KR20220069270A - pH-dependent tablet-in-capsule combination formulation containing dexransoprazole as an active ingredient and method for preparing the same - Google Patents

Abstract

The present invention relates to a pH-dependent tablet-in-capsule composite formulation comprising dexlansoprazole as an active ingredient, and a method for preparing the same. More specifically, the present invention relates to a hard capsule comprising a plurality of first tablets which release dexlansoprazole as an active ingredient at a pH of 5.5 and second tablets which release dexlansoprazole as an active ingredient at a pH of 7.0 or higher, wherein the tablets are tables for controlling release time according to pH by being coated with an enteric coating agent having different solubility according to the pH; are formulations designed to continuously maintain blood concentration; and are excellent in the convenience of administration by including several mini tablets in one hard capsule.

Description

A pH-dependent tablet-in-capsule combination formulation containing dexransoprazole as an active ingredient and a method for preparing the same

The present invention relates to a pH-dependent tablet-in-capsule combination formulation comprising dexransoprazole as an active ingredient and a method for preparing the same. Specifically, the present invention is a hard capsule comprising a plurality of first tablets that release dexlansoprazole, an active ingredient, at pH 5.5, and a second tablet, a plurality of second tablets, which release dexlansoprazole, an active ingredient, at pH 7.0 or higher in the capsule, wherein the tablet Silver is a tablet that is coated with an enteric coating agent that has different solubility depending on the pH and can control the release time depending on the pH. It is excellent in terms of convenience.

Dexransoprazole is a type of proton pump inhibitors (H ⁺ pump inhibitors). It effectively inhibits gastric acid production to treat and maintain erosive esophagitis, and treat heartburn associated with symptomatic non-erosive gastroesophageal reflux disease. As a drug approved by the Food and Drug Administration (FDA), it is widely used as a treatment for peptic ulcer.

However, the dexlansoprazole is poorly soluble in water, is very unstable to acid, and is easily decomposed in gastric juice, which is an acidic solution. In an aqueous solution, the pH affects the stability of dexlansoprazole. In other words, dexlansoprazole is structurally very unstable in acidic conditions, so it is easily decomposed by gastric acid when administered orally, so it is difficult to expect pharmacological effects.

Therefore, for effective delivery of dexlansoprazole into the body through oral administration, it is necessary to design a controlled drug release formulation with improved dissolution properties in the upper small intestine while minimizing the loss of activity due to gastric acid by enteric coating. This is because, if delayed release from the small intestine is achieved, not only the bioavailability of the drug can be improved, but also the medication compliance can be greatly improved by reducing the number of times taken.

On the other hand, a controlled drug release formulation controls the release rate of a drug so that the active ingredient can be absorbed into the body under desired conditions. The controlled release agent has the advantage of being able to effectively control the blood concentration of the drug. A drug has a specific blood concentration range (therapeutic index) that can be expected to be treated, and a therapeutic effect can be expected only when the blood concentration reaches and maintains this range. If the release is not controlled, the blood concentration is too high, indicating toxicity, or the concentration cannot be maintained for a long time. On the other hand, the controlled release formulation has the advantage of overcoming these disadvantages and continuously maintaining the effective blood concentration. This point has an outstanding advantage in that it reduces the number of administration of the drug and improves the patient's medication compliance.

Under this background, the present inventors tried to develop an effective formulation through controlled release of dexlansoprazole.

Korean Patent Registration No. 10-1401913 (2014.05.26.)

In the case of a hard capsule combination formulation in which a plurality of tablets coated with an enteric coating agent having different pH solubility to release dexlansoprazole at different pHs in a single capsule, the ease of administration of the drug is increased, and at the same time, it is not decomposed in the stomach. The present invention was completed by knowing that dexlansoprazole was continuously released according to the change of pH in the small intestine and the frequency of administration of the drug could be reduced. Specifically, in the case of the hard capsule combination formulation according to the present invention, it is not released in the stomach at a pH of 1.0 to 1.5, the first tablet is rapidly released when the pH is near 5.5, and when the pH is near 7.0, the second tablet is released from 30 minutes to It is possible to realize sustained release in which the drug is slowly released through a lag time that is rapidly released after having a lag time of about 60 minutes.

Accordingly, it is an object of the present invention to provide a pH-dependent tablet-in-capsule combination formulation comprising dexlansoprazole as an active ingredient and a method for preparing the same.

Accordingly, in order to achieve the above object, the present invention provides a core containing dexlansoprazole or a salt thereof as an active ingredient in a capsule, and an enteric coating layer that melts at pH 5.5 or higher as a coating film covering the surface of the core. a first tablet; and a second tablet comprising a core comprising Dexlansoprazole or a salt thereof as an active ingredient, and an enteric coating layer that dissolves at pH 7.0 or higher as a coating film covering the surface of the core, pH-dependent tablet-in- Capsule combination formulations are provided.

In addition, the present invention comprises the steps of (a) mixing dexlansoprazole, a stabilizer, and a disintegrant in an alcohol solution to form granules; (b) mixing the granules with a diluent, a disintegrant, a lubricant, and a glidant and tableting to prepare a tablet; (c) coating the tablet with a water-soluble coating agent to form a water-soluble film layer; (d) a first tablet having a pH of 5.5 at which dissolution starts by coating an enteric coating agent having a pH of 5.5 or an enteric coating agent having a pH of 7.0 or higher at which dissolution starts on the tablets prepared in step (c), respectively, and preparing a second tablet having a pH of 7.0 or higher, respectively; and (e) encapsulating the first tablet and the second tablet in a capsule to prepare a pH-dependent tablet-in-capsule combination preparation;

Tablet-in-capsule combination formulation according to the present invention is protected by a coating film so that dissolution starts at pH 5.5 or higher, dexlansoprazole corresponding to a proton pump inhibitor (PPI) from the stomach under acidic conditions can protect

In addition, since it contains a plurality of heterogeneous tablets with different pH where the coating film dissolves and starts dissolution, delayed release is possible in two steps according to the pH change in the intestine, reducing the number of medications to once or twice a day. This can improve patient adherence to medication.

