EXTENDED-RELEASE PHARMACEUTICAL COMPOSITION CONTAINING LACOSAMIDE

Abstract

Disclosed is an extended-release lacosamide preparation which can be taken once a day. Also disclosed is a method for treating a subject with epilepsy including administering the extended-release lacosamide preparation once a day.

Claims

1. A pharmaceutical composition comprising lacosamide or a salt thereof as an active ingredient, the composition comprising an immediate release layer and an extended release layer, wherein the extended release layer comprises cellulose derivative and wax or wax-like lipid in a weight ratio of 1:0.1 to 1:10, and wherein the pharmaceutical composition can be administered orally once a day.

2. The pharmaceutical composition according to claim 1, wherein the cellulose derivative is at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, methylcellulose and hydroxyethyl cellulose.

3. The pharmaceutical composition according to claim 1, wherein the wax or wax-like lipid is at least one selected from the group consisting of glyceryl behenate, glyceryl palmitostearate and glyceryl stearate.

4. The pharmaceutical composition according to claim 1, wherein the active ingredient in the immediate release layer and the active ingredient in the extended release layer are in a weight ratio of 1:1 to 1:7.

5. The pharmaceutical composition of claim 1, wherein the content of the cellulose derivative and the wax or wax-like lipid is 5 to 50 wt % with respect to the extended release layer.

6. The pharmaceutical composition of claim 1, which is in a dosage form of 100 mg, 200 mg, 300 mg, or 400 mg of lacosamide.

7. A method for treating a subject with epilepsy comprising administering the pharmaceutical composition of claim 1 orally once a day to the subject.

8. The method according to claim 7, wherein the cellulose derivative is at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, methylcellulose and hydroxyethyl cellulose.

9. The method according to claim 7, wherein the wax or wax-like lipid is at least one selected from the group consisting of glyceryl behenate, glyceryl palmitostearate and glyceryl stearate.

10. The method according to claim 7, wherein the active ingredient in the immediate release layer and the active ingredient in the extended release layer are in a weight ratio of 1:1 to 1:7.

11. The method according to claim 7, wherein the content of the cellulose derivative and the wax or wax-like lipid is 5 to 50 wt % with respect to the extended release layer.

12. The method according to claim 7, wherein the pharmaceutical composition is provided as a dosage form of 100 mg, 200 mg, 300 mg, or 400 mg of lacosamide.

Description

DESCRIPTION OF DRAWINGS

[0021] FIG. 1 shows the dissolution profiles of 100 mg and 400 mg lacosamide preparation of Example 1.

[0022] FIG. 2 shows the dissolution profiles of 100 mg and 400 mg lacosamide preparation of Example 2.

[0023] FIG. 3 shows the dissolution profiles of 100 mg and 400 mg lacosamide preparation of Example 3.

[0024] FIG. 4 shows the dissolution profiles of 100 mg and 400 mg lacosamide preparation of Example 4.

[0025] FIG. 5 shows the dissolution profiles of 100 mg and 400 mg lacosamide preparation of Example 5.

[0026] FIG. 6 shows the dissolution profiles of 100 mg and 400 mg lacosamide preparation of Example 6.

[0027] FIG. 7 shows the dissolution profiles of 100 mg and 400 mg lacosamide preparation of Example 7.

[0028] FIG. 8 shows the dissolution profiles of 100 mg and 400 mg lacosamide preparation of Example 8.

[0029] FIG. 9 shows the dissolution profiles of 100 mg and 400 mg lacosamide preparation of Example 9.

[0030] FIG. 10 shows the dissolution profile of 100 mg and 400 mg lacosamide preparation of Example 10.

[0031] FIG. 11 shows the dissolution profiles of 100 mg and 400 mg lacosamide preparation of Example 11.

[0032] FIG. 12 shows the dissolution profiles of 100 mg and 400 mg lacosamide preparation of Comparative Example 1.

[0033] FIG. 13 shows the dissolution profiles of 100 mg and 400 mg lacosamide preparation of Comparative Example 2.

[0034] FIG. 14 shows the dissolution profiles of 100 mg and 400 mg lacosamide preparation of Comparative Example 3.

[0035] FIG. 15 shows the dissolution profiles of 100 mg and 400 mg lacosamide preparation of Comparative Example 4.

[0036] FIG. 16 shows the dissolution profiles of 100 mg and 400 mg lacosamide preparation of Comparative Example 5.

