PHARMACEUTICAL COMPOSITION INCLUDING MULTI-UNIT SPHEROIDAL TABLET CONTAINING ESOMEPRAZOLE AND SPHEROIDAL PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, AND METHOD OF PREPARING THE PHARMACEUTICAL COMPOSITION

Abstract

Provided are a pharmaceutical composition including a core in a form of a multi-unit spheroidal tablet (MUST) containing esomeprazole or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is dissolved by 50 percent (%) or more within 15 minutes of an in vitro dissolution test; and a method of preparing the pharmaceutical composition. According to this, in case that the pharmaceutical composition is developed as the multi-unit spheroidal tablet, the dissolution may be accelerated in a condition of a slow stirring rate than that of a conventional pellet formulation or single tablet. Also, proton pump inhibitors (PPI)-based drugs including esomeprazole may be dissociated by gastric acid having a low pH, consequently inducing a decrease in bioavailability of the drug, but the pharmaceutical composition according to this may be minimize this.

Claims

1. A pharmaceutical composition comprising a core in a form of multi-unit spheroidal tablet (MUST) containing esomeprazole or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is dissolved by 50 percent (%) or more within 15 minutes of a dissolution test in presence of simulated intestinal fluid at 25 revolutions per minute (rpm).

2. The pharmaceutical composition of claim 1, wherein the esomeprazole or a pharmaceutically acceptable salt thereof is in a form of a dry granule.

3. The pharmaceutical composition of claim 1, wherein a disintegration time of the core is within 30 seconds.

4. The pharmaceutical composition of claim 1, wherein the core further comprises at least one excipient selected from a diluent, a disintergrant, a binder, a lubricant, a surfactant, an antioxidant, a preservative, and a stabilizer.

5. The pharmaceutical composition of claim 4, wherein the disintergrant is low-substituted hydroxypropyl cellulose.

6. The pharmaceutical composition of claim 5, wherein a content of the low-substituted hydroxypropyl cellulose is in a range of about 12 percent by weight (wt %) to about 30 wt %, based on a total weight of the core.

7. The pharmaceutical composition of claim 1, wherein a diameter or a longest diagonal length of the core is in a range of about 1.0 millimeter (mm) to about 6.0 mm.

8. The pharmaceutical composition of claim 1, wherein a diameter or a longest diagonal length of the core is in a range of about 1.0 mm to about 5.0 mm.

9. The pharmaceutical composition of claim 1, wherein a diameter or a longest diagonal length of the core is in a range of about 1.0 mm to about 3.0 mm.

10. A method of preparing the pharmaceutical composition of claim 1, the method comprising: preparing a mixture by mixing esomeprazole or a pharmaceutically acceptable salt thereof with at least one excipient selected from a diluent, a disintergrant, a binder, a lubricant, a surfactant, an antioxidant, a preservative, and a stabilizer; and dry-granulating and tableting the mixture to obtain a core in a form of a multi-unit spheroidal tablet (MUST).

Description

DESCRIPTION OF DRAWINGS

[0036] These and/or other aspects will become apparent and more readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings in which:

[0037] FIG. 1A is a graph of a dissolution rate (percent, %) of esomeprazole versus dissolution time (minutes, mins) of the formulations prepared in Examples 1 to 3 and Comparative Examples 1 to 6;

[0038] FIG. 1B is a graph of a dissolution rate (%) of esomeprazole versus dissolution time (mins) of the formulations prepared in Examples 1, 4, and 5 and Comparative Example 8, varying in terms of multi-unit spheroidal tablet (MUST) punch diameter;

[0039] FIG. 1C is a graph of a dissolution rate (%) of esomeprazole versus dissolution time (mins) of the tablet formulation (Example 1) and the pellet formulation; and

[0040] FIG. 2 is a graph of disintegration time (seconds, sec) of the formulations prepared in Examples 1 to 3 and Comparative Examples 1 to 6.

MODE FOR INVENTION

[0041] Hereinafter, the present disclosure will be described in further detail with reference to Examples. However, these examples are not intended to limit the scope of the one or more embodiments of the present disclosure.

Example 1: Preparation of Tablet Esomeprazole Magnesium Salt

[0042] As in Table 1, first, esomeprazole magnesium salt was mixed with mannitol, and then was sieved through a 30-mesh round sieve. The prepared mixture, low-substituted hydroxypropyl cellulose, croscarmellose sodium, hydroxypropyl cellulose, and sodium stearyl fumarate were added to an empty blender, followed by mixing for 15 minutes, thereby preparing a final mixture. The final mixture was added to a roller compactor for dry granulation. The obtained granules were sieved through a 30-mesh round sieve.