In addition, storage stability of the drug was also secured because the storage stability was improved even under severe conditions.

Figure 1 (a) shows a cross-section of the pH-dependent tablet-in-capsule combination formulation according to the present invention, and Figure 1 (b) shows the pH-dependent dissolution change of the tablet-in-capsule combination formulation according to the present invention. This is the graph shown.
Figure 2 is a result of confirming the dissolution pattern according to the presence / absence and type of disintegrant in the tablet.
3 is a result confirming the dissolution pattern at pH 1.2 and 5.5 of the first tablet according to the present invention.
4 is a result confirming the dissolution pattern at pH 1.2 and 7.0 of the second tablet according to the present invention.
5 is a comparison result of dissolution experiments in pH 1.2 and 7.0 solutions of the tablet-in-capsule combination formulation according to the present invention and the commercially available product.
6 is a comparison result of dissolution experiments in a pH 7.5 solution of the tablet-in-capsule combination formulation according to the present invention and a commercially available product.
7 shows the first tablet and the second tablet before coating, ethanol coating, and after water-based coating, and stored for 10 days at room temperature (20 ℃), or for 30 days under severe (40 ℃, relative humidity 75%) conditions. This is the result of checking the color change inside the tablet.
8 is a result confirming the change in the content of the active ingredient of the tablet-in-capsule combination formulation according to the present invention and a commercially available product as a comparative example.

The present inventors developed an effective formulation through controlled release of dexlansoprazole, in the capsule, a first tablet that releases dexlansoprazole, an active ingredient, at pH 5.5, and a second tablet that releases dexlansoprazole, an active ingredient, at pH 7.0 or higher. In the case of a hard capsule combination formulation containing a plurality of In addition, the present invention was completed by finding that it is convenient to take the bar containing several mini-tablets in one hard capsule (FIG. 1). Specifically, in the case of the hard capsule combination formulation according to the present invention, it is not released in the stomach at a pH of 1.0 to 1.5, the first tablet is rapidly released when the pH is near 5.5, and when the pH is near 7.0, the second tablet is released from 30 minutes to It is possible to realize sustained release in which the drug is slowly released through a lag time that is rapidly released after having a lag time of about 60 minutes.

Hereinafter, the present invention will be described in more detail.

The present invention provides a first tablet comprising a core containing dexlansoprazole or a salt thereof as an active ingredient in a capsule, and an enteric coating layer that melts at pH 5.5 or higher as a coating film covering the surface of the core; and a second tablet comprising a core comprising Dexlansoprazole or a salt thereof as an active ingredient, and an enteric coating layer that dissolves at pH 7.0 or higher as a coating film covering the surface of the core, pH-dependent tablet-in- Capsule combination formulations are provided.

The active ingredient of the present invention, “dexlansoprazole”, is a compound represented by the following formula (1), which acts as a proton pump inhibitor (PPI), such as gastric acid secretion inhibitory action or gastric mucosal defense action, and is digestible. It is widely used as a treatment for ulcers.

[Formula 1]

The pH-dependent tablet-in-capsule combination formulation according to the present invention comprises a first tablet comprising dexlansoprazole or a salt thereof in the core, and an enteric coating layer that dissolves at pH 5.5 or higher; and a second tablet including a plurality of second tablets including an enteric coating layer that melts at pH 7.0 or higher, in which the tablet is included in the capsule (FIG. 1).

In addition, the tablet in the present invention is a tablet capable of controlling the release of dexlansoprazole in the core by coating it with a material that dissolves in a pH-dependent manner. In the present invention, the enteric coating layer does not disintegrate and dissolution for 2 hours in gastric juice conditions near pH 1.2. However, upon reaching the upper digestive tract and the surrounding pH is 5.5, the coating of the first tablet dissolves and rapidly releases the dexlansoprazole in the core. Thereafter, when the ambient pH becomes 7.0 or higher, the coating layer of the second tablet dissolves the coating layer with a lag time of 30 minutes to 1 hour to completely elute dexlansoprazole in the core tablet.

In the present invention, "pH dependence" means that the coating material is dissolved or eluted under an environment exceeding a specific pH value to release the active ingredient. While conventional enteric coatings elute at a pH of about 5.5 and start drug release, in the present invention, it is a drug designed to dissolve slowly at a pH of 5.5 and a pH of 7.0 or more with a time difference. You can control it with preference. In addition, the thickness of the coating was adjusted so that dexlansoprazole was released from the second tablet after necessarily having a lag time of 30 to 60 minutes when the surrounding pH reached near 7.0.

In the present invention, the enteric coating layer is a coating layer located at the outermost portion of the oral tablet according to the present invention, and serves to inhibit the release of the drug from the stomach. The enteric coating layer refers to a coating layer formed by coating the surface of the core with an enteric coating.