[0037] FIG. 17 shows the dissolution profiles of 100 mg and 400 mg lacosamide preparation of Comparative Example 6.

[0038] FIG. 18 shows the lacosamide blood concentration over time in beagle dogs when lacosamide 200 mg preparation (Example 3) is orally administered once a day and when Vimpat tablet 100 mg (control preparation) is orally administered twice a day.

MODE FOR INVENTION

[0039] Lacosamide immediate-release tablets are disclosed. It is Vimpat tablet, and it is taken twice a day. Immediate-release tablets release 98% of the active ingredient within 15 minutes when contact with aqueous medium. Tmax of immediate-release tablets are usually reached within 1.4-1.5 hours after administration, and the excretion half-life is about 13-14 hours. Therefore, immediate-release tablet is ideal for administration of twice a day. Currently, lacosamide is commercially available only as an immediate-release tablet, and no extended-release tablet of lacosamide is commercially available. However, since lacosamide is a drug that requires long-term use due to the nature of the indicated disease for treatment, it has been required to develop a preparation for once a day, the preparation having the same efficacy with that of a preparation for twice a day.

[0040] The present invention relates to a lacosamide extended-release tablet that meets the above-mentioned needs.

[0041] In the specification, the term lacosamide may refer to any component in which the active ingredient is lacosamide. For example, lacosamide or a salt thereof may correspond to this term. Hereinafter, lacosamide or a salt thereof is also referred to as an active ingredient or main ingredient.

[0042] The idea of simply extended-release lacosamide exists. However, if the lacosamide formulation is implemented with only an extended-release system, it may be insufficient in the initial drug efficacy compared with that of an immediate-release tablet. Therefore, the present invention is characterized in that it includes both immediate-release and extended-release.

[0043] There has been no case in which lacosamide preparation including both immediate-release and extended-release has achieved bioequivalence to the immediate-release tablets which is administered twice a day. However, the present inventor surprisingly found out that, if lacosamide in the immediate-release layer and lacosamide in extended-release layer are in a weight ratio of 1:1 to 1:7 and the extended-release layer comprises cellulose derivative and a wax or wax-like lipid in a weight ratio of 1:0.1 to 1:10 in a preparation, such preparation can be proved to have a bioequivalence.

[0044] In addition, although it is generally accepted that dissolution rate profile may be varied since the surface area of the preparation is different depending on the content of the active ingredient, the present inventor found out that if extended-release layer comprises cellulose derivative and a wax or wax-like lipid in a weight ratio of 1:0.1 to 1:10 in a preparation, such preparation has an equivalent dissolution rate profile to each other.

[0045] The immediate release layer of the present invention may include active ingredient, disintegrant and filler. If necessary, other additives conventionally used in immediate release tablets may be included.

[0046] For example, as the disintegrant, at least one selected from the group consisting of crospovidone, croscarmellose sodium and sodium starch glycolate may be used.

[0047] As the filler, at least one selected from the group consisting of microcrystalline cellulose, starch, low-substituted hydroxypropyl cellulose, calcium phosphate and lactose can be used.

[0048] The disintegrant and the filler may be appropriately blended with an appropriately ratio by a skilled person in the art considering the content of the active ingredient. For example, they may be added in the amount of 10 to 80 wt %, preferably 10 to 50 wt % based on the immediate release layer, respectively.

[0049] The immediate release layer of the present invention may further comprise glidant, binder, lubricant, and the like, if necessary. For example, as the glidant, at least one selected from the group consisting of calcium silicate, colloidal silicon dioxide, magnesium aluminometasilicate and talc may be used. As the binder, at least one selected from the group consisting of povidone, hydroxypropyl cellulose and copovidone may be used. As the lubricant, at least one selected from the group consisting of sodium stearyl fumarate, stearic acid and magnesium stearate may be used. The blending ratio may also be appropriately adjusted by a person skilled in the art. For example, they may be included in the amount of 1 to 30 wt %, preferably 1 to 10 wt % based on the immediate release layer, respectively.

[0050] The immediate release layer of the present invention may be prepared by mixing lacosamide, glidant, and filler, adding binder, granulating, sizing the granulation and then mixing with disintegrant and lubricant.

[0051] The extended release layer of the present invention includes active ingredient and base for controlled-release. The base for controlled-release is characterized in that the cellulose derivative and the wax or wax-like lipid are blended in a weight ratio of 1:0.1 to 1:10. The base for controlled-release may be included in the amount of 5 to 50 wt %, preferably 5 to 40 wt %. If the content of the base for control-release exceeds 50 wt %, the drug is too slowly released, and thus, the controlled release cannot be achieved and the size of the tablet increases, which causes decrease of drug compliance. If the content of the base for control-release is less than 5 wt %, the release of the drug becomes faster, and thus, the continuous controlled-release cannot be achieved.

