KR20200097564A - Stable pharmaceutical formulation for oral administration comprising dexlansoprazole or a pharmaceutically acceptable salt thereof - Google Patents

Abstract

The present invention provides a composition containing dexlansoprazole having improved stability and improved solubility and/or dissolution rate, particularly containing amorphous dexlansoprazole. The present invention also provides a capsule formulation containing dexlansoprazole, which is a new formulation containing tablets and pellets, wherein the capsule formulation containing dexlansoprazole of the present invention is easier to manufacture, has a high manufacturing yield, ensures improved stability, and exhibits preferable double delayed-release patterns.

Description

Stable pharmaceutical formulation for oral administration comprising dexlansoprazole or a pharmaceutically acceptable salt thereof

The present invention relates to an oral formulation containing dexransoprazole, and specifically relates to an oral formulation containing dexransoprazole that is easier to manufacture, has a high production yield, improves stability, and exhibits a double delayed-release pattern. The present invention also relates to a pharmaceutical composition with improved stability and/or solubility (dissolution rate) of dexlansoprazole or a pharmaceutically acceptable salt thereof, in particular amorphous dexlansoprazole.

Dexlansoprazole is the (R) -(+) isomer of lansoprazole, and is a proton-pump inhibitor. Dexlansoprazole is currently sold by Takeda Pharmaceuticals under the brand name Dexilant DR capsule. Dexant dial capsules are designed to release the drug in a pH-dependent manner at different times by containing two types of enteric-coated granules in the capsule by applying a dual delayed-release technology. That is, when taken, part of the granules is released at a pH of 5.5 within 1 to 2 hours, and the remaining granules are released at a pH of 6.75 within 3 to 4 hours. Due to this release pattern, it shows rapid efficacy and has a long duration of efficacy, making it suitable for night heartburn treatment. In addition, since there is no significant difference in blood concentration and effect according to the time of administration (fasting, before meals, after meals), it is possible to take it regardless of the meal time, so it has the advantage of high medication convenience and compliance.

Deck sealant dial capsule has a structure containing two types of enteric-coated pellets in a hard capsule. By increasing the surface area of the pellets, dexlansoprazole, a poorly soluble drug, can be easily released from the body. However, such pellets are difficult to manufacture, take a long time to manufacture, and the coating agent is not uniformly coated in the enteric coating process, resulting in poor manufacturing yield.

On the other hand, dexransoprazole is very unstable in acid and easily decomposed in an acidic environment, so it is necessary to use it with an alkalinizing stabilizer. To this end, Dexanthal Capsule contains magnesium carbonate as a stabilizer in both pellets.

Republic of Korea Patent Publication No. 1061750

Accordingly, the present invention provides an oral formulation containing dexlansoprazole that is easier to manufacture, has a high manufacturing yield, improves stability, and exhibits a double delayed-release pattern.

The present invention also provides a composition with improved stability and/or solubility of dexlansoprazole, in particular amorphous dexlansoprazole. The present invention provides a method for improving the stability and/or solubility of dexlansoprazole, in particular amorphous dexlansoprazole.

In order to solve the above problems, the present invention provides a dexlansoprazole-containing pharmaceutical composition containing potassium phosphate, potassium carbonate or a mixture thereof as a stabilizer in a composition containing dexlansoprazole or a pharmaceutically acceptable salt thereof.

Dexransoprazole or a pharmaceutically acceptable salt thereof is very unstable in an acidic environment, and in particular, amorphous pharmaceuticals are generally less stable than crystalline forms. The stability of dexlansoprazole is not improved simply by adding alkalizing agents. That is, as a result of the experiment, some alkalizing agents do not have an effect on the stability of amorphous dexlansoprazole or rather have a negative effect on the stability.

As a result of evaluating various stabilizers, the present inventors confirmed that a specific alkalizing agent exerts a very excellent effect on improving the stability of dexlansoprazole, particularly amorphous dexransoprazole, compared to other alkalizing agents. Accordingly, the present invention provides a pharmaceutical composition containing dexlansoprazole containing potassium phosphate, potassium carbonate or a mixture thereof as a stabilizer, and further comprising mixing potassium phosphate, potassium carbonate or a mixture thereof with dexlansoprazole as a stabilizer. Provides a method for stabilizing dexlansoprazole, especially amorphous dexransoprazole.