The first tablet and the second tablet may be included in a weight ratio of 1 to 5: 5 to 1, preferably 1: 2 to 3 by weight. This is, when the surrounding of the tablet is pH 5.5, it primarily releases the dexlansoprazole of the first tablet quickly, and then has a lag time of 30 minutes to 60 minutes at 7.0 and secondarily, the dexlansoprazole of the second tablet This is to achieve the effect of delayed-release and sustained-release of maintaining blood concentration for a long time by completely releasing

In the present invention, 'lag time' means a time interval from when the coated tablet reaches a predetermined pH until the coating film is peeled off and the dissolution of the drug, dexlansoprazole, starts.

Specifically, the enteric coating layer of the first tablet is an enteric coating layer that dissolves at pH 5.5 or higher, and as a methacrylic acid copolymer that dissolves at pH 5.5, Eudragit L100-55, Eudragit L100, Eudragit RS100, Eudragit RS100 It may be at least one selected from the group consisting of Jit L 12.5 P, Eudragit L 12.5, Eudragit L 30 D-55, Eudragit S 12.5 P, Eudragit S 12.5, and Eudragit FS 30 D. Preferably, it may be one selected from the group consisting of Eudragit L100-55, Eudragit L100, and Eudragit RS100, and more preferably, Eudragit L100-55.

The enteric coating layer of the second tablet is an enteric coating layer that dissolves at a pH of 7.0 or higher, and preferably has a pH of 7.0 to 8.0. Eudragit S100, Eudragit RL 12.5, Eudragit RL 100, Eudragit L100, Eudragit L100-55, Eudragit RL P0, Eudragit RL P0 as a methacrylic acid copolymer soluble at pH 7.0 or higher RL 30 D, Eudragit RS 12.5, Eudragit RS 100, Eudragit RS P0, Eudragit RS 30 D, Eudragit NE 30 D, Eudragit NE 40 D and Eudragit NM 30 D, etc. It may be at least one selected from the group consisting of. Preferably, it may be one selected from the group consisting of Eudragit S100, Eudragit L100-55, and Eudragit RS100, and more preferably, Eudragit S100.

In addition, the enteric coating layer in the first tablet and the second tablet is added to at least one alcohol solution selected from the group consisting of methanol, ethanol, propanol and its isomers, butanol and its isomers, pentanol and its isomers, hexanol and its isomers. It is a coating layer formed by coating a coating agent prepared by mixing an enteric coating material. When the coating agent contains water, such as water, it is preferable to use an alcohol solution because it inhibits the stability of the tablet.

In addition, the tablet may have a water-soluble subcoating formed between the core and the enteric coating layer. The water-soluble film layer may be at least one selected from the group consisting of cellulose ether, polyvinylpyrrolidone, and polyvinyl alcohol (opadry).

The water-soluble coating layer is a coating layer present between the core comprising the oral tablet composition and the enteric coating layer, and allows the enteric coating layer to be coated effectively and stably, and the effect of dexlansoprazole on the pH of the enteric coating layer during coating serves to minimize

Both the enteric coatings of the first tablet and the second tablet should not dissolve for more than 2 hours in an acidic gastrointestinal environment, pH 1.0 to 1.5 (preferably pH 1.2). On the other hand, the coating of the first tablet elutes rapidly at a pH of about 5.5 and starts drug release, and the coating of the second tablet has a lag time of 30 to 60 minutes when the surrounding pH reaches 7.0 or higher. Be sure to dissolve after stirring to release dexlansoprazole.

More specifically, the first tablet and the second tablet have a dissolution rate of dexlansoprazole of 5% or less for 2 hours in an acidic condition of pH 1.0 to 1.5, and the first tablet is dexlansoprazole for 0 to 30 minutes when pH 5.5 is reached dissolution rate of 85% or more, and when the second tablet reaches pH 7.0 or higher, the dissolution rate of dexlansoprazole is 5% or less within 0 to 60 minutes, and thereafter, the dissolution rate of dexlansoprazole is 85 for 0 to 60 minutes again % or more. In other words, the second tablet releases the core component after having a lag time of at least 30 to 60 minutes at pH 7.0.

The tablet-in-capsule combination formulation comprising the first tablet and the second tablet has a dissolution rate of 5% or less of the total dexlansoprazole for 2 hours under acidic conditions of pH 1.0 to 1.5, and then at pH 7.0 for 20 minutes More than 15% of the total dexlansoprazole is eluted, less than 35% is eluted in 50 minutes, and more than 80% of the total amount is eluted within 105 minutes. will do

On the other hand, in the case of the content, the enteric coating layer formed by the enteric coating agent of the first tablet is preferably included in an amount of 5 to 15 parts by weight based on 100 parts by weight of the first tablet, more preferably 8 to 10 parts by weight.

In addition, the enteric coating layer formed by the enteric coating agent of the second tablet is preferably included in an amount of 5 to 20 parts by weight, more preferably 9 to 13 parts by weight, based on 100 parts by weight of the second tablet.

This is to design to have a delay time difference between the rapid release of the first tablet and the drug release of the second tablet. Ultimately, sustained release of the drug can be realized through dual release by two types of tablets with different dissolution patterns according to pH.

In this case, the size of the capsule containing the tablets may be no. 0 or less. This is because the composition and manufacturing method of the present invention can be conveniently taken by encapsulating three mini-tablets in one capsule.

