KR102727681B1 - 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, particularly amorphous dexlansoprazole, having improved stability, improved solubility and/or dissolution rate. The present invention also provides a capsule formulation containing dexlansoprazole, which is a novel dosage form containing tablets and pellets, and the capsule formulation containing dexlansoprazole of the present invention is easier to manufacture and has a higher manufacturing yield, while having improved stability and exhibiting a desirable dual delayed-release pattern.

Description

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

The present invention relates to an oral formulation containing dexlansoprazole, and more particularly, to an oral formulation containing dexlansoprazole which is easier to manufacture and has a higher manufacturing yield, has improved stability, and exhibits a dual delayed-release pattern. The present invention also relates to a pharmaceutical composition having improved stability and/or solubility (dissolution rate) of dexlansoprazole or a pharmaceutically acceptable salt thereof, particularly amorphous dexlansoprazole.

Dexlansoprazole is the (R) -(+) enantiomer of lansoprazole and is a proton pump inhibitor. Dexlansoprazole is currently sold by Takeda Pharmaceutical Company under the trade name Dexilant DR capsule. Dexilant DR capsule uses dual delayed-release technology, containing two types of enteric-coated granules within the capsule, each designed to release the drug at different times depending on the pH. That is, some of the granules are released at the pH 5.5 point within 1 to 2 hours after ingestion, and the remaining granules are released at the pH 6.75 point within 3 to 4 hours. This release pattern allows for rapid onset of action and a long duration of action, making it suitable for treating heartburn at night. In addition, since there is no significant difference in blood concentration and effect depending on the time of administration (fasting, before meals, after meals), it can be taken regardless of meal times, so it has the advantage of high convenience and compliance.

Dexilant-Dial capsules are structured to contain two types of enteric-coated pellets inside a hard capsule. The pellets increase the surface area, thereby allowing the insoluble drug dexlansoprazole to be easily released in the body. However, these pellets are difficult to manufacture, take a long time to manufacture, and have the disadvantage of low manufacturing yield because the coating agent is not uniformly coated during the enteric coating process.

On the other hand, dexlansoprazole is very unstable in acid and easily decomposes in an acidic environment, so it is necessary to use it together with an alkalizing stabilizer. For this purpose, both types of pellets of Dexilant DR capsules contain magnesium carbonate as a stabilizer.

Republic of Korea Patent Publication No. 1061750

Accordingly, the present invention provides an oral formulation containing dexlansoprazole which is easier to manufacture, has a higher manufacturing yield, has improved stability, and exhibits a dual delayed-release pattern.

The present invention also provides compositions having improved stability and/or solubility of dexlansoprazole, particularly amorphous dexlansoprazole. The present invention provides methods for improving the stability and/or solubility of dexlansoprazole, particularly amorphous dexlansoprazole.

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

Dexlansoprazole or its pharmaceutically acceptable salt is very unstable in acidic environments, and in particular, amorphous drugs are usually less stable than crystalline ones. The stability of dexlansoprazole is not improved simply by adding alkalizing agents. That is, experimental results have shown that some alkalizing agents do not affect the stability of amorphous dexlansoprazole, and in many cases, they even have a negative effect on the stability.

The present inventors have evaluated various stabilizers and confirmed that a specific alkalizing agent is more effective than other alkalizing agents in improving the stability of dexlansoprazole, particularly amorphous dexlansoprazole. Accordingly, the present invention provides a pharmaceutical composition containing dexlansoprazole, which contains potassium phosphate, potassium carbonate or a mixture thereof as a stabilizer, and also provides a method for stabilizing dexlansoprazole, particularly amorphous dexlansoprazole, which comprises mixing potassium phosphate, potassium carbonate or a mixture thereof as a stabilizer with dexlansoprazole.

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

In addition, preferably, in one embodiment of the present invention, the dexransoprazole composition according to the present invention comprises polysorbate 80, poloxamer or a mixture thereof as a solubilizer in addition to the stabilizer.

In the case of dexlansoprazole, it was confirmed that the solubility or dissolution rate is relatively low compared to other raw pharmaceutical ingredients. In addition, the solubility or dissolution rate of dexlansoprazole may be low depending on the formulation. In such cases, it is desirable to add a solubilizer to promote dissolution, and in the case of dexlansoprazole, especially amorphous dexlansoprazole, polysorbate 80 and/or poloxamer are preferable to other solubilizers due to their physical properties.