Preferably, the stabilizer is present in an amount of 0.1 to 2 parts by weight, more preferably 0.25 to 2 parts by weight, based on 1 part by weight of dexransoprazole. More specifically, it is more preferable to include potassium carbonate in an amount of 0.1 to 2 parts by weight based on 1 part by weight of dexlansoprazole, and potassium phosphate in an amount of 0.25 to 2 parts by weight based on 1 part by weight of dexlansoprazole.

In addition, preferably, in one aspect of the present invention, the dexlansoprazole composition according to the present invention includes polysorbate 80, poloxamer, or a mixture thereof as a solubilizing agent in addition to the stabilizer.

In the case of dexransoprazole, it was found that the solubility or dissolution rate was relatively low compared to other drug substances. In addition, the solubility or dissolution rate of dexlansoprazole may decrease depending on the formulation. In this case, it is preferable to add a solubilizing agent to promote dissolution, and in the case of dexlansoprazole, particularly amorphous dexransoprazole, polysorbate 80 and/or poloxamer is preferable to other solubilizing agents in terms of physical properties.

In particular, as described later, in the capsule formulation containing the (mini) tablet and pellets, which is an aspect of the present invention, since the dissolution rate of the tablet is relatively lower than that of the pellet, the need to add a preferable solubilizing agent is further increased. That is, in the capsule formulation containing (mini) tablets and pellets, which is an aspect of the present invention, the importance of a specific solubilizing agent becomes even greater.

This solubilizing agent is preferably present in an amount of 0.5 to 2 parts by weight based on 1 part by weight of dexransoprazole.

The present invention is also a hard capsule formulation comprising dexlansoprazole or a pharmaceutically acceptable salt thereof, wherein the hard capsule is (a) a (mini) tablet comprising dexlansoprazole or a pharmaceutically acceptable salt thereof, and ( b) contains two formulations of pellets containing dexlansoprazole or a pharmaceutically acceptable salt thereof; The tablets and pellets are coated with a coating layer containing an enteric polymer, and the enteric coating layer of the tablet begins to dissolve at a relatively lower pH than the enteric coating layer of the pellets; The amount of dexlansoprazole contained in the tablet is less than the amount of dexlansoprazole contained in the pellets, providing a pharmaceutical preparation containing dexlansoprazole.

In the case of such a new formulation, since the capsule formulation contains a tablet, it is easier to manufacture and shorten the manufacturing time, thereby increasing the manufacturing yield and exhibiting a double delayed-release pattern. The mini-tablet according to the present invention has a shorter manufacturing time and easier manufacturing than the pellet, and the coating agent is uniformly applied in the enteric coating process, resulting in a high manufacturing yield. In addition, the new formulation according to the present invention is easy to control the release pattern, and it is possible to make the first release faster and faster, so that the formulation can be more advantageous to the patient.

In the case of tablets, there is a disadvantage in that the dissolution (rate) is lower than that of pellets, but the present invention overcomes these disadvantages and secures a desirable double delayed release pattern by using a specific solubilizing agent confirmed through several tests.

In the present invention, the (mini) tablet has a size that can be filled in a hard capsule. For example, the mini-tablets may have a diameter of 1 mm to 8 mm, more specifically 3 mm to 7 mm, preferably 4 mm to 6 mm, for example 5 to 5.9 mm. The mini-tablets may be filled in one or more, more specifically, 1 to 10 or less in the capsule of the present invention. Preferably, the (mini) tablets are filled with 1-5 tablets, more preferably 1-3 tablets, and even more preferably 1-2 tablets. The mini-tablets may be prepared according to a conventional method known in the art.

In such a hard capsule formulation, the dexlansoprazole contained in the tablet is 20-30% by weight based on the total dexlansoprazole content of the pharmaceutical preparation, and the content of dexlansoprazole in the pellets is 70-80% by weight based on the total dexlansoprazole content. This is desirable. More preferably, the dexlansoprazole contained in the tablet is 25% by weight based on the total dexlansoprazole content of the pharmaceutical formulation, and the content of dexlansoprazole contained in the pellets is 75% by weight based on the total dexlansoprazole content.

