediate-release layer relative to the sustained-release layer is less than the above-described range, the inner core is not rapidly separated and dissolved, and thus the dissolution may be delayed, and on the other hand, when the proportion is more than the above-described range, the stability of the inner core is decreased in tableting, and thus it is likely that cracks occur during the dissolution. 
     In the sustained-release layer of the outer layer part, as the release-modifying agent, a mixture of hydroxypropyl methylcellulose having a viscosity of 75,000 to 140,000 mPa·s and hydroxypropyl methylcellulose having a viscosity of 3,000 to 5,600 mPa·s is used, and, with respect to the 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·s and 30 to 40 wt % of the hydroxypropyl methylcellulose having a viscosity of 3,000 to 5,600 mPa·s are preferably included. 
     When the composition ratio of the release-modifying agent is out of the above-described range, the dissolution of the active ingredient is excessively delayed, or the active ingredient is excessively released at the early stage, so that a sufficient sustained-release effect is not exhibited. 
     Each of the immediate-release layer and sustained-release layer of the outer layer part contains mosapride citrate as an active ingredient. In this case, the immediate-release layer preferably contains 4 to 6 mg of the active ingredient, and the sustained-release layer preferably contains 9 to 12 mg of the active ingredient. 
     When the immediate-release layer contains less than 4 mg of the active ingredient or the sustained-release layer contains less than 9 mg of the active ingredient, the active ingredient is not sufficiently dissolved at the early stage, and thus the pharmacological effects equivalent to that of administration three times a day is not exhibited. On the other hand, when the immediate-release layer contains more than 6 mg of the active ingredient or the sustained-release layer contains more than 12 mg of the active ingredient, the blood concentration of the active ingredient may be excessively increased, and thus side effects such as vomiting, dizziness, and the like may occur. 
     According to the tablet-in-tablet combined preparation of the present invention, the sustained-release layer of the outer layer part contains, with respect to the total weight of the sustained-release layer, 12 to 16 wt % of mosapride citrate and 20 to 40 wt % of the release-modifying agent. When the release-modifying agent is contained in an amount of less than 20 wt %, sustained release is not sufficiently achieved, and when contained at more than 40 wt %, the dissolution of the active ingredient is excessively delayed, and thus a pharmacological effect is decreased. 
     Since the tablet-in-tablet combined preparation of the present invention has a structure in which the outer layer part surrounds the inner core, the size of the whole formulation depends on the size of the inner core. Therefore, a total weight of the inner core is preferably 70 mg or less for a patient&#39;s medication convenience and 30 mg or more for maintaining the stability of the inner core in tableting, and is more preferably 40 mg to 60 mg. In addition, the inner core may be coated with an enteric coating agent to enhance the bioavailability of rabeprazole. 
     In addition, a total weight of the tablet-in-tablet combined preparation including the inner core and the outer layer part is preferably 250 mg or more for the stability of the tablet and 350 mg or less for a patient&#39;s medication convenience. 
     The tablet-in-tablet combined preparation of the present invention is prepared by a method including the following steps: 
     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. 
     When the steps are performed, particularly, in the order of a step of feeding immediate-release layer granules; a step of adding an inner core; a step of applying pre-pressure; a step of feeding sustained-release layer granules; and a step of performing tableting while applying main pressure, the position of the inner core relative to the outer layer part and the stability of the tablet are most preferably exhibited. 
     In addition, the pre-pressure preferably ranges from 0.5 to 2 kgf/cm 2 , and the main pressure preferably ranges from 3 to 20 kgf/cm 2 , and most preferably, 8 to 15 kgf/cm 2 . 
     When the pre-pressure does not reach the above-described range, the inner core is not uniformly positioned. When the main pressure is less than 3 kgf/cm 2 , the hardness of the tablet-in-tablet combined preparation is decreased, and thus the combined preparation may easily disintegrate, and when the main pressure is more than 20 kgf/cm 2 , cracks may occur due to excessive pressure. 
     Advantageous Effects 
     A tablet-in-tablet combined preparation according to the present invention can have the same effect as administering a single rabeprazole tablet once and a single mosapride immediate-release tablet three times by only one oral administration of a single tablet a day. 
     In addition, the tablet-in-tablet combined preparation of the present invention has a structure in which an inner core containing a proton pump inhibitor (PPI) is surrounded by an outer layer part having a bilayer structure and containing mosapride. This formulation has not been proposed in the prior art, and the size of the tablet is smaller than that of a conventional tablet-in-tablet preparation, resulting in high medication convenience and excellent stability of the formulation. 
    