In particular, as described below, in the capsule formulation containing (mini)tablets and pellets, which is one embodiment of the present invention, the dissolution rate of the tablets is relatively lower than that of the pellets, so the need for adding a preferred solubilizer becomes even greater. That is, in the capsule formulation containing (mini)tablets and pellets, which is one embodiment of the present invention, the importance of a specific solubilizer becomes even greater.

It is preferred that such solubilizing agent is present in an amount of 0.5 to 2 parts by weight per 1 part by weight of dexlansoprazole.

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

In the case of these new formulations, since the capsule formulation contains the tablet, it is easier to manufacture, the manufacturing time is shortened, the manufacturing yield is high, and a double delayed-release pattern can be exhibited. The minitablet according to the present invention is easier to manufacture and has a shorter manufacturing time than the pellet, and the coating agent is applied uniformly during the enteric coating process, so the manufacturing yield is high. In addition, the new formulation according to the present invention can be a more advantageous formulation for the patient because it is easy to control the release pattern and it is possible to make the first release more rapid and quicker.

In the case of tablets, there is a disadvantage in that the dissolution (speed) is lower than that of pellets, but the present invention can overcome this disadvantage and secure a desirable double-delayed release pattern by using a specific solubilizer confirmed through various tests.

In the present invention, the (mini)tablet has a size that can be filled into a hard capsule. For example, the mini-tablet 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-tablet may be filled in the capsule of the present invention in a number of 1 or more, more specifically 1 to 10 or less. Preferably, the (mini-)tablet is filled in the capsule in a number of 1 to 5, more preferably 1 to 3, and even more preferably 1 to 2. The mini-tablet may be manufactured according to a conventional method known in the art.

In these hard capsule formulations, the dexlansoprazole contained in the tablet is preferably 20-30 wt% based on the dexlansoprazole content of the entire pharmaceutical formulation, and the dexlansoprazole contained in the pellets is preferably 70-80 wt% based on the entire dexlansoprazole content. More preferably, the dexlansoprazole contained in the tablet is 25 wt% based on the dexlansoprazole content of the entire pharmaceutical formulation, and the dexlansoprazole contained in the pellets is 75 wt% based on the entire dexlansoprazole content.

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

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

In the hard capsule preparation containing tablets and pellets, which are novel formulations according to the present invention, it is preferable that the tablets and/or pellets contain potassium phosphate, potassium carbonate or a mixture thereof as a stabilizer of dexlansoprazole, and in particular, in order to control the dissolution (speed) of the tablets included according to the novel formulation, in addition to the stabilizer, the tablets and/or pellets, especially the tablets, preferably contain polysorbate 80, poloxamer or a mixture thereof as a solubilizer.

In the hard capsule formulation containing tablets and pellets, which are novel formulations according to the present invention, the contents of the stabilizer and solubilizer are as mentioned above.

In the hard capsule preparation containing tablets and pellets, which are novel formulations according to the present invention, the tablets and pellets are enteric-coated (delayed-release coated), and the enteric polymer used in the enteric coating of the tablets and pellets may be a methacrylic acid copolymer, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, ethyl cellulose, cellulose acetate phthalate, or a mixture thereof.

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

In the present invention, the tablets and pellets may contain other additives in addition to the stabilizers and solubilizers mentioned above, and may further contain, for example, additives described in Korean Patent Publication No. 1061750.

The present invention provides a composition containing dexlansoprazole, particularly amorphous dexlansoprazole, having improved stability and secured solubility and/or dissolution rate. The present invention also provides a novel dexlansoprazole-containing pharmaceutical preparation containing tablets and pellets, wherein the dexlansoprazole-containing preparation of the present invention is easier to manufacture and has a higher manufacturing yield, while having improved stability and exhibiting a desirable dual delayed-release pattern.

Figure 1 shows the results of a dissolution test of a portion (immediate-release portion) corresponding to 0.25 weight percent of dexlansoprazole of a mini-tablet and a comparative preparation (Dexilant DL capsule, Takeda Korea) to which a surfactant (solubilizer) manufactured according to the present invention is not added.
Figure 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.
FIG. 3 shows the dissolution rates of hard capsules 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 comparative preparations (Dexilant DR capsules, Takeda Korea). In FIG. 3, Example 2 is the dissolution results of hard capsules containing mini tablets using potassium phosphate and polysorbate 80 among the mini tablets in Table 7 below and pellets using potassium phosphate and polysorbate 80 among the mini tablets in Table 8 below, and Example 3 is the dissolution results of hard capsules containing mini tablets using potassium phosphate and poloxamer among the mini tablets in Table 7 below and pellets using potassium phosphate and polysorbate 80 among the mini tablets in Table 8 below.