The pellets contained in the hard capsule of the present invention can be prepared by a conventional method in the field to which the present invention belongs. For example, it may be manufactured by the method described in Korean Patent Publication No. 1061750.

Specifically, the pellet according to the present invention comprises a) an inert core, b) a drug coating layer comprising dexlansoprazole or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient formed on the surface of the inert core, and c) a drug. It may be a pellet comprising a release controlling layer including a delayed-release polymer (enteric polymer) formed on the coating layer.

In the hard capsule formulation containing tablets and pellets, which are new formulations according to the present invention, the tablets and/or pellets preferably contain potassium phosphate, potassium carbonate or a mixture thereof as a stabilizer for dexlansoprazole, and in particular In order to control the dissolution (rate) of tablets included according to the formulation, not only the stabilizer, but also the tablets and/or pellets, in particular, the tablets preferably contain polysorbate 80, poloxamer, or a mixture thereof as a solubilizing agent. Do.

In the hard capsule formulation containing tablets and pellets, which are new formulations according to the present invention, the contents of the stabilizing agent and the solubilizing agent are as mentioned above.

In the hard capsule formulation containing tablets and pellets, which are new formulations according to the present invention, the tablets and pellets have an enteric coating (delayed release coating), and the enteric polymer used in the enteric coating of these tablets and pellets is methacrylic. Acid copolymers, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, ethylcellulose, cellulose acetate phthalate, or mixtures thereof may be used.

Preferably, the tablets and/or pellets according to the present invention are pre-coated with a hydrophilic polymer prior to coating the enteric polymer.

In the present invention, the tablets and pellets may contain other additives in addition to the aforementioned stabilizer and solubilizing agent, for example, may further contain additives described in Korean Patent Publication No. 1061750.

The present invention provides a composition containing dexlansoprazole, particularly an amorphous dexlansoprazole, having improved stability and secured solubility and/or dissolution rate. The present invention also provides a new pharmaceutical formulation containing dexlansoprazole containing tablets and pellets, wherein the formulation containing dexlansoprazole of the present invention is easier to manufacture, has a high production yield, improves stability, and exhibits a preferred double delayed-release pattern. .

1 is an elution of a portion (immediate-release part) of 0.25 to 1 weight of dexlansoprazole of mini-tablets and comparative formulations (dexantant dialcapsule, Takeda Korea) to which a surfactant (solubilizer) prepared according to the present invention is not added Shows the test results.
2 shows the solubility of dexlansoprazole according to the type of each surfactant (solubilizer) for increasing the solubility of dexlansoprazole according to the present invention.
3 is a hard capsule containing tablets and pellets containing polysorbate 80 or poloxamer as a surfactant, and potassium carbonate or potassium phosphate as a stabilizer according to the present invention, and the dissolution rate of a comparative formulation (Deck sealant dial capsule, Takeda Korea) Represents. In Figure 3, Example 2 is a result of elution of a hard capsule containing a mini tablet using potassium phosphate and polysorbate 80 among the mini tablets shown in Table 7 below, and a pellet using potassium phosphate and polysorbate 80 shown in Table 8 below, Example 3 is an elution result of a hard capsule containing a mini-tablet using potassium phosphate and poloxamer among the mini-tablets shown in Table 7 below, and a pellet using potassium phosphate and polysorbate 80 shown in Table 8 below.

Hereinafter, examples, etc. will be described in detail to aid understanding of the present invention. However, the embodiments according to the present invention may be modified in various different forms, and the scope of the present invention should not be construed as being limited to the following examples. Embodiments of the present invention are provided to more completely describe the present invention to those with average knowledge in the field to which the present invention belongs.

In the following experiments according to the present invention, amorphous dexransoprazole was used as dexransoprazole.

Experimental Example 1: Stability test according to the type of alkaline stabilizer

A solid mixture was prepared in which 11 kinds of alkaline stabilizers and dexlansoprazole powder were mixed in a 1:1 ratio, including calcium carbonate used in commercially available dexantyl capsules, and packaged in a glass bottle to be harsh (temperature 60℃ , 75% relative humidity) stability test was performed for 7 days. The results are shown in Table 1 below.