In addition, the present invention comprises the steps of (a) mixing dexlansoprazole, a stabilizer and a disintegrant with a binder and an alcohol solution, and forming granules; (b) mixing the granules with a diluent, a disintegrant, a lubricant, and a glidant and tableting to prepare a tablet; (c) coating the tablet with a water-soluble coating agent to form a water-soluble film layer; (d) a first tablet having a pH of 5.5 at which dissolution starts by coating the tablet with an enteric coating agent having a pH of 5.5 or an enteric coating agent having a pH of 7.0 or higher to start dissolution, and a second tablet having a pH of 7.0 or higher preparing each; and (e) encapsulating the first tablet and the second tablet in a capsule to prepare a pH-dependent tablet-in-capsule combination preparation.

In step (a), dexlansoprazole, a stabilizer, a binder, and a disintegrant are mixed in an alcohol solution to form granules, and dexlansoprazole, a stabilizer and a disintegrant are mixed in a dry state for 5 to 30 minutes. After mixing, polyvinylpyrrolidone as a binder and an alcohol solution as a binder are added, mixed, and then wet granulation to prepare granules. The binder may be at least one selected from the group consisting of polyvinylpyrrolidone, carboxymethylcellulose, pregelatinized starch, polyvinyl alcohol and hydroxypropyl cellulose, but must be It is not limited thereto.

The granules in step (a) may be granulocytes passed when sieved with a sieve of 16 to 20 mesh. The granules may be dried at a temperature of 30 to 50° C. and used.

In preparing the pH-dependent tablet-in-capsule combination formulation, the stabilizing agent is important in terms of maintaining the stability of dexlansoprazole, and the disintegrating agent is important in terms of the rapid release of dexlansoprazole.

In the present invention, it is preferable to use magnesium carbonate (MgCO ₃ ) or disodium phosphate (Na ₂ HPO ₄ ) or a complex thereof as a stabilizer, and croscarmellose sodium as a disintegrant.

In addition, the alcohol solution may include at least one selected from the group consisting of methanol, ethanol, propanol and its isomers, butanol and its isomers, pentanol and its isomers, hexanol and its isomers. Water is not included in the coating, because it impairs the stability of the drug.

Step (b) is a step of preparing a tablet by mixing a diluent, a disintegrant, a lubricant, and a glidant with the granules and tableting.

The diluent serves to increase the total amount of powder sufficient for tablet compression. The diluent is one selected from the group consisting of lactose, Avicel, cellulose, kaolin, mannitol, sodium chloride, dry sugar and calcium sulfate It may include the above, but is not necessarily limited thereto.

The lubricant improves the fluidity of the dexlansoprazole particles, prevents friction between the particles, and prevents the dexlansoprazole particles from adhering to the tableting machine. The lubricant may include one or more selected from the group consisting of magnesium stearate, stearic acid, zinc stearate, calcium stearate, talc, sodium stearyl fumarate, talc, silicon dioxide and colloidal silicon dioxide, but is not necessarily limited thereto. .

The fluidizing agent prevents the tablet constituents from adhering to the surface of the compression machine, and serves to improve the flow rate of tablet granules to facilitate tablet compression. The fluidizing agent is selected from the group consisting of talc, magnesium stearate, calcium stearate, stearic acid, glyceryl behanate and polyethylene glycol. It may include, but is not necessarily limited to, more than one species. In the present invention, the tablet may be manufactured by a dry direct hitting method, but is not limited thereto.

Step (c) is a step of forming a water-soluble film layer by coating the tablet with a water-soluble coating agent.

The water-soluble coating agent may include at least one selected from the group consisting of cellulose ether, polyvinylpyrrolidone, and polyvinyl alcohol mixture (opadry).

As an embodiment, the water-soluble coating agent prepared by dissolving polyvinyl alcohol mixed (Opadry) powder in an alcohol solution may be coated in an amount of 1 to 5 parts by weight based on 10 parts by weight of the tablet, and the process of dissolving the polyvinyl alcohol mixed powder is ethanol Add polyvinyl alcohol mixed powder while stirring the solution, and it is preferable to stir quickly at a speed of 10 to 200 rpm so that the powder does not float on the surface.

It is also preferable to use an alcohol solvent as the solvent of the water-soluble coating agent, since it inhibits the stability of the drug.

In the step (d), the dissolution starting pH is 5.5, or the dissolution starting pH is 7.0 or higher by coating the enteric coating agent on the tablet, respectively, the dissolution starting pH 5.5 the first tablet and the first tablet at pH 7.0 or higher It is a step to manufacture 2 tablets, respectively.

The enteric coating agent of the first tablet is a methacrylic acid copolymer having a pH of 5.5 at which dissolution begins, Eudragit L100-55, Eudragit L100, Eudragit RS100, Eudragit L 12.5 P, Eudragit L 12.5, Eudragit L 30 D-55, Eudragit S 12.5 P, Eudragit S 12.5, and may be at least one selected from the group consisting of Eudragit FS 30 D. Preferably, it may be one selected from the group consisting of Eudragit L100-55, Eudragit L100, and Eudragit RS100, and more preferably, Eudragit L100-55.

The enteric coating agent of the second tablet is an enteric coating layer having a pH of 7.0 or higher at which dissolution starts, and Eudragit S100, Eudragit RL 12.5, Eudragit RL 100, as a methacrylic acid copolymer that dissolves at pH 7.0 or higher, Eudragit L100, Eudragit L100-55, Eudragit RL P0, Eudragit RL 30 D, Eudragit RS 12.5, Eudragit RS 100, Eudragit RS P0, Eudragit RS 30 D, It may be at least one selected from the group consisting of Eudragit NE 30 D, Eudragit NE 40 D and Eudragit NM 30 D. Preferably, it may be one selected from the group consisting of Eudragit S100, Eudragit L100-55, and Eudragit RS100, and more preferably, Eudragit S100.