Hereinafter, in order to help understand the present invention, examples and the like will be described in detail. However, the examples 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. The examples of the present invention are provided to more completely explain the present invention to a person having average knowledge in the field to which the present invention belongs.

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

Experimental Example 1: Stability Test According to Type of Alkaline Stabilizer

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

Sample name Initial Stress
3 days Stress
7 days 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 confirmed in Table 1 above, when dexlansoprazole powder was used together with potassium carbonate or potassium phosphate stabilizers, the dexlansoprazole content remained stable for 7 days. On the other hand, when dexlansoprazole powder was used alone or together with other stabilizers such as calcium carbonate stabilizer, the dexlansoprazole content decreased rapidly for 7 days.

Experimental Example 2: Stability Test According to the Content of Selected Alkaline Stabilizer

In addition, in order to confirm the stability according to the content of potassium carbonate and potassium phosphate, dexlansoprazole and potassium carbonate or potassium phosphate were mixed at different ratios to prepare a solid mixture, and packaged in a glass bottle in the same manner as above, a stability test was performed for 7 days under harsh conditions (temperature 60℃, relative humidity 75%). The results are as shown in Table 2 below.

Sample name Initial Stress
3 days Stress
7 days 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, it was confirmed that the stability of dexlansoprazole was maintained most excellently when potassium carbonate was included in an amount of 0.1 to 2 parts by weight per 1 part by weight of dexlansoprazole and potassium phosphate was included in an amount of 0.25 to 2 parts by weight per 1 part by weight of dexlansoprazole. If the amount of the alkaline stabilizer, potassium carbonate, is less than 0.1 and potassium phosphate is less than 0.25, there is a concern that the stability of dexlansoprazole may decrease, and if the amount is more than this, there is a concern that the solubility of dexlansoprazole, which is poorly soluble in water, may be problematic as the amount of water used to dissolve the water-soluble stabilizer during pellet manufacturing (i.e., to prepare a coating solution) increases.

Example 1: Preparation of rapid-release mini-tablets

Using the potassium carbonate stabilizer or potassium phosphate stabilizer confirmed above, immediate-release mini-tablets containing dexlansoprazole were manufactured. The specific ingredients and contents are as shown in Table 3 below. The contents in Table 3 mean the contents (mg) per unit tablet.

A binding solution was prepared by dissolving hydroxypropyl methyl cellulose in ethanol. Dexlansoprazole, hydroxypropyl cellulose, 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 through a 20 mesh sieve. Colloidal silicon dioxide, crospovidone, croscarmellose sodium, and magnesium stearate were added to the obtained granules, mixed, tableted, and first coated with an intermediate layer using Opadry Clear, and then secondly, enteric-coated tablets containing dexlansoprazole were prepared by enteric-coating with a methacrylic acid copolymer.

　 division Ingredient name Example 1 Dosage (mg) Core chief ingredient Dexlansoprazole 15.0 Siblings Low-substituted hydroxy cellulose 19.0 Siblings Microcrystalline Cellulose 14.0 Stabilizer Potassium phosphate (Example 1-2) or potassium carbonate (Example 1-1) 4.0 Siblings colloidal silicon dioxide 1.2 Disintegrant Croscarmellose sodium 1.5 Siblings Crospovidone 3.6 binder Hydroxypropyl methyl cellulose 1.0 Active agent Magnesium stearate 0.7 Middle layer Coating agent Opadry Clear 1.2 Long layer Long-lasting coating device Methacrylic acid copolymer Type C 7.16 Anticoagulant Talk 0.71 Plasticizer Triethyl Citrate 3.58 Ethanol Appropriate amount

Experimental Example 3: Elution Evaluation of Examples 1-1 and 1-2

To confirm the release of the drug from the mini tablets manufactured as above, a dissolution experiment was conducted in a pH 7.0 buffer solution containing 1.44% SLS.