[0043] Subsequently, tablets having a hardness of about 1 kiloponds (kp) to about 2 kp and a weight of about 75 milligrams (mg) per 10 tablets were prepared by a tablet machine using a MUST punch having a diameter of 2.0 mm.

TABLE-US-00001 TABLE 1 Weight (mg/10 Percent by Ingredient tablets) weight (%) Esomeprazole magnesium 22.3 29.7 salt trihydrate Mannitol 28.7 38.3 Low-substituted 13.8 18.4 hydroxypropyl cellulose Croscarmellose sodium 4.8 6.4 Hydroxypropyl cellulose 2.4 3.2 Sodium stearyl fumarate 3.0 4.0 Total 75.0 100.0

Examples 2 and 3: Preparation of Tablet Esomeprazole Magnesium Salt

[0044] Tablets were prepared in substantially the same manner as in Example 1, except that the amount of low-substituted hydroxypropyl cellulose was different. The compositions of the prepared tablets are shown in Table 2.

TABLE-US-00002 TABLE 2 Example 1 Example 2 Example 3 (mg/10 (mg/10 (mg/10 Ingredient tablets) tablets) tablets) Esomeprazole magnesium 22.3 22.3 22.3 salt trihydrate Mannitol 28.7 32.9 24.5 Low-substituted 13.8 9.6 18 hydroxypropyl cellulose Croscarmellose sodium 4.8 4.8 4.8 Hydroxypropyl cellulose 2.4 2.4 2.4 Sodium stearyl fumarate 3.0 3.0 3.0 Total 75.0 75.0 75.0

Examples 4 and 5: Preparation of Tablet Esomeprazole Magnesium Salt

[0045] Tablets were prepared in substantially the same manner as in Example 1 with the same composition as Example 1, except that the diameter of the MUST punch was different. [0046] Example 4: Tablets were prepared using a MUST punch having a diameter of 1 mm such that a weight of 40 tablets was about 75 mg. [0047] Example 5: Tablets were prepared using a MUST punch having a diameter of 4 mm such that a weight of 2 tablets was about 75 mg.

Comparative Example 1: Preparation of Tablet Esomeprazole Magnesium Salt

[0048] As in Table 3, first, esomeprazole magnesium salt was mixed with mannitol, and then was sieved through a 30-mesh round sieve. The prepared mixture, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and sodium stearyl fumarate were added to an empty blender, followed by mixing for 15 minutes, thereby preparing a final mixture. The final mixture was added to a roller compactor for dry granulation. The obtained granules were sieved through a 20-mesh round sieve.

[0049] Subsequently, tablets having a hardness of about 1 kp to about 2 kp and a weight of about 75 mg per 10 tablets were prepared by a tablet machine using a MUST punch having a diameter of 2.0 mm.

TABLE-US-00003 TABLE 3 Weight (mg/10 Percent by Ingredient tablets) weight (%) Esomeprazole magnesium 22.3 29.7 salt trihydrate Mannitol 29.7 39.6 Microcrystalline cellulose 15.2 20.3 Croscarmellose sodium 2.4 3.2 Hydroxypropyl cellulose 2.4 3.2 Sodium stearyl fumarate 3.0 4.0 Total 75.0 100.0

Comparative Examples 2 to 6: Preparation of Tablet Esomeprazole Magnesium Salt

[0050] Tablets were prepared in substantially the same manner as in Example 1, except that the amount of low-substituted hydroxypropyl cellulose were different. The compositions thereof are shown in Table 4.

TABLE-US-00004 TABLE 4 Comp. Comp. Comp. Comp. Comp. Exam- Exam- Exam- Exam- Exam- ple 2 ple 3 ple 4 ple 5 ple 6 (mg/10 (mg/10 (mg/10 (mg/10 (mg/10 Ingredient tablets) tablets) tablets) tablets) tablets) Esomeprazole 22.3 22.3 22.3 22.3 22.3 magnesium salt trihydrate Mannitol 27.3 24.3 37.7 19.5 Lactose hydrate 27.3 Microcrystalline 15.2 15.2 cellulose Anhydrous dibasic 13.8 potassium phosphate Low-substituted 4.8 23.0 hydroxypropyl cellulose Croscarmellose 4.8 4.8 4.8 4.8 4.8 sodium Hydroxypropyl 2.4 2.4 2.4 2.4 2.4 cellulose Sodium stearyl 3.0 3.0 3.0 3.0 3.0 fumarate Total 75.0 75.0 75.0 75.0 75.0 (Comp. Example: comparative Example)

Comparative Examples 7 and 8: Preparation of Tablet Esomeprazole Magnesium Salt

[0051] Tablets were prepared in substantially the same manner as in Example 1 with the same composition as Example 1, except that the diameter of the MUST punch was different. [0052] Comparative Example 7: Tablets were prepared using a MUST punch having a diameter of 0.7 mm such that a weight of 75 tablets was about 75 mg. [0053] Comparative Example 8: Tablets were prepared using a MUST punch having a diameter of 7.0 mm such that a weight of 1 tablet was about 75 mg.