    
     
       DESCRIPTION OF DRAWINGS 
         FIG. 1  is a schematic diagram of a tablet-in-tablet preparation according to the present invention. 
         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. 
         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. 
         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. 
         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. 
         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. 
         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. 
         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. 
         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 
     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. 
     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. 
     Step 1: Preparation of a proton pump inhibitor (PPI) portion (rabeprazole sodium) as a core tablet. 
     Step 2: Preparation of a digestive tract motility promoter portion (mosapride citrate dihydrate) as an immediate-release layer of an outer layer part. 
     Step 3: Preparation of a digestive tract motility promoter portion (mosapride citrate dihydrate) as a sustained-release layer of an outer layer part. 
     Step 4: Tableting of the core tablet and mixtures which are prepared in the Step 1 to Step 3 into a tablet in tablet. 
     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. 
     Step 1: Preparation of PPI Portion (Rabeprazole Sodium) as Inner Core 
     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). 
     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. 
     Step 2: Preparation of Digestive Tract Motility Promoter Portion (Mosapride Citrate Dihydrate) as Immediate-Release Layer of Outer Layer Part 
     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. 
     Step 3: Preparation of Digestive Tract Motility Promoter Portion (Mosapride Citrate Dihydrate) as Sustained-Release Layer of Outer Layer Part 
     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·s and hydroxypropyl methylcellulose having a viscosity of 3,000 to 5,600 mPa·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. 
     Step 4: Tableting of Core Tablet and Mixtures which are Prepared in Step 1 to Step 3 into a Tablet in Tablet 
     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. 
     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 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 2 , preferably, 8 to 15 kgf/cm 2 . 
     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. 
     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&#39;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. 
     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. 
     &lt;Experiment 1&gt; Design of Outer Layer Part and Selection of Optimal Composition 
     Based on the applicant&#39;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. 
     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. 
     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. 
     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. 
     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 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·s) 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                 Release- 
                 Hypromellose 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                 modifying 
                 2208 (viscosity 
                 12.0 
                 16.0 
                 12.0 
                 15.0 
                 18.0 
                 17.0 
               
               
                   
                   
                 agent 
                 100,000 
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 mPa·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 
               
               
                   
               
            
           
         
       
     
     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 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) 
               
               
                   
               
            
           
         
       
     
     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. 
     Particularly, Example 3 whose dissolution pattern was very similar to that of the control drug was shown to be the most preferable. 
     &lt;Experiment 2&gt; Design of Inner Core and Selection of Optimal Composition 
     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&#39;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. 
     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. 
     In the preparation of the inner core, a circular punch with a 4π diameter was used. 
     
       
         
           
               
               
               
               
             
               
                 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 
               
               
                   
               
            
           
         
       
     
     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 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) 
               
               
                   
                   
               
            
           
         
       
     
     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. 
     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. 
     &lt;Experiment 3&gt; Preparation of Tablet in Tablet and Selection of Optimal Composition According to Weight Ratio of Each Layer of Outer Layer Part 
     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. 
     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. 
     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. 
     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. 
     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. 
     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. 
     Meanwhile, each preparation method listed in Table 5 is as follows. 
     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 2 . 
     Preparation method 2: feeding immediate-release layer granules; adding the inner core; applying a pre-pressure of 1 kgf/cm 2 ; feeding sustained-release layer granules; and applying a main pressure of 8.5 kgf/cm 2 . 
     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 2 ; feeding sustained-release layer granules; and applying a main pressure of 8.5 kgf/cm 2 . 
     
       
         
           
               
               
             
               
                 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·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·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 
               
               
                   
               
            
           
         
       
     
     Observation of Presence or Absence of Separation and Disintegration Stability of Inner Core 
     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 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) 
               
               
                   
               
            
           
         
       
     
     Discussion 
     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. 
     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. 
     Taken together, GSP 5 (Example 6) prepared by Preparation Method 2 is shown to have the most preferable separability, disintegrability and inner core stability. 
     &lt;Experiment 4&gt; Experiment for Comparing Active Ingredient Mosapride Dissolution of Outer Layer Part and Control 
     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. 
     In-Vitro Dissolution Test for Active Ingredient Mosapride 
     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. 
     Detailed conditions used in the dissolution test are as follows. 
     Subject: GSP 5 (mosapride- and rabeprazole-containing tablet-in-tablet combined preparation for oral administration) 
     Dissolution test solution: pH 1.2, pH 4.0, pH 6.8, and water according to the dissolution test method in the Korean Pharmacopoeia 
     Volume of dissolution solution: 900 ml, Test temperature: 37±0.5° C. 
     Test method: The dissolution test method II (paddle method) in the Korean Pharmacopoeia (50 revolutions/min) 
     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. 
     Analysis equipment: HPLC 
     Test Results 
     The in-vitro dissolution test results are shown in the following Tables 7 to 10 and  FIGS. 5 to 8 . 
     
       
         
           
               
             
               
                 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 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 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 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) 
               
               
                   
               
            
           
         
       
     
     Discussion 
     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. 
     &lt;Experiment 5&gt; Experiment for Comparing Active Ingredient Rabeprazole Dissolution of Inner Core and Control 
     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. 
     In-Vitro Dissolution Test for Active Ingredient Rabeprazole Sodium 
     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. 
     Detailed conditions used in the dissolution test are as follows. 
     Subject: GSP 5 (mosapride- and rabeprazole-containing tablet-in-tablet combined preparation for oral administration) 
     Dissolution test solution: pH 6.8 according to the dissolution test method in the Korean Pharmacopoeia 
     Volume of dissolution solution: 900 ml, Test temperature: 37±0.5° C. 
     Test method: The dissolution test method II (paddle method) in the Korean Pharmacopoeia (50 revolutions/min) 
     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. 
     Analysis equipment: HPLC 
     Test Results 
     The in-vitro dissolution test results are shown in the following Table 11 and  FIG. 9 . 
     
       
         
           
               
             
               
                 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) 
                   
                   
                   
                   
                   
               
               
                   
               
            
           
         
       
     
     Discussion 
     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. 
     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.