The results of the dissolution experiment are as shown in Fig. 1. As shown in the results of Fig. 1, it was confirmed that the manufactured mini tablets had significantly lower drug release than the control formulation, dexlansoprazole immediate-release pellets. Since the control formulation, dexlansoprazole, was formulated as an immediate-release pellet while the test formulation was formulated as a mini tablet, it can be seen that the decrease in drug release was due to the difference in formulation. However, since mini tablets have the advantages of a shorter manufacturing process and manufacturing time than pellets and can reduce coating deviation during enteric coating, the aim was to improve drug release by increasing the solubility of dexlansoprazole.

Experimental Example 4: Dissolution Test According to Use of Solubilizer

In order to overcome the shortcomings identified in the dissolution evaluation results of Examples 1-1 and 1-2 above, solubility tests were conducted using various solubilizing agents.

Poloxamer 407, HPMC, Tween 80, Soluplus, Solutol HS 15, Cremophor EL, and Gelucire 44/14 were each dissolved in an amount of 0.2 (200 mg) per weight of dexlansoprazole of 30 ml of pH 7.0+SLS solute, 1 g of dexlansoprazole was added, and stirred for 24 hours. After that, the concentration was obtained through HPLC through a 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, dexlansoprazole showed a solubility more than twice as good as when dexlansoprazole was used alone. Therefore, it can be seen that polysorbate 80 and poloxamer in the present invention greatly improve the physicochemical properties of dexlansoprazole, a poorly soluble drug, thereby acting very favorably on the absorption and dissolution of the drug, and are very advantageous for commercialization of the drug.

Experimental Example 5: Evaluation of the Effect According to the Content of Selected Solubilizer

In addition, in order to confirm the optimal ratio of polysorbate 80 and poloxamer to improve the solubility of dexlansoprazole, polysorbate 80 and poloxamer were dissolved in the pH 7.0+SLS solute at different ratios in the same manner as the above solubility test method, and then a certain amount of dexlansoprazole was added, 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 confirmed in the results in Table 4 above, it was confirmed that when polysorbate 80 and poloxamer are present in an amount of 0.5 to 2 parts by weight per 1 part by weight of dexlansoprazole, the solubility of dexlansoprazole can be improved, thereby enhancing drug release. When a solubilizer such as polysorbate 80 and poloxamer is added in a small amount, the drug release of poorly soluble dexlansoprazole is delayed. On the other hand, when the amount of the solubilizer exceeds 2 parts by weight, the size of the mini tablets inevitably increases, making it difficult to encapsulate them in hard capsules. In addition, when manufacturing pellets, especially when manufacturing pellets using spherical sugar, the volume of the coating solution including the solubilizer increases and the coating solution becomes sticky, which increases the pellet manufacturing time and makes the manufacturing process difficult.

Experimental Example 6: Stability Test of Dexlansoprazole Including Solubilizer and Alkaline Stabilizer

As shown in Table 5 below, a solid mixture containing dexlansoprazole; polysorbate 80 or poloxamer as a solubilizer used to improve the solubility of dexlansoprazole; and potassium carbonate or potassium phosphate as an alkalizing agent used to secure the stability of dexlansoprazole was prepared. The solid mixture contains 1 part by weight of the stabilizer and 0.2 part by weight of the solubilizer per 1 part by weight of dexlansoprazole. As before, it was packaged in a glass bottle and a stability test was performed for 7 days under harsh conditions (temperature 60°C, relative humidity 75%). The results are shown in Tables 5 and 6 below.

Sample name Initial Stress
3 days Stress
7 days 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 days Stress
7 days 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

The results are as shown in Tables 5 and 6 above. The dexlansoprazole powder containing dexlansoprazole and each stabilizer showed a rapid decrease in the content of dexlansoprazole over a harsh 7-day period, whereas the content of dexlansoprazole containing potassium carbonate and potassium phosphate showed a result of maintaining a stable state without a decrease in the content compared to other stabilizers, and maintained much better stability than magnesium carbonate used in the comparative preparation, Dexilant. These results reconfirm that potassium carbonate and potassium phosphate can be used as stabilizers for dexlansoprazole.