Sample name Initial Stress
3 day Stress
7 day content (%) content (%) content (%) API (Dexlansoprazole) 104.8 95.8 61.6 API + Calcium carbonate 102.6 91.9 52.6 API + Calcium hydroxide 102.1 93.2 52.0 API + Magnesium oxide 105.0 91.9 53.8 API + Sodium carbonate 97.9 83.3 58.2 API + Sodium bicarbonate 96.3 85.3 57.9 API + Potassium carbonate 107.4 104.4 92.6 API + Sodium chloride 91.4 75.3 59.8 API + Potassium phosphate 101.3 99.9 91.1 API + Sodium citrate dihydrate 99.7 88.0 57.9 API + Meglumine 101.2 93.3 78.7 API + Magnesium carbonate 98.6 89.8 59.5

As shown in Table 1 above, when the dexlansoprazole powder was used together with a potassium carbonate or potassium phosphate stabilizer, the dexransoprazole content was stably maintained for 7 days. On the other hand, when dexlansoprazole powder was used alone or in combination with other stabilizers such as calcium carbonate stabilizers, the content of dexransoprazole drastically decreased for 7 days.

Experimental Example 2: Stability test according to the content of the selected alkaline stabilizer

In addition, in order to check the stability according to the contents of potassium carbonate and potassium phosphate, a solid mixture was prepared by mixing dexlansoprazole and potassium carbonate or potassium phosphate by ratio. 75% humidity) stability test was performed for 7 days. The results are shown in Table 2 below.

Sample name Initial Stress
3 day Stress
7 day content (%) content (%) content (%) API (Dexlansoprazole) 100.84 97.46 78.46 API: Potassium carbonate = 1: 0.1 100.94 96.07 93.48 API: Potassium carbonate = 1: 0.25 100.54 99.02 96.77 API: Potassium carbonate = 1: 0.5 100.88 98.04 98.73 API: Potassium carbonate = 1: 0.75 101.32 99.28 99.27 API: Potassium carbonate = 1: 1 100.07 99.43 98.63 API: Potassium carbonate = 1: 2 100.49 100.00 100.89 API: Potassium phosphate = 1: 0.1 100.13 96.91 79.99 API: Potassium phosphate = 1: 0.25 99.81 96.27 93.16 API: Potassium phosphate = 1: 0.5 101.02 99.02 100.44 API: Potassium phosphate = 1: 0.75 101.28 99.68 100.56 API: Potassium phosphate = 1: 1 100.22 99.99 96.33 API: Potassium phosphate = 1: 2 101.03 100.07 100.95

As shown in the table above, when potassium carbonate is contained in an amount of 0.1 to 2 parts by weight based on 1 part by weight of dexlansoprazole, and potassium phosphate is contained in an amount of 0.25 to 2 parts by weight based on 1 part by weight of dexlansoprazole, the stability of dexlansoprazole is the most. It was confirmed that it was maintained excellently. If the alkaline stabilizer, potassium carbonate is less than 0.1 and potassium phosphate is less than 0.25, the stability of dexlansoprazole may decrease, and if it is higher than this amount, it is necessary to dissolve the water-soluble stabilizer during pellet production (i.e., coating solution As the amount of water increases, there is a concern that a problem may arise in the solubility of dexrasoprazole, which is poorly soluble in water.

Example 1: Preparation of immediate-release mini-tablets

Using the potassium carbonate stabilizer or potassium phosphate stabilizer identified above, an immediate-release mini-tablet containing dexlansoprazole was prepared. Specific components and contents are shown in Table 3 below. The content in Table 3 means the content per unit tablet (mg).

A binding solution was prepared by dissolving hydroxypropylmethylcellulose in ethanol. Dexlansoprazole, hydroxypropylcellulose, microcrystalline cellulose, and crospovidone were mixed at high speed in a high-speed kneader, and granulated while adding the binding solution. The obtained wet granules were dried and sieved with a 20 mesh sieve. Colloidal silicon dioxide, crospovidone, croscarmellose sodium, and magnesium stearate were added to the obtained granules, mixed, tableted, firstly coated with the intermediate layer using Opadry Clear, and then secondarily coated with methacrylic acid copolymer for enteric coating. An enteric coated tablet containing dexransoprazole was prepared.