[0052] The extended-release layer of the present invention may further be suitably blended with the above-mentioned glidant, filler, binder, and lubricant. For example, as the filler, at least one selected from the group consisting of microcrystalline cellulose, starch, low-substituted hydroxypropyl cellulose, calcium phosphate and lactose may be used. As glidant, at least one selected from the group consisting of calcium silicate, colloidal silicon dioxide, magnesium aluminometasilicate and talc may be used. As binder, at least one selected from the group consisting of povidone, hydroxypropyl cellulose and copovidone may be used. As lubricant, at least one selected from the group consisting of sodium stearyl fumarate, stearic acid and magnesium stearate may be used. For example, they may be included in the amount of 1 to 50 wt %, preferably 1 to 30 wt % based on the extended release layer, respectively.

[0053] The extended-release layer of the present invention may be prepared by mixing lacosamide, glidant, filler and base for controlled-release, adding binder, granulating, sizing the granulation and then mixing lubricant.

[0054] The final preparation can be obtained as two-layered tablets by tableting the immediate-release layer and the extended-release layer. If necessary, the obtained tablets may be coated. As the film coating base, at least one selected from the group consisting of hydroxypropyl methyl cellulose and polyvinyl alcohol may be used. The film coating base may be 1-10 wt % based on tablet.

[0055] The present invention can be a preparation containing 100 mg, 200 mg, 300 mg, 400 mg content on the basis of lacosamide.

EXAMPLES

[0056] Hereinafter, the present invention will be more detailed illustrated with following examples. However, it should be noted that following examples are only embodiments of the present invention, and the scope of the present invention is not limited thereby.

1. Examples

[0057] 1-1. Extended-Release Base Ingredient (Active Ingredient 200 mg Prescription Table)

TABLE-US-00001 TABLE 1 Exam- Exam- Exam- Ingredient ple 1 ple 2 ple 3 Extended Lacosamide 150.0 150.0 150.0 release Colloidal silicon dioxide 9.0 9.0 9.0 Microcrystalline cellulose 78.0 78.0 78.0 Hydroxypropyl cellulose 10.0 10.0 10.0 Ethyl cellulose 20.0 Hydroxy propyl methyl 20.0 cellulose Hydroxyethyl cellulose 20.0 Glyceryl behenate 20.0 20.0 20.0 Magnesium stearate 3.0 3.0 3.0 Immediate Lacosamide 50.0 50.0 50.0 release Colloidal silicon dioxide 4.0 4.0 4.0 Low-substituted 22.0 22.0 22.0 hydroxypropyl cellulose Microcrystalline cellulose 60.5 60.5 60.5 Hydroxypropyl cellulose 5.0 5.0 5.0 Crospovidone 7.0 7.0 7.0 Magnesium stearate 1.5 1.5 1.5 coating 13.2 13.2 13.2 Total (mg/tablet) 453.2 453.2 453.2 * Unit: mg (same in following tables)

[0058] The extended release layer is prepared by mixing lacosamide with colloidal silicon dioxide, microcrystalline cellulose, extended-release polymer (base for controlled-release) and wax or wax-like lipids, and then adding binder wherein hydroxypropyl cellulose is dissolved, kneading, granulating, drying at a temperature of 60 C. for 1-2 hours in a dryer, sizing the granulation and mixing with lubricant.

[0059] The immediate release layer is prepared by mixing lacosamide with colloidal silicon dioxide, microcrystalline cellulose and low-substituted hydroxypropyl cellulose, and then adding binder wherein hydroxypropyl cellulose is dissolved, kneading, granulating, drying at a temperature of 60 C. for 1-2 hours in a dryer, sizing the granulation and mixing with disintergrant and lubricant.

[0060] The extended-release granules and the immediate-release granules prepared in the above are compressed into two-layered tablets, and the obtained tablets are coated with hydroxypropyl methyl cellulose or polyvinyl alcohol based Opadry coating agent according to a conventional method to obtain extended-release tablets comprising lacosamide 200 mg per film coated tablet.

[0061] Extended-release tablets of lacosamide 100 mg, 200 mg, 300 mg and 400 mg are prepared according to a multiplied prescription wherein the amount of each component in the based prescription is multiplied by a factor, respectively.