In addition, the coating agent is a plasticizer that serves to increase the solubility of drugs, propylene glycol, triethyl citrate, polyethylene glycol, acetyl monoglyceride, glycerin, tributyl citrate, triacetin, diacetin, monoacetin, diethyl It may include one or more selected from the group consisting of phthalates.

Both the enteric coatings of the first tablet and the second tablet should not be dissolved for more than 2 hours in an acidic condition of pH 1.0 to 1.5, which is an acidic gastrointestinal environment. On the other hand, the coating of the first tablet elutes rapidly at a pH of about 5.5 and starts drug release, and the coating of the second tablet has a lag time of 30 to 60 minutes when the surrounding pH reaches 7.0 or higher. Be sure to dissolve after stirring to release dexlansoprazole. More specifically, the first tablet and the second tablet have a dissolution rate of dexlansoprazole of 5% or less under acidic conditions of pH 1.0 to 1.5, and the dissolution rate of dexlansoprazole for 0 to 30 minutes when the first tablet reaches pH 5.5 85% or more, and when the second tablet reaches pH 7.0 or higher, the dissolution rate of dexlansoprazole is 5% or less within 0 to 60 minutes, and the dissolution rate of dexlansoprazole is 85% or more for 0 to 60 minutes thereafter again desirable. In other words, the second tablet releases the core component after having a lag time of at least 30 to 60 minutes at pH 7.0.

The tablet-in-capsule combination formulation comprising the first tablet and the second tablet has a dissolution rate of 5% or less of the total dexlansoprazole for 2 hours under acidic conditions of pH 1.0 to 1.5, and then for 20 minutes at pH 7.0 More than 15% of the total dexlansoprazole is eluted, less than 35% is eluted in 50 minutes, and more than 80% of the total amount is eluted within 105 minutes. will do

On the other hand, in the case of the content, the enteric coating layer formed by the enteric coating agent of the first tablet is preferably included in an amount of 5 to 15 parts by weight based on 100 parts by weight of the first tablet, more preferably 8 to 10 parts by weight.

In addition, the enteric coating layer formed by the enteric coating agent of the second tablet is preferably included in an amount of 5 to 20 parts by weight, more preferably 9 to 13 parts by weight, based on 100 parts by weight of the second tablet.

This is to design to have a delay time difference between the rapid release of the first tablet and the drug release of the second tablet. Ultimately, sustained release of the drug can be realized through dual release by two types of tablets with different dissolution patterns according to pH.

Finally, step (e) is a step of preparing a pH-dependent tablet-in-capsule combination formulation by encapsulating the first tablet and the second tablet in a capsule. Compression at the time of manufacturing the tablet may be a dry direct hitting method, but is not limited thereto.

The tablet-in-capsule combination preparation prepared according to the manufacturing method of the present invention does not dissolution at acidic pH, and is prepared so that dissolution occurs at intestinal pH, and furthermore, the active ingredient is rapidly eluted from the immediate-release tablet at intestinal pH, It is a capsule designed to maintain the blood concentration of the drug over time for a long time.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

Example 1. Preparation of first and second tablets

Tablets of Preparation Examples 1 and 2 containing dexlansoprazole as an active ingredient were prepared based on the composition and content of Table 1 below. Specifically, according to the contents in Table 1, dexlansoprazole, a stabilizer, and a disintegrant were mixed in a dry state for 10 minutes, and then put in an ethanol solution as a binder and polyvinylpyrrolidone K25 as a binder, and a wet granulation method ( Wet granulation) to prepare granules. When the granules thus prepared were sieved through a 16 mesh sieve, granulocytes passing through were obtained, which were dried at a temperature of 40°C. Thereafter, when the granulocytes were sieved again with a 20 mesh sieve, the granulocytes passing through were used as final granules. The granulocytes thus prepared were prepared into tablets using the dry direct hitting method.

Composition (unit: mg) Preparation Example 1 Preparation 2 Granule composition active ingredient Dexlansoprazole 15 15 stabilizer Magnesium carbonate 15 15 disintegrant Croscarmellose sodium 6 - disintegrant Crospovidone - 6 binder PVP K25 2.4 2.4 binder EtOH 10 μL 10 μL Extragranular composition diluent Avicel 38.7 38.7 diluent Lactose 38.7 38.7 disintegrant Croscarmellose sodium 3 - disintegrant Crospovidone - 3 lubricant Magnesium stearate 0.6 0.6 emollient Talc 0.6 0.6 Total tablet mass (mg) 120 120

Experimental Example 1. Confirmation of dissolution rate according to presence/absence and type of disintegrant

For the tablets of Preparation Examples 1 and 2, a dissolution test was performed to compare the dissolution rate difference according to the presence/absence and type of disintegrant. Specifically, the dissolution test was performed at 37 ± 0.5 ° C, pH 7.0, 900 mL of phosphate buffer (containing 5 mM SDS) at 100 rpm for 30 minutes according to the first method according to the United States Pharmacopoeia (USP).

As a result of Figure 2, it was confirmed that the degree of dissolution rate may vary depending on the type of disintegrant. In the present invention, in the case of Preparation Example 1 using croscarmellose sodium, the dissolution effect was the most excellent, and it can be determined that it is most preferable to use croscarmellose sodium as a disintegrant.