division Ingredient name Example 1 Usage (mg) core chief ingredient Dexlansoprazole 15.0 Excipient Low substituted hydroxy cellulose 19.0 Excipient Microcrystalline cellulose 14.0 Stabilizer Potassium Phosphate (Example 1-2) or Potassium Carbonate (Example 1-1) 4.0 Excipient Colloidal silicon dioxide 1.2 Disintegrant Croscarmellose sodium 1.5 Excipient Crospovidone 3.6 Binder Hydroxypropyl methyl cellulose 1.0 Lubricant Magnesium stearate 0.7 Middle floor Coating agent Clear Opadry 1.2 Enteric layer Enteric coating base Methacrylic acid copolymer Type C 7.16 Anticoagulant Talc 0.71 Plasticizer Triethyl citrate 3.58 ethanol Appropriate amount

Experimental Example 3: Evaluation of dissolution of Example 1-1 and Example 1-2

In order to confirm the release of the drug from the minitablets prepared as above, an elution experiment was performed in a pH 7.0 buffer to which 1.44% SLS was added.

The dissolution test results are shown in FIG. 1. As shown in the result of FIG. 1, it was confirmed that the prepared mini-tablets had significantly lower drug release compared to the control agent dexantane immediate release pellets. The control agent, dexantant, is composed of pellets, whereas the test formulation is formulated as a mini-tablet, which can be seen as a decrease in drug release due to the difference in formulation. However, in the case of mini-tablets, compared to pellets, the manufacturing process and manufacturing time are shortened and variations in coating can be reduced during enteric coating, so that the solubility of dexlansoprazole is increased to improve drug release.

Experimental Example 4: Dissolution test according to the use of solubilizing agent

In order to overcome the disadvantages identified in the dissolution evaluation results of Examples 1-1 and 1-2 above, a solubility test was performed using various solubilizing agents.

Poloxamer 407, HPMC, Tween 80, Soluplus, Solutol HS 15, Cremophor EL, Gelucire 44/14 were dissolved in 30 ml of pH 7.0+SLS solute in an amount of 0.2 (200 mg) based on 1 weight of dexlansoprazole, and then dexlansoprazole 1 g Was added and stirred for 24 hours. After that, the concentration was obtained through HPLC by PVDF filter. The results obtained through the solubility test are shown in FIG. 2.

As shown in FIG. 2, when polysorbate 80 and poloxamer were used as surfactants at pH 7.0 + SLS, dexransoprazole was found to have an excellent solubility of at least two times more than when dexlansoprazole was used alone. Therefore, in the present invention, it can be seen that polysorbate 80 and poloxamer act very advantageously for absorption and dissolution of drugs by greatly improving the physicochemical properties of dexransoprazole, which is a poorly soluble drug, so that it is very advantageous for commercialization of drugs.

Experimental Example 5: Evaluation of the effect according to the content of the selected solubilizer

In addition, in order to determine the optimal ratio of polysorbate 80 and poloxamer to improve the solubility of dexlansoprazole, polysorbate 80 and poloxamer are dissolved in each ratio in pH 7.0 + SLS solute in the same manner as in the above solubility test method. A certain amount of dexransoprazole was added and stirred for 24 hours, and a certain concentration was measured. The results are shown in Table 4 below.

Sample Concentration (μg/mL) API (Dexlansoprazole) 78.66 API: Polysorbate 80 = 1: 0.1 35.84 API: Polysorbate 80 = 1: 0.25 55.40 API: Polysorbate 80 = 1: 0.5 125.80 API: Polysorbate 80 = 1: 0.75 164.76 API: Polysorbate 80 = 1: 1 184.71 API: Polysorbate 80 = 1: 2 260.29 API: Poloxamer = 1: 0.1 79.81 API: Poloxamer = 1: 0.25 108.86 API: Poloxamer = 1: 0.5 141.51 API: Poloxamer = 1: 0.75 198.14 API: Poloxamer = 1: 1 207.37 API: Poloxamer = 1: 2 260.96

As can be seen from the results of Table 4 above, when polysorbate 80 and poloxamer are present in an amount of 0.5 to 2 parts by weight based on 1 part by weight of dexlansoprazole, the solubility of dexransoprazole can be improved to improve drug release. Was confirmed. When less solubilizing agents such as polysorbate 80 and poloxamer are added, the drug release of poorly soluble dexlansoprazole is delayed. On the other hand, when 2 parts by weight of the solubilizing agent is exceeded, the size of the mini-tablet is inevitably increased, making it difficult to encapsulate it in the hard capsule. In addition, in the case of pellet manufacturing, especially in the case of pellet manufacturing using spherical sugar, the volume of the coating solution including the solubilizer increases and the coating solution has sticky properties, increasing the time for manufacturing the pellet and making the manufacturing process difficult.