[0062] 1-2. Content Ratio of Extended-Release Base Combination

TABLE-US-00002 TABLE 2 Ingredient Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Extended Lacosamide 150.0 150.0 150.0 150.0 150.0 150.0 release Colloidal silicon dioxide 9.0 9.0 9.0 9.0 9.0 9.0 Microcrystalline cellulose 78.0 78.0 78.0 78.0 78.0 78.0 Hydroxypropyl cellulose 10.0 10.0 10.0 10.0 10.0 10.0 Hydroxyethyl cellulose 36.0 25.0 15.0 10.0 5.0 3.6 Glyceryl behenate 4.0 15.0 25.0 30.0 35.0 36.4 Magnesium stearate 3.0 3.0 3.0 3.0 3.0 3.0 Immediate Lacosamide 50.0 50.0 50.0 50.0 50.0 50.0 release Colloidal silicon dioxide 4.0 4.0 4.0 4.0 4.0 4.0 Low-substituted 22.0 22.0 22.0 22.0 22.0 22.0 hydroxypropyl cellulose Microcrystalline cellulose 60.5 60.5 60.5 60.5 60.5 60.5 Hydroxypropyl cellulose 5.0 5.0 5.0 5.0 5.0 5.0 Crospovidone 7.0 7.0 7.0 7.0 7.0 7.0 Magnesium stearate 1.5 1.5 1.5 1.5 1.5 1.5 coating 13.2 13.2 13.2 13.2 13.2 13.2 Total (mg/tablet) 453.2 453.2 453.2 453.2 453.2 453.2

[0063] Lacosamide extended-release tablets having various ratio of hydroxyethyl cellulose (HEC)/glyceryl behenate (GB) (1:0.1 to 1:10) were prepared according to the same manufacturing method as in Example 1-1.

[0064] 1-3. Active Ingredient Content Ratio

TABLE-US-00003 TABLE 3 Compar- Exam- Exam- ative Ingredient ple 10 ple 11 Example 1 Extended Lacosamide 100.0 175.0 200.0 release Colloidal silicon dioxide 9.0 9.0 9.0 Microcrystalline cellulose 141.4 46.4 14.6 Hydroxypropyl cellulose 10.0 10.0 10.0 Hydroxyethyl cellulose 13.3 23.3 26.7 Glyceryl behenate 13.3 23.3 26.7 Magnesium stearate 3.0 3.0 3.0 Immediate Lacosamide 100.0 25.0 release Colloidal silicon dioxide 4.0 4.0 4.0 Low-substituted 22.0 22.0 22.0 hydroxypropyl cellulose Microcrystalline cellulose 10.5 85.5 110.5 Hydroxypropyl cellulose 5.0 5.0 5.0 Crospovidone 7.0 7.0 7.0 Magnesium stearate 1.5 1.5 1.5 coating 13.2 13.2 13.2 Total (mg/tablet) 453.2 453.2 453.2

[0065] Lacosamide extended-release tablets having various amount of active ingredient were prepared according to the same manufacturing method as in Example 1.1.

2. Comparative Examples

[0066] 2-1. Ingredient of Base for Extended-Release

TABLE-US-00004 TABLE 4 Comparative Comparative Comparative Comparative Ingredient Example 2 Example 3 Example 4 Example 5 Extended Lacosamide 150.0 150.0 150.0 150.0 release Colloidal silicon dioxide 9.0 9.0 9.0 9.0 Microcrystalline cellulose 78.0 78.0 78.0 78.0 Hydroxypropyl cellulose 10.0 10.0 10.0 10.0 Ethyl cellulose 40.0 Hydroxypropyl methyl cellulose 40.0 Hydroxyethyl cellulose 40.0 Glyceryl behenate 40.0 Magnesium stearate 3.0 3.0 3.0 3.0 Immediate Lacosamide 50.0 50.0 50.0 50.0 release Colloidal silicon dioxide 4.0 4.0 4.0 4.0 Low-substituted 22.0 22.0 22.0 22.0 hydroxypropyl cellulose Microcrystalline cellulose 60.5 60.5 60.5 60.5 Hydroxy propyl cellulose 5.0 5.0 5.0 5.0 Crospovidone 7.0 7.0 7.0 7.0 Magnesium stearate 1.5 1.5 1.5 1.5 coating 13.2 13.2 13.2 13.2 Total (mg/tablet) 453.2 453.2 453.2 453.2

[0067] Lacosamide extended-release tablets having various extended-release polymer were prepared according to the same manufacturing method as in Example 1-1.