Example 2: Preparation of dexlansoprazole oral formulations comprising immediate-release minitablets and sustained-release pellets

(1) Preparation of rapid-release mini-tablets containing solubilizing agent and alkalizing agent

Mini tablets containing dexlansoprazole, a surfactant, and a stabilizer were manufactured according to the ingredients and contents of Table 7 below. Granules were manufactured and compressed into tablets using the same method as in Example 1 above, and enteric coating was performed.

　 division Ingredient name Example 2 Dosage (mg) Mini tablet chief ingredient Dexlansoprazole 15.0 Siblings Low-substituted hydroxy cellulose 15.5 Siblings Microcrystalline Cellulose 10.0 Stabilizer Potassium phosphate 4.0 Surfactant Polysorbate 80 or Poloxamer 7.5 Siblings colloidal silicon dioxide 1.2 Disintegrant Croscarmellose sodium 1.5 Siblings Crospovidone 3.6 binder Hydroxypropyl methyl cellulose 1.0 Active agent Magnesium stearate 0.7 Middle layer Coating agent Opadry Clear 1.2 Long layer Long-lasting coating device Methacrylic acid copolymer Type C 7.16 Anticoagulant Talk 0.71 Plasticizer Triethyl Citrate 3.58 　 Ethanol Appropriate amount

(2) Manufacturing of Western pellets

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

A suspension was prepared by dissolving dexlansoprazole, hydroxypropyl cellulose, polysorbate 80 or poloxamer, and potassium carbonate or potassium phosphate corresponding to the central granule layer in an organic solvent, and dexlansoprazole was sprayed onto inert spherical sugar in a fluidized spray drying apparatus. The prepared central layer was coated as an intermediate layer using Opadry Clear containing hydroxypropyl methyl cellulose, and an enteric coating layer prepared by dissolving a methacrylic acid copolymer, talc, polysorbate 80, and triethyl citrate in an organic solvent was sprayed onto the pellets prepared up to the intermediate layer coating in a fluidized spray drying apparatus, to prepare a sustained-release pellet layer.

　 division Ingredient name Example 3 Dosage (mg) Central granule Siblings Old white sugar 30.0 chief ingredient Dexlansoprazole 45.0 binder Hydroxypropyl cellulose 18.1 Surfactant Polysorbate 80 22.5 Stabilizer Potassium phosphate 12 Middle layer Coating agent Opadry Clear 27.1 Long layer Long-lasting coating device Methacrylic acid copolymer Type B 48.7 Siblings Talk 12.4 Surfactant Polysorbate 80 1.3 Plasticizer Triethyl Citrate 7.4 slush Fluidizer Talk 2.0 Antistatic agent colloidal silicon dioxide 1.0 menstruum 　
　 Purified water Appropriate amount Ethanol Appropriate amount

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

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

Experimental Example 7: Dissolution test of hard capsules containing immediate-release and sustained-release dexlansoprazole

The hard capsules containing the immediate-release mini-tablets and sustained-release pellets manufactured in the above examples were subjected to a dissolution test with the commercially available Dexilant DR capsules as a control preparation at pH 7.0+SLS solute. The results are shown in FIG. 3. In FIG. 3, Example 2 is a hard capsule including a mini-tablet using potassium phosphate and polysorbate 80 among the mini-tablets in Table 7 and a pellet using potassium phosphate and polysorbate 80 of Table 8, and Example 3 is a hard capsule including a mini-tablet using potassium phosphate and poloxamer among the mini-tablets in Table 7 and a pellet using potassium phosphate and polysorbate 80 of Table 8.

As a result, as shown in Fig. 3, in the immediate-release mini tablets containing the surfactant and stabilizer, 25% of dexlansoprazole corresponding to the immediate-release part was dissolved in the same manner as the comparative formulation, Dexilant, up to 40 minutes due to increased acid resistance and solubility. In addition, it was confirmed that the sustained-release pellets were not released in the beginning but were maintained, and the drug was gradually released after 50 minutes. Based on these results, it can be confirmed that in the hard capsules containing the surfactant polysorbate 80 or poloxamer and the stabilizer potassium carbonate or potassium phosphate, polysorbate 80 and poloxamer act as solubilizers to improve the dissolution of dexlansoprazole, and potassium carbonate and potassium phosphate act as stabilizers to secure acid resistance.

Experimental Example 8: Bioavailability Evaluation

The bioavailability of the hard capsule manufactured in Example 3 was evaluated using beagle dogs. In addition, commercially available Dexilant DR capsule (Takeda Korea) was also evaluated as a comparative preparation. Dexilant as a comparative preparation and the capsule manufactured in Example 2 were orally administered to 16 beagle dogs each weighing about 10 kg and fasted for 12 hours. After administration, blood was collected using a heparinized syringe after 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, and 12 hours. The collected blood was placed in a centrifuge tube, centrifuged at 3000 rpm for 5 minutes, and the separated plasma was collected and stored frozen at -20℃ until analysis.