Experimental Example 6: Dexlansoprazole stability test including a solubilizing agent and an alkaline stabilizer

As shown in Table 5 below, dexransoprazole; Polysorbate 80 or poloxamer, a solubilizing agent used to improve the solubility of dexransoprazole; And a solid mixture containing potassium carbonate or potassium phosphate, which is an alkalizing agent used to secure the stability of dexransoprazole. This solid mixture contains 1 stabilizing agent and 0.2 parts by weight of solubilizing agent relative to 1 weight of dexransoprazole. As before, it was packaged in a glass bottle and subjected to a stability test for 7 days under severe (temperature 60°C, relative humidity 75%) conditions. The results are shown in Tables 5 and 6 below.

Sample name Initial Stress
3 day Stress
7 day content (%) content (%) content (%) API　 (Dexlansoprazole)+ Tween80 99.2 91.1 75.7 API + Tween80 + Calcium　 hydroxide 95.7 85.5 59.4 API + Tween80 + Magnesium oxide 101.5 94.7 66.6 API + Tween80 + Calcium　 carbonate 102.0 90.5 65.7 API + Tween80 + Sodium　 carbonate 97.3 92.2 65.1 API + Tween80 + Sodium　 bicarbonate 98.8 89.5 78.4 API + Tween80 + Potassium bicarbonate 100.0 94.4 92.9 API + T ween80 + Sodium　 chloride 92.5 85.4 69.8 API + Tween80 + Potassium phosphate 97.1 96.9 94.7 API + Tween80 + Sodium　 citrate dihydrate 90.1 82.0 73.9 API + Tween80 + Meglumine 96.9 95.6 87.6 API + Tween80 + Magnesium carbonate 99.8 90.8 64.8

Sample name Initial Stress
3 day Stress
7 day content (%) content (%) content (%) API　 (Dexlansoprazole)+ Poloxamer 100.0 92.3 62.2 API + Poloxamer + Calcium　 hydroxide 98.6 90.7 75.6 API + Poloxamer + Magnesium oxide 102.5 94.4 80.5 API + Poloxamer + Calcium　 carbonate 99.1 85.7 57.8 API + Poloxamer + Sodium　 carbonate 97.6 84.6 77.1 API + Poloxamer + Sodium　 bicarbonate 99.7 95.7 71.2 API + Poloxamer + Potassium bicarbonate 96.2 91.8 92.5 API + Poloxamer + Sodium　 chloride 96.6 86.7 51.6 API + Poloxamer + Potassium phosphate 99.5 96.7 98.4 API + Poloxamer + Sodium　 citrate dihydrate 101.2 82.8 62.9 API + Poloxamer + Meglumine 98.5 92.2 79.6 API + Poloxamer + Magnesium carbonate 99.7 93.5 63.1

As a result, as shown in Tables 5 and 6, the dexlansoprazole powder containing dexlansoprazole and each stabilizer showed a sharp decrease in the content of dexlansoprazole for 7 days, whereas it contained potassium carbonate and potassium phosphate. The content of dexlansoprazole showed a result of maintaining a stable state without any decrease in content compared to other stabilizers, and maintained much better stability than the magnesium carbonate used in the comparative formulation, dexanant. From these results, it can be reconfirmed that potassium carbonate and potassium phosphate can be used as stabilizers for dexlansoprazole.