[0068] 2-2. Content Ratio of Extended-Release Base Combination

TABLE-US-00005 TABLE 5 Comparative Example 6 Extended Lacosamide 150.0 release Colloidal silicon dioxide 9.0 Microcrystalline cellulose 78.0 Hydroxypropyl cellulose 10.0 Hydroxyethyl cellulose 3.3 Glyceryl behenate 36.7 Magnesium stearate 3.0 Immediate Lacosamide 50.0 release Colloidal silicon dioxide 4.0 Low-substituted hydroxypropyl cellulose 22.0 Microcrystalline cellulose 60.5 Hydroxypropyl cellulose 5.0 Crospovidone 7.0 Magnesium stearate 1.5 coating 13.2 Total (mg/tablet) 453.2

[0069] Lacosamide extended-release tablets having various ratio of hydroxyethyl cellulose/glyceryl behenate were prepared according to the same manufacturing method as in Example 1-1.

3. Experimental Example

[0070] 3-1. Dissolution Rate Evaluation (Examples 1-3)

[0071] Dissolution rate of each preparation of Examples 1 to 3 were evaluated according to the second method (paddle method) of the Korean Pharmacopoeia Dissolution Test Method using the condition of 900 ml purified water at 50 rpm. The dissolution test solution was analyzed by HPLC after 0.45 um filter of PVDF. Analysis conditions were as follows.

[0072] <Analysis Condition> [0073] Column: a column of stainless steel pipe having an inside diameter of about 4.6 mm and a length of about 50 mm filled with 3 m octadecylsilyl silica gel for liquid chromography (Ultracarb ODS, 4.650 mm, 3 m) or its equivalent column [0074] Mobile phase: wateracetonitriletrifluoroacetic acid (v/v/v)=7003001 [0075] Detection wavelength: UV, 215 nm [0076] Injection volume: 2 uL [0077] Flow rate: 1.0 mL/min

[0078] Dissolution profiles of 100 mg and 400 mg preparation prepared according to Examples 1 to 3 were evaluated and the results are shown in Table 6.

TABLE-US-00006 TABLE 6 Example 1 Example 2 Example 3 Hour(hr) 100 mg 400 mg 100 mg 400 mg 100 mg 400 mg 1 43.7 43.5 42.0 38.1 39.4 40.5 2 55.6 53.3 52.7 47.5 49.8 49.4 4 70.8 68.1 71.9 62.1 66.2 64.9 6 80.4 77.3 83.9 74.0 78.1 78.1 8 88.1 83.2 91.3 91.5 87.8 86.2 10 95.3 88.9 95.2 88.5 95.7 90.5 12 98.9 93.3 99.8 96.6 99.5 96.4

[0079] 3-2. Dissolution Rate Evaluation (Examples 4 to 9)

[0080] Dissolution profiles of 100 mg and 400 mg preparations prepared according to Examples 4 to 9 were evaluated according to the same method as in the Experiment Example 3-1 of dissolution rate evaluation. The results are shown in Tables 7-8 below.

TABLE-US-00007 TABLE 7 Example 4 Example 5 Example 6 Hour(hr) 100 mg 400 mg 100 mg 400 mg 100 mg 400 mg 1 40.7 41.1 40.5 39.1 43.0 39.2 2 53.0 48.9 51.1 47.5 53.9 49.7 4 72.4 65.8 65.8 60.3 67.3 61.5 6 84.9 77.1 77.9 71.9 77.8 73.3 8 93.5 85.1 88.7 82.0 88.0 83.8 10 100.3 93.3 96.2 90.8 95.4 89.6 12 103.5 97.0 104.0 97.0 100.4 96.8

TABLE-US-00008 TABLE 8 Example 7 Example 8 Example 9 Hour(hr) 100 mg 400 mg 100 mg 400 mg 100 mg 400 mg 1 40.9 41.3 40.7 41.2 38.6 40.7 2 51.1 50.3 52.9 49.3 52.7 49.6 4 66.8 60.5 69.2 64.2 67.7 60.9 6 78.5 72.1 79.6 72.5 77.8 68.9 8 86.0 78.3 87.2 79.0 87.6 77.8 10 93.0 84.9 94.2 85.9 95.1 85.7 12 97.6 89.5 98.9 92.8 99.0 90.6

[0081] 3-3. Dissolution Rate Evaluation (Examples 10-11, Comparative Example 1)

[0082] Dissolution profile of the 400 mg preparations prepared according to Examples 10 to 11 was evaluated according to the same method as in the Experiment Example 3-1 of dissolution rate evaluation. The results are shown in Table 9 below.