Experimental Example 2. Confirmation of dissolution pattern change according to the thickness of the coating layer of the first tablet

A first tablet of the composition of Preparation Example 3 and Preparation Example 4 was prepared in which an enteric-coated core tablet having the same composition as in Preparation Example 1 was coated with different thicknesses as shown in Table 2. The tablet was coated with a water-soluble coating agent prepared by dissolving polyvinyl alcohol (Opadry) powder in an alcohol solution so as to be 4 parts by weight based on 100 parts by weight of the tablet. After coating with a water-soluble coating agent, the enteric coating agent prepared by putting Eudragit L100-55 soluble at pH 5.5 or higher in an ethanol solution was coated so as to be 8 parts by weight or 10 parts by weight based on the total weight of the tablet, respectively, Preparation Example 3 and Preparation Example A first tablet of 4 was prepared.

For the first tablet of Preparation Examples 3 and 4 prepared in this way, according to the first method according to the United States Pharmacopoeia (USP), in an aqueous buffer solution of 37 ± 0.5 ° C, pH 1.2, 500 mL at 100 rpm for 120 minutes. After the dissolution test, 400 mL of buffer was continuously added, and the dissolution test was performed in a phosphate buffer (containing 5 mM SDS) at 37 ± 0.5 °C and pH 7.0 at 100 rpm for 60 minutes. That is, after dissolution at pH 1.2 (acidic condition), the dissolution test was performed by jumping the pH to pH 7.0.

Composition (unit: mg) Preparation 3 Preparation 4 Granule composition active ingredient Dexlansoprazole 15 15 stabilizer Magnesium carbonate 15 15 disintegrant Croscarmellose sodium 6 6 disintegrant Crospovidone - - binder PVP K25 2.4 2.4 binder EtOH 10 μL 10 μL Extragranular composition diluent Avicel 38.7 38.7 diluent Lactose 38.7 38.7 disintegrant Croscarmellose sodium 3 3 disintegrant Crospovidone - - lubricant Magnesium stearate 0.6 0.6 glidant Talc 0.6 0.6 Total tablet mass (mg) 120 120 Water-soluble coating (Opadry II) 4.8 4.8 Enteric coating agent (Eudragit L100-55) 9.6 12.0

As a result of FIG. 3 , the dissolution rate of dexlansoprazole was less than 5% by weight for 120 minutes in an aqueous buffer of pH 1.2, and the dissolution rate of dexlansoprazole within 60 minutes in an aqueous buffer of pH 7.0 or higher was 80% by weight or more. In the case of the first tablet of Preparation Example 3 having a low coating layer content, that is, a relatively thin coating layer, dexlansoprazole was released more rapidly, and it was determined that it was most preferable.

Experimental Example 3. Confirmation of dissolution pattern change according to the coating thickness of the second tablet

In the same composition as in Preparation Example 1, the amount of dexlansoprazole and the additive was increased by 1.5 times to the core tablet, which was enteric-coated with different thicknesses as shown in Table 3, and second tablets having the composition of Preparation Examples 5 and 6 were prepared. The tablet was coated with a water-soluble coating agent prepared by dissolving polyvinyl alcohol (Opadry) powder in an alcohol solution so as to be 4 parts by weight based on 100 parts by weight of the tablet. After coating with a water-soluble coating agent, the enteric coating agent prepared by putting Eudragit S100 soluble at pH 7.0 or higher in an ethanol solution was coated so as to be 9 parts by weight or 13 parts by weight based on the total weight of the tablet, respectively, in Preparation Examples 5 and 6 A second tablet was prepared.

For the second tablets of Preparation Examples 5 and 6 thus prepared, according to the first method according to the United States Pharmacopoeia (USP), in an aqueous buffer solution of 37 ± 0.5 ° C., pH 1.2, 500 mL at 100 rpm for 120 minutes. After the dissolution test, 400 mL of buffer was continuously added, and the dissolution test was performed at 37 ± 0.5 °C and pH 7.0 in a phosphate buffer (containing 5 mM SDS) at 100 rpm for 120 minutes.

Composition (unit: mg) Preparation 5 Preparation 6 Granule composition active ingredient Dexlansoprazole 22.5 22.5 stabilizer Magnesium carbonate 22.5 22.5 disintegrant Croscarmellose sodium 9 9 binder PVP K25 2.4 2.4 binder EtOH 15 μL 15 μL Extragranular composition diluent Avicel 31.2 31.2 diluent Lactose 31.2 31.2 lubricant Magnesium stearate 0.6 0.6 emollient Talc 0.6 0.6 Total tablet mass (mg) 120 120 Water-soluble coating (Opadry II) 4.8 4.8 Enteric coating agent (Udragit S-100) 15.6 10.8

As a result of FIG. 4 , the dissolution rate of dexlansoprazole was less than 5% by weight for 120 minutes for both the tablets of Preparation Examples 5 and 6 in the pH 1.2 aqueous buffer.

However, in an aqueous buffer of pH 7.0 or higher, Preparation Example 5 and Preparation Example 6 started to be rapidly released after a lag time of 60 minutes and 30 minutes, respectively, and the dissolution rate of dexlansoprazole was 80% by weight within 30 minutes thereafter. showed abnormality.

Therefore, it could be confirmed that the time at which the dissolution of dexlansoprazole starts was controlled by the degree of enteric coating, and in the present invention, it could be confirmed that a pH-dependent dissolution pattern was exhibited. In addition, since the second tablet of Preparation Example 5 having a high coating layer content, that is, a relatively thick coating layer, released dexlansoprazole rapidly after a delay time difference of about 60 minutes at pH 7.0, it was judged most preferable.