Example 2: Preparation of an oral formulation of dexlansoprazole containing an immediate-release mini-tablet and a sustained-release pellet

(One) Preparation of immediate release mini-tablets containing solubilizing agent and alkalizing agent

Minitablets containing dexransoprazole, surfactant and stabilizer were prepared according to the components and contents of Table 7 below. The manufacturing method was granulated and tableted in the same manner as in Example 1 above, and enteric coating was performed.

division Ingredient name Example 2 Usage (mg) Mini tablet chief ingredient Dexlansoprazole 15.0 Excipient Low substituted hydroxy cellulose 15.5 Excipient Microcrystalline cellulose 10.0 Stabilizer Potassium phosphate 4.0 Surfactants Polysorbate 80 or poloxamer 7.5 Excipient Colloidal silicon dioxide 1.2 Disintegrant Croscarmellose sodium 1.5 Excipient Crospovidone 3.6 Binder Hydroxypropyl methyl cellulose 1.0 Lubricant Magnesium stearate 0.7 Middle floor Coating agent Clear Opadry 1.2 Enteric layer Enteric coating base Methacrylic acid copolymer Type C 7.16 Anticoagulant Talc 0.71 Plasticizer Triethyl citrate 3.58 ethanol Appropriate amount

(2) Preparation of slow-release pellets

Pellets containing dexlansoprazole were prepared according to the components and contents of Table 8 below. The content in the table below refers to the content per unit tablet (mg), and the dexlansoprazole content in the sustained-release pellet is 0.75 parts by weight relative to 1 part by weight of the total dexlansoprazole contained in the formulation.

Dexlansoprazole, hydroxypropyl cellulose, polysorbate 80 or poloxamer, and potassium carbonate or potassium phosphate, which are the central granular layer, are dissolved in an organic solvent to prepare a suspension and spray dexlansoprazole on inert spherical sugar in a fluidized spray dryer. I did. The prepared core layer was coated as an intermediate layer using Opadry Clear containing hydroxyproryl methyl cellulose, and an enteric coating layer in which methacrylic acid copolymer, talc, polysorbate 80, and triethyl citrate were dissolved in an organic solvent was fluidized and sprayed. A sustained-release pellet layer was prepared by spraying the pellets prepared from the drying device to the intermediate layer coating.

division Ingredient name Example 3 Usage (mg) Central granule Excipient Spherical white sugar 30.0 chief ingredient Dexlansoprazole 45.0 Binder Hydroxypropyl cellulose 18.1 Surfactants Polysorbate 80 22.5 Stabilizer Potassium phosphate 12 Middle floor Coating base Clear Opadry 27.1 Enteric layer Enteric coating base Methacrylic acid copolymer Type B 48.7 Excipient Talc 12.4 Surfactants Polysorbate 80 1.3 Plasticizer Triethyl citrate 7.4 slush Fluidizing agent Talc 2.0 Antistatic agent Colloidal silicon dioxide 1.0 menstruum 　
　 Purified water Appropriate amount ethanol Appropriate amount

(3) Preparation of hard capsules containing mini-tablets and sustained-release pellets

The immediate-release mini-tablets and sustained-release pellets prepared in the above example were filled in one hard capsule.

Experimental Example 7: Hard capsule dissolution test including an immediate release part and a sustained release part of dexlansoprazole

The dissolution test was performed on the hard capsules containing the immediate-release mini-tablets and sustained-release pellets prepared in the above example in a commercially available dexealant dialcapsule as a control agent and a pH 7.0+SLS solute. The results are shown in FIG. 3. In FIG. 3, Example 2 is a hard capsule comprising a mini tablet using potassium phosphate and polysorbate 80 among the mini tablets of Table 7 and a pellet using potassium phosphate and polysorbate 80 of Table 8, and Example 3 It is a hard capsule containing a mini-tablet using potassium phosphate and poloxamer among the mini-tablets in Table 7 and a pellet using potassium phosphate and polysorbate 80 in Table 8.

As a result, as shown in FIG. 3, in the immediate-release mini-tablet containing a surfactant and a stabilizer, 25% of dexlansoprazole equivalent to the immediate-release portion is eluted in the same manner as the comparative agent, dexlanant, through an increase in acid resistance and solubility. Became. In addition, it was confirmed that the sustained-release pellet was not released at the beginning but was maintained, and the drug was gradually released after 50 minutes. From these results, in hard capsules containing a surfactant of polysorbate 80 or poloxamer and a stabilizer of potassium carbonate or potassium phosphate, polysorbate 80 and poloxamer are solubilizing agents for improving the dissolution of dexlansoprazole. , It can be seen that potassium carbonate and potassium phosphate act as stabilizers through securing acid resistance.