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

Parameters 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 in Table 9 above, it can be seen that the hard capsule of Example 3 manufactured according to the present invention is biologically equivalent to the comparative preparation.

Claims (14)

In a composition containing dexlansoprazole or a pharmaceutically acceptable salt thereof,
Containing potassium phosphate, potassium carbonate or a mixture thereof as a stabilizer,
When potassium phosphate is contained as the above stabilizer, potassium phosphate is contained in an amount of 0.25 to 2 parts by weight per 1 part by weight of dexlansoprazole.
When potassium carbonate is contained as the above stabilizer, potassium carbonate is contained in an amount of 0.1 to 2 parts by weight per 1 part by weight of dexlansoprazole.
A pharmaceutical composition containing dexlansoprazole, wherein the mixture of potassium phosphate and potassium carbonate as the above-mentioned stabilizer is contained in an amount of 0.1 to 2 parts by weight per 1 part by weight of dexlansoprazole. A pharmaceutical composition containing dexlansoprazole, wherein in claim 1, the composition comprises polysorbate 80, poloxamer or a mixture thereof as a solubilizing agent. A pharmaceutical composition containing dexlansoprazole, wherein in claim 1, the stabilizer is potassium phosphate, and the potassium phosphate is present in an amount of 0.25 to 2 parts by weight based on 1 part by weight of dexlansoprazole. A pharmaceutical composition containing dexlansoprazole, wherein in claim 2, the solubilizing agent is present in an amount of 0.5 to 2 parts by weight based on 1 part by weight of dexlansoprazole. A pharmaceutical composition containing dexlansoprazole according to any one of claims 1 to 4, wherein the dexlansoprazole is amorphous dexlansoprazole. A hard capsule formulation containing dexlansoprazole or a pharmaceutically acceptable salt thereof,
The above hard capsule contains two dosage forms: (a) tablets containing dexlansoprazole or a pharmaceutically acceptable salt thereof, and (b) pellets containing dexlansoprazole or a pharmaceutically acceptable salt thereof.
The above tablets, pellets or both contain potassium phosphate, potassium carbonate or a mixture thereof as a stabilizer for dexlansoprazole,
When potassium phosphate is contained as the above stabilizer, potassium phosphate is contained in an amount of 0.25 to 2 parts by weight per 1 part by weight of dexlansoprazole.
When potassium carbonate is contained as the above stabilizer, potassium carbonate is contained in an amount of 0.1 to 2 parts by weight per 1 part by weight of dexlansoprazole.
When the stabilizer comprises a mixture of potassium phosphate and potassium carbonate, the mixture is included in an amount of 0.1 to 2 parts by weight per 1 part by weight of dexlansoprazole.
The above 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 pellets.
A pharmaceutical preparation containing dexlansoprazole, wherein the content of dexlansoprazole contained in the above tablets is less than the content of dexlansoprazole contained in the pellets. In claim 6, the dexlansoprazole contained in the tablet is 20-30 wt% based on the dexlansoprazole content of the entire pharmaceutical preparation, and the dexlansoprazole contained in the pellets is 70-80 wt% based on the entire dexlansoprazole content, a pharmaceutical preparation containing dexlansoprazole. delete A pharmaceutical preparation containing dexlansoprazole, wherein in claim 6, the stabilizer is potassium phosphate, and the content of the potassium phosphate is present in an amount of 0.25 to 2 parts by weight based on 1 part by weight of dexlansoprazole. A pharmaceutical preparation containing dexlansoprazole, wherein the tablet, pellet or both contain polysorbate 80, poloxamer or a mixture thereof as a solubilizing agent in claim 6. A pharmaceutical preparation containing dexlansoprazole, wherein in claim 10, the solubilizing agent is present in an amount of 0.5 to 2 parts by weight per 1 part by weight of dexlansoprazole. A pharmaceutical preparation containing dexlansoprazole, wherein the enteric polymer used in the coating of the tablets and pellets in claim 6 is a methacrylic acid copolymer, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, ethyl cellulose, cellulose acetate phthalate, or a mixture thereof. A pharmaceutical preparation containing dexlansoprazole, wherein the tablet, pellet or both are pre-coated with a hydrophilic polymer before the enteric polymer coating. A pharmaceutical preparation containing dexlansoprazole according to any one of claims 6, 7, and 9 to 13, wherein the dexlansoprazole is amorphous dexlansoprazole.