Experimental Example 4. Comparison of dissolution patterns between the tablet-in-capsule combination formulation and the commercial formulation

The tablet of Preparation Example 3 as a first tablet and the tablet of Preparation Example 5 as a second tablet, but the first tablet is one and the second tablet is put into a hard capsule and finally a tablet-in-capsule combination Jane Example 2 was prepared. In addition, a dissolution experiment was performed using a currently commercially available product, Dexilant DR (trade name: Dexilant DR) as Comparative Example 1.

Specifically, according to the first method according to the United States Pharmacopoeia (USP), after the dissolution test at 100 rpm in an aqueous buffer solution of 37 ± 0.5 ° C, pH 1.2, 500 mL at 100 rpm, 400 mL of buffer was continuously added. The dissolution test was carried out at 100 rpm for 120 minutes in a phosphate buffer (containing 5 mM SDS) at 37 ± 0.5 °C and pH 7.0.

As a result of Figure 5, in the case of Example 2, the dissolution rate of dexlansoprazole in the aqueous buffer at pH 1.2 for 120 minutes was less than 5% by weight, and the dissolution rate of dexlansoprazole in the aqueous buffer at pH 7.0 or higher was 25% by weight or less within 60 minutes, 120 80% by weight or more within minutes. That is, the formulation according to the present invention exhibited a gradual dissolution pattern under conditions of pH 7.0 or higher. For reference, in the case of a currently commercially available dexilant product (Dexilant DR), at a pH of 7.0 or higher, 15% by weight or less for 20 minutes, 35% by weight or less for 50 minutes, and 80% by weight or more for 105 minutes are eluted. It was confirmed that Example 2 according to the present invention exhibited a similar dissolution pattern when compared with Comparative Example 1, which is a commercially available dexlansoprazole delayed-release formulation.

Experimental Example 5. Comparison of dissolution patterns of tablet-in-capsule combination formulation and commercial formulation in pH 7.5 solution

The dissolution experiment was performed in the same manner as in Experimental Example 1, but the dissolution patterns of Example 2 and Comparative Example 1 were confirmed in 900 mL of a phosphate buffer (containing 5 mM SDS) having a pH of 7.5 for 3 hours.

As a result of FIG. 6 , it was confirmed that the dissolution rate of dexlansoprazole was 75% by weight or more for 180 minutes in both Example 2 and Comparative Example 1 in a phosphate buffer of pH 7.5. However, in Comparative Example 1, the release started rapidly without a lag time, whereas in Example 2, only the first tablet (Preparation Example 3) was released first, and the second tablet (Preparation Example 5) was 30 minutes or longer. Release was started after the lag time had elapsed. Therefore, it was confirmed that the formulation of Example 2 according to the present invention maintains the designed delayed release pattern well even when the pH in the intestine exceeds 7.0.

Experimental Example 6. Confirmation of storage stability

The tablet of Preparation Examples 3 and 5 applied to Example 2 (tablet with an ethanol-based coating layer) and the same as Preparation Examples 3 and 5, except that the tablet of Comparative Example 1 prepared using water instead of an ethanol solution (trade name Dexilant DR, delayed release) The storage stability was confirmed by observing the color change for the capsule).

In detail, after storing the tablets of Preparation Examples 3 and 5 at room temperature (20 ℃) and harsh (40 ℃, 75% relative humidity) for 30 days, the storage stability was evaluated by observing the color change inside and outside the tablet. did

In addition, the currently commercially available product, Dexilant DR (trade name: Dexilant DR, delayed release capsule) (Comparative Example 1) and the tablet-in-capsule formulation of Example 2 were subjected to severe conditions (40 ° C., relative humidity 75%) for 30 days. After storage, the content of dexlansoprazole was analyzed to calculate the percentage of the initial content.

As a result of FIG. 7, in the case of Preparation Examples 3 and 5 according to the present invention using ethanol as a solvent, a change in the color of the tablet was observed for 30 days at both room temperature (20 ℃) and severe (40 ℃, relative humidity 75%) conditions. Therefore, it could be confirmed that all drug stability was maintained. On the other hand, in the case of a tablet using water instead of ethanol as a solvent for the coating agent, it was already changed to brown at the beginning of manufacture, and it was observed that the color changed more darkly as time passed. Therefore, it was found that it is important to block moisture during the manufacturing process of the first tablet and the second tablet. In particular, it was found that the stability of the drug could not be guaranteed when it was carried out based on water (water).

In addition, as shown in FIG. 8 , in the case of Example 2 and Comparative Example 1 according to the present invention, no difference in drug content was observed even after 30 days under severe conditions.

Taken together, in the case of Example 2 according to the present invention, it was confirmed that both stability and storage stability in acidic conditions were improved. Stability in acidic conditions was achieved by inhibiting dissolution in acid through the enteric coating, and storage stability was realized by inhibiting contact of the drug with moisture and the outside due to the coating layer.

As described above, the pH-dependent tablet-in-capsule combination formulation according to the present invention comprises a first tablet that releases dexlansoprazole as an active ingredient at pH 5.5 and a second tablet that releases dexlansoprazole as an active ingredient at pH 7.0 or higher. As a hard capsule complex formulation comprising a plurality of tablets, the tablet is coated with an enteric coating agent having a different solubility depending on the pH, so that the release time can be adjusted according to the pH.