Experimental Example 1. Dissolution Test of Esomeprazole Preparation

[0054] (1) Comparison of Examples 1 to 5 with Comparative Examples 1 to 8

[0055] Under the dissolution conditions and analysis conditions described herein, the dissolution rates of esomeprazole of the formulations of Examples 1 to 5 and Comparative Examples 1 to 8 were measured.

[0056] <Dissolution Conditions>

[0057] Eluent: 900 milliliters (mL) of simulated intestinal fluid (pH 6.8)

[0058] Apparatus: Paddle test, 25 rpm

[0059] Temperature: 37 C.

[0060] Dissolution time: 5 minutes, 10 minutes, 15 minutes, 30 minutes, and 45 minutes (max)

[0061] (After a lapse of 30 minutes, the stirring rate was adjusted to 150 rpm)

[0062] <Analysis Conditions>

[0063] Used device: high-performance liquid chromatography (HPLC, Hitachi 5000 series, Japan)

[0064] Detector: Ultraviolet absorptiometer (measured wavelength: 302 nanometers (nm))

[0065] Column: a column of a stainless still pipe having an inner diameter of about 4.0 mm and a length of about 10 cm, which is packed with silica gel having a particle diameter of 5 m for liquid chromatography

[0066] Mobile phase: sodium phosphate buffer solution (pH 7.3): acetonitrile:distilled water=50:35:15

[0067] Flow rate: 1.0 milliliter per minute (mL/min)

[0068] Column temperature: 30 C.

[0069] The measured dissolution rate of esomeprazole are shown in Table 5, Table 6, and FIG. 1A.

TABLE-US-00005 TABLE 5 Dissolution rate of esomeprazole (%) Example Example Example Example Example Time 1 2 3 4 5 (mins) AVG. S.D. AVG. S.D. AVG. S.D. AVG. S.D. AVG. S.D. 0 0.0 0.0 0.0 0.0 0.0 0.0 0 0 0 0 5 33.6 2.4 30.7 2.7 36.7 2.9 39.8 1.4 24.3 4.2 10 47.7 3.7 45.8 1.6 50.8 3.1 53.3 1.7 40.3 2.8 15 54.0 2.1 59.8 1.8 60.3 1.3 58.8 2.2 52.1 2.3 30 66.1 1.3 67.1 2.1 68.9 1.2 67.2 0.6 63.2 2.6 45(Max) 101.4 1.0 99.6 2.0 98.9 1.4 99.4 0.4 99.5 0.2 (AVG.: average, S.D.: standard deviation)

TABLE-US-00006 TABLE 6 Dissolution rate of esomeprazole (%) Comp. Comp. Comp. Comp. Comp. Comp. Comp. Time Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 8 (mins) AVG. S.D. AVG. S.D. AVG. S.D. AVG. S.D. AVG. S.D. AVG. S.D. AVG. S.D. 0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0 0 0.0 0.0 0 0 5 11.6 6.5 10.9 3.8 15.6 1.3 14.3 1.9 31.2 2.1 13.1 1.9 13.2 7.6 10 20.0 4.9 19.9 4.6 22.4 2.8 22.8 2.7 48.3 2.6 24.8 3.1 24.7 5.6 15 27.7 6.4 30.6 3.6 28.7 2.9 28.9 3.7 57.7 2.3 27.8 2.7 28.6 4.5 30 43.9 3.8 45.9 3.4 41.8 3.0 37.9 1.9 68.2 2.7 40.2 2.5 36.6 4.5 45 (Max) 97.5 2.9 100.6 2.4 98.9 1.8 100.8 2.2 99.5 1.1 100.1 1.4 99.4 0.4 (Comp. Example: comparative Example, AVG.: average, S.D.: standard deviation)

[0070] As shown in Tables 5 and 6 and FIGS. 1A and 1B, the formulations of Examples 1 to 5 and Comparative Examples 5 exhibited rapid release characteristics of drugs, whereas the formulations of Comparative Examples 1 to 4, 6, and 8 exhibited low dissolution rates as well as slow disintegration of the tablets.

[0071] In the case of the formulation of Comparative Example 7, insufficient packing of granules in a hole die was observed with naked eye in a tableting process, and difficulties were found in the tableting process because an edge of the punch was broken by a slight error in assembling of equipment.