TABLE-US-00009 TABLE 9 Comparative Example 10 Example 11 Example 1 Hour(hr) 100 mg 400 mg 100 mg 400 mg 100 mg 400 mg 1 61.2 55.1 24.5 20.1 18.1 11.4 2 71.6 67.7 39.7 32.5 36.0 25.2 4 82.5 80.0 63.9 54.5 57.0 44.5 6 93.2 90.4 75.8 67.0 70.6 57.4 8 100.1 97.7 87.9 80.7 88.8 73.1 10 101.2 99.4 96.6 94.5 96.4 85.1 12 101.4 100.8 101.5 98.1 101.7 93.2

[0083] 3-4. Dissolution Rate Evaluation (Comparative Examples 2 to 6)

[0084] Dissolution profiles of 100 mg and 400 mg preparations prepared according to Comparative Examples 2 to 6 were evaluated according to the same method as in the Experiment Example 3-1 of dissolution rate evaluation. The results are shown in Tables 10-11 below.

TABLE-US-00010 TABLE 10 Comparative Comparative Comparative Example 2 Example 3 Example 4 Hour(hr) 100 mg 400 mg 100 mg 400 mg 100 mg 400 mg 1 45.4 42.9 47.8 48.1 41.8 34.1 2 56.5 51.5 63.5 58.0 51.8 43.4 4 71.1 63.6 81.4 68.5 67.9 55.5 6 83.8 71.7 92.4 79.0 80.5 65.8 8 95.3 79.2 100.1 85.1 90.5 75.7 10 101.3 84.4 103.8 89.7 98.3 85.2 12 103.1 90.4 104.8 92.1 102.8 88.2

TABLE-US-00011 TABLE 11 Comparative Example 5 Comparative Example 6 Hour(hr) 100 mg 400 mg 100 mg 400 mg 1 42.7 37.3 42.3 37.7 2 55.0 45.5 55.5 47.0 4 68.9 56.9 68.2 57.3 6 79.9 64.8 80.7 68.7 8 87.0 70.1 87.9 75.1 10 93.9 76.0 94.8 83.5 12 100.4 80.6 101.5 88.9

[0085] The dissolution profiles for each preparation are shown in FIGS. 1-17. As shown in FIGS. 1 to 11, which are embodiments of the present invention, the dissolution profiles of lacosamide 100 mg and 400 mg are equivalent to each other. It is generally accepted that the dissolution profiles are equivalent when they have difference within 10%. However, in Comparative Examples 12 to 17, the dissolution profiles were not equivalent to each other depending on the content of lacosamide.

[0086] 3-5. Beagle Dog PK Evaluation

[0087] Pharmaceutical activity of the preparation of Examples was evaluated in the beagle dogs by comparing the dissolution pattern and the pharmacological kinetics of the preparation in order to predict the influence on the efficacy in human body. Experiments were conducted using the tablets prepared according to Example 3 of the paragraph Example 1-1 and commercially available Vimpat tablet 100 mg (Vimpat Tab Korea UCB Co. Ltd.) as a control preparation. Example 3 was administered orally once a day and the control preparation was administered orally twice a day to beagle dogs about 11 months of age. The control preparation was additionally administered once after blood collection at 12 hours. For the preparation of examples, the blood collection was conducted from the beagle dogs through the jugular vein at 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 16, 24, 30 and 36 hours elapse. For the control preparation, the blood collection was conducted from the beagle dogs through the jugular vein at 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 12.5, 13, 13.5, 14, 15, 16, 18, 24, 30 and 36 hours elapse. The results are shown in FIG. 18. Blood samples were analyzed by LC-MS to compare PK profiles.

TABLE-US-00012 TABLE 12 Cmax(ng/mL) AUC.sub.0.fwdarw.36 hr(ng/mL*hr) Tmax(hr) Example 3 22681.0 143856.6 2.5 Control 19092.4 151942.6 1.3 preparation

[0088] As a result, as shown in Table 12, the preparation of Example 3 exhibited 94.7% of AUC with respect to the control preparation and 118.8% of Cmax with respect to the control paration. Therefore, it was confirmed that the preparation of Example 3 and the control preparation are biologically equivalent.