Specifically, in the case of the tablet-in-capsule combination formulation according to the present invention, it is not released in the stomach at a pH of 1.0 to 1.5, the first tablet is rapidly released when the pH is near 5.5, and the second tablet is released when the pH is near 7.0. It is possible to implement sustained-release properties in which the drug is slowly released through a lag time that is rapidly released after having a lag time of about 30 to 60 minutes, so that it is possible to continuously maintain the blood concentration It is an excellent invention in terms of ease of administration by including several mini-tablets in one hard capsule as a designed formulation.

As described above in detail a specific part of the present invention, for those of ordinary skill in the art, this specific description is only a preferred embodiment, and it is clear that the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (15)

In the capsule, a core containing dexlansoprazole or a salt thereof as an active ingredient, and a first tablet comprising an enteric coating layer that melts at pH 5.5 or higher as a coating film covering the surface of the core; and
A pH-dependent tablet-in-capsule comprising a core comprising dexlansoprazole or a salt thereof as an active ingredient, and a second tablet comprising an enteric coating layer that dissolves at pH 7.0 or higher as a coating film covering the surface of the core Combination formulations.
The method of claim 1,
The first tablet and the second tablet are pH-dependent tablet-in-capsule complex formulation, characterized in that it comprises a weight ratio of 1 to 5: 5 to 1.
The method of claim 1,
The enteric coating layer of the first tablet is Eudragit L100-55, Eudragit L100, Eudragit RS100, Eudragit L 12.5 P, Eudragit L 12.5, Eudragit L 30 D-55, Eudragit S 12.5 P, Eudragit S 12.5, and Eudragit FS 30 D, characterized in that it contains at least one selected from the group consisting of, pH-dependent tablet-in-capsule combination formulation.
The method of claim 1,
The enteric coating layer of the second tablet is Eudragit S100, Eudragit RL 12.5, Eudragit RL 100, Eudragit L100, Eudragit L100-55, Eudragit RL P0, Eudragit RL 30 D, 1 selected from the group consisting of DRAGIT RS 12.5, EUDRAGIT RS 100, EUDRAGIT RS P0, EUDRAGIT RS 30 D, EUDRAGIT NE 30 D, EUDRAGIT NE 40 D and EUDRAGIT NM 30 D A pH-dependent tablet-in-capsule complex formulation comprising more than one species.
The method of claim 1,
The tablet is a pH-dependent tablet-in, characterized in that a water-soluble coating layer comprising one selected from the group consisting of cellulose ether, polyvinylpyrrolidone and polyvinyl alcohol (opadry) is formed between the core and the enteric coating layer. - Capsule complex formulation.
The method of claim 1,
The first tablet and the second tablet have a dissolution rate of 5% or less for 2 hours of dexlansoprazole under acidic conditions of pH 1.0 to 1.5,
The first tablet has a dissolution rate of 85% or more of dexlansoprazole for 0 to 30 minutes when pH 5.5 is reached,
When the second tablet reaches pH 7.0 or higher, the dissolution rate of dexlansoprazole is 5% or less within 0 to 60 minutes, and the dissolution rate of dexlansoprazole for 0 to 60 minutes thereafter is 85% or more, characterized in that the pH Dependent tablet-in-capsule combination formulation.
The method of claim 1,
The second tablet is a pH-dependent tablet-in-capsule complex formulation, characterized in that the core component is released after having a lag time of 30 to 60 minutes at pH 7.0.
The method of claim 1,
The capsule is a pH-dependent tablet-in-capsule combination formulation, characterized in that no. 0 capsule or less.
(a) mixing dexlansoprazole, a stabilizer and a disintegrant with a binder and an alcohol solution to form granules;
(b) mixing the granules with a diluent, a disintegrant, a lubricant, and a glidant and tableting to prepare a tablet;
(c) coating the tablet with a water-soluble coating agent to form a water-soluble film layer;
(d) a first tablet having a pH of 5.5 at which dissolution starts by coating an enteric coating agent having a pH of 5.5 or an enteric coating agent having a pH of 7.0 or higher at which dissolution starts on the tablets prepared in step (c), respectively, and preparing a second tablet having a pH of 7.0 or higher, respectively; and
(e) encapsulating the first tablet and the second tablet in a capsule to prepare a pH-dependent tablet-in-capsule combination;
A method for producing a pH-dependent tablet-in-capsule combination formulation comprising a.
10. The method of claim 9,
The stabilizer is magnesium carbonate (MgCO ₃ ) or disodium phosphate (Na ₂ HPO ₄ ) or a complex thereof, characterized in that the pH-dependent tablet-in-capsule complex preparation method.
10. The method of claim 9,
The disintegrant is croscarmellose sodium, characterized in that the pH-dependent tablet-in-capsule complex preparation method.
10. The method of claim 9,
The water-soluble coating agent, characterized in that it comprises at least one selected from the group consisting of cellulose ether, polyvinylpyrrolidone and polyvinyl alcohol mixture (opadry), pH-dependent tablet-in-capsule manufacturing method.
10. The method of claim 9,
The method for producing a pH-dependent tablet-in-capsule combination formulation, characterized in that the water-soluble film layer comprises 1 to 5 parts by weight based on 100 parts by weight of the tablet.
10. The method of claim 9,
The enteric coating layer formed by the enteric coating agent of the first tablet is characterized in that 5 to 15 parts by weight based on 100 parts by weight of the first tablet, the method for producing a pH-dependent tablet-in-capsule composite formulation.
10. The method of claim 9,
The enteric coating layer formed by the enteric coating agent of the second tablet is characterized in that it contains 5 to 20 parts by weight based on 100 parts by weight of the second tablet.

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