[0072] When a dissolution rate of the drug is lowered due to the delayed disintegration time, the drug may be dissociated by gastric acid before absorbed into a living matter, thus decreasing bioavailability of the drug. To overcome this end, rapid disintegration of a tablet is required. In the case of the formulations of Examples 1 to 3, the drugs were rapidly dissolved, and thus the drugs were absorbed into a living matter, without dissociation by gastric acid or excretion of the drug. In contrast, in the case of the formulations of Comparative Examples 1 to 6, it was found that the formulations of Comparative Examples 1 to 6 were not suitable because disintegration of the drugs was delayed, which may result in excretion of the drug from a living matter.

[0073] (2) Comparison of Tablet Formulation with Pellet Formulation

[0074] To compare dissolution rates of the formulations of esomeprazole, the tablet formulation of Example 1 and a pellet formulation of esomeprazole (esomeprazole 20 mg) were prepared. As for the pellet formulation of esomeprazole, 20 mg of Nexium (available from Astrazeneca), which is currently commercially available in the market, was purchased for the comparison test.

[0075] The dissolution rates of esomeprazole were measured following the method described in Experimental Example 1.(1). The results thereof are shown in Table 7 and FIG. 1B.

TABLE-US-00007 TABLE 7 Pellet formulation Example 1 (esomeprazole) Time Standard Standard (mins) Average deviation Average deviation 0 0.0 0.0 0.0 0.0 5 33.6 2.4 9.8 5.3 10 47.7 3.7 19.9 2.9 15 54.0 2.1 24.0 3.1 30 66.1 1.3 54.9 2.9 45 101.4 1.0 101.3 1.3 (Max)

[0076] As shown in Table 7 and FIG. 1B, the tablet formulation of Example 1 was found to have rapid release characteristics, as compared with the pellet formulation. In particular, after a lapse of about 15 minutes, the dissolution rate of the pellet formulation was about 24%, however, the dissolution rate of the tablet formulation was about 54%, which is about 2 or more times higher than that of the pellet formulation.

Experimental Example 2. Disintegration Test of Esomeprazole Preparation

[0077] To compare disintegration times of the formulations of Examples 1 to 3 with the formulations of Comparative Examples 1 to 6, an experiment was performed according to the disintegration test method for general release preparations described in Korean Pharmacopoeia (KP). The disintegration time of each of the formulations was measured, and the results thereof are shown in Table 8 and FIG. 2.

TABLE-US-00008 TABLE 8 Disintegration Formulation time (sec) Example 1 15.3 Example 2 16.1 Example 3 14.9 Example 4 10.4 Example 5 25.6 Comparative Example 1 49.6 Comparative Example 2 50.3 Comparative Example 3 49.9 Comparative Example 4 45.7 Comparative Example 5 13.1 Comparative Example 6 52.1 Comparative Example 8 63.1

[0078] As shown in Table 8 and FIG. 2, the formulations of Example 1 to 3 and Comparative Example 1 to 6 are not commonly developed tablet formulations, the disintegration time of each of the formulations was within 1 minute, except the single tablet of Comparative Example 8. In particular, the formulations of Examples 1 to 5 each had a disintegration time within about 15 seconds.

[0079] To secure rapid release characteristics in a living matter, disintegration of the drug is required to be completed within about 30 seconds. Thus, the formulations of Examples 1 to 5 were found to be suitable in this regard.

Experimental Example 3. Evaluation of Physical Properties of Granules

[0080] The physical properties of the granules prepared in Examples 1 to 3 and Comparative Examples 1 to 6 were evaluated. When tableting, as 19 tips are tableted at once, flowability of granules is an important variable in securing mass deviation and uniformity of the tablets. The results of evaluation of physical properties are shown in Table 9.

TABLE-US-00009 TABLE 9 Flowability of granules Formulation (angle of repose ) Example 1 38.0 Example 2 39.0 Example 3 39.5 Comparative Example 1 36.0 Comparative Example 2 35.1 Comparative Example 3 37.9 Comparative Example 4 37.9 Comparative Example 5 42.3 Comparative Example 6 38.8

[0081] As shown in Table 9, a suitable angle of repose for tableting was within 40. As tableting of mini-tablets are required, a diameter of the punch may be small, and a diameter of a hole die, through which granules are packed, may also be small. As a small punch is used, the flowability of granules was found to be an important factor in producing tablets having a uniform mass and hardness. When an angle of repose is 40 or greater, uniform packing of granules is difficult, and thus, it is difficult to secure uniform mass and hardness of tablets. The formulations of Examples 1 to 3 were found to have satisfactory flowability of granules within 40. On the other hand, the formulation of Comparative Example 5 had an angle of repose of 40 or greater, thus being improper in tableting uniform mini-tablets.

[0082] While this disclosure has been particularly shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the disclosure as defined by the appended claims. The disclosed embodiments should be considered in descriptive sense only and not for purposes of limitation. Therefore, the scope of the disclosure is defined not by the detailed description of the disclosure but by the appended claims, and all differences within the scope will be construed as being included in the present disclosure.