Experimental Example 8: Evaluation of bioavailability

The bioavailability of the hard capsule prepared in Example 3 was evaluated using a beagle dog. In addition, commercially available dexealant dialectal capsules (Takeda Korea) were evaluated together as a comparative formulation. To each of 16 beagle dogs of about 10 kg in weight, which had been fasting for 12 hours, dexealant and the capsule prepared in Example 2 were orally administered as a comparative formulation on an empty stomach. After administration, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12 hours later, blood was collected with a heparin-treated syringe. The collected blood was placed in a centrifuge tube and centrifuged at 3000 rpm for 5 minutes, and the separated plasma was taken and stored frozen at -20°C until analysis.

The pharmacokinetic parameters of the obtained blood concentration profile are shown in Table 9 below.

parameter Example Comparative formulation AUC0-24hr (ng hr/ml) 7581.1±1965.4 7466.2±2627.0 Cmax (ng/ml) 2607.3±844.2 2270.1±878.8 Tmax (hr) 2.3±1.5 1.8±1.0

From the results of Table 9, it can be seen that the hard capsule of Example 3 prepared according to the present invention is biologically equivalent to the comparative formulation.

Claims (14)

In the composition containing dexlansoprazole or a pharmaceutically acceptable salt thereof,
Dexlansoprazole-containing pharmaceutical composition containing potassium phosphate, potassium carbonate or a mixture thereof as a stabilizer. The pharmaceutical composition containing dexlansoprazole according to claim 1, wherein the composition comprises polysorbate 80, poloxamer, or a mixture thereof as a solubilizing agent. The pharmaceutical composition containing dexransoprazole according to claim 1, wherein the stabilizer is present in an amount of 0.25 to 2 parts by weight based on 1 part by weight of dexlansoprazole. The pharmaceutical composition containing dexlansoprazole according to claim 2, wherein the solubilizing agent is present in an amount of 0.5 to 2 parts by weight based on 1 part by weight of dexlansoprazole. The pharmaceutical composition containing dexlansoprazole according to any one of claims 1 to 4, wherein the dexlansoprazole is an amorphous dexlansoprazole. A hard capsule formulation containing dexlansoprazole or a pharmaceutically acceptable salt thereof,
The hard capsule contains two formulations of (a) a tablet containing dexlansoprazole or a pharmaceutically acceptable salt thereof, and (b) a pellet containing dexlansoprazole or a pharmaceutically acceptable salt thereof,
The tablets and pellets are coated with a coating layer containing an enteric polymer, and the enteric coating layer of the tablet begins to dissolve at a lower pH than the enteric coating layer of the pellet,
The amount of dexlansoprazole contained in the tablet is less than the amount of dexlansoprazole contained in the pellets, a pharmaceutical formulation containing dexlansoprazole. The method of claim 6, wherein the dexlansoprazole contained in the tablet is 20-30% by weight based on the total dexlansoprazole content in the pharmaceutical formulation, and the content of dexlansoprazole in the pellets is 70-80% by weight based on the total dexlansoprazole content. , Dexransoprazole-containing pharmaceutical formulation. The dexlansoprazole-containing pharmaceutical formulation according to claim 6, wherein the tablets, pellets, or both contain potassium phosphate, potassium carbonate or a mixture thereof as a stabilizer for dexlansoprazole. According to claim 8, The content of the stabilizer is present in an amount of 0.25 to 2 parts by weight based on 1 part by weight of dexlansoprazole, dexransoprazole-containing pharmaceutical formulation. The pharmaceutical formulation containing dexlansoprazole according to claim 6, wherein the tablets, pellets or both contain polysorbate 80, poloxamer, or a mixture thereof as a solubilizing agent. The pharmaceutical formulation containing dexlansoprazole according to claim 10, wherein the solubilizing agent is present in an amount of 0.5 to 2 parts by weight based on 1 part by weight of dexlansoprazole. The method of claim 6, wherein the enteric polymer used in the coating of the tablets and pellets is a methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, ethylcellulose, cellulose acetate phthalate, or A mixture, a pharmaceutical preparation containing dexlansoprazole. The pharmaceutical formulation containing dexlansoprazole according to claim 6, wherein the tablets, pellets, or both are pre-coated with a hydrophilic polymer before coating the enteric polymer. The pharmaceutical formulation containing dexlansoprazole according to any one of claims 6 to 13, wherein the dexlansoprazole is an amorphous dexlansoprazole.

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