Film coated tablet containing choline alfoscerate and process for preparing the same

Abstract

The present invention provides a film coated tablet comprising a first film coating layer comprising hydroxypropyl methylcellulose and a second film coating layer comprising polyvinyl alcohol, on a tablet containing choline alfoscerate as an active ingredient and magnesium aluminometasilicate as an additive; and a process for preparing the same.

Claims

1. A film coated tablet comprising: a first film coating layer comprising hydroxypropyl methylcellulose, and a second film coating layer comprising polyvinyl alcohol, wherein the tablet contains an active ingredient of choline alfoscerate and an additive of magnesium aluminometasilicate.

2. The film coated tablet according to claim 1, wherein the magnesium aluminometasilicate is present in an amount of 0.35 to 0.45 part by weight based on 1 part by weight of the choline alfoscerate.

3. The film coated tablet according to claim 1, wherein the hydroxypropyl methylcellulose in the first film coating layer is present in an amount of 0.02 to 0.1 part by weight based on 1 part by weight of the choline alfoscerate.

4. The film coated tablet according to claim 1, wherein the polyvinyl alcohol in the second film coating layer is present in an amount of 0.02 to 0.2 part by weight based on 1 part by weight of the choline alfoscerate.

5. A process for preparing a film coated tablet comprising: (a) wet-granulating a mixture of choline alfoscerate, magnesium aluminometasilicate, and a pharmaceutically acceptable excipient, (b) mixing the granules obtained in step (a) with a pharmaceutically acceptable excipient, followed by compressing to form a tablet, (c) forming a first film coating layer comprising hydroxypropyl methylcellulose on the tablet obtained in step (b), and (d) forming a second film coating layer comprising polyvinyl alcohol on the film coating layer obtained in step (c).

6. The process according to claim 5, wherein the magnesium aluminometasilicate in the mixture of step (a) is present in an amount of 0.35 to 0.45 part by weight based on 1 part by weight of the choline alfoscerate.

7. The process according to claim 5, wherein the mixture of step (a) consists of 0.35 to 0.45 part by weight of magnesium aluminometasilicate, 0.01 to 0.04 part by weight of low substituted hydroxypropyl cellulose, and 0.1 to 0.4 part by weight of microcrystalline cellulose, based on 1 part by weight of the choline alfoscerate.

8. The process according to claim 7, wherein the mixture of step (a) consists of 400 mg of choline alfoscerate, 170 mg of magnesium aluminometasilicate, 10 mg of low substituted hydroxypropyl cellulose, and 25 mg of microcrystalline cellulose, per 1 tablet of the film coated tablet.

9. The process according to claim 5, wherein the wet-granulation of step (a) is carried out by using a hydroxypropyl cellulose solution as a binder solution.

10. The process according to claim 5, wherein the pharmaceutically acceptable excipient of step (b) comprises a disintegrant selected from the group consisting of silicified microcrystalline cellulose, croscarmellose sodium, sodium starch glycolate, and crospovidone; an additive selected from the group consisting of microcrystalline cellulose, lactose, and mannitol; and a lubricant selected from the group consisting of magnesium stearate, calcium stearate, and talc.

11. The process according to claim 5, wherein the hydroxypropyl methylcellulose of step (c) is used in an amount of 0.02 to 0.1 part by weight based on 1 part by weight of the choline alfoscerate.

12. The process according to claim 5, wherein step (c) is carried out by coating the tablet obtained in step (b) with a film coating solution obtained by dissolving hydroxypropyl methylcellulose in a mixed solvent of anhydrous ethanol and methylene chloride.

13. The process according to claim 5, wherein the polyvinyl alcohol of step (d) is used in an amount of 0.02 to 0.2 part by weight based on 1 part by weight of the choline alfoscerate.

14. The process according to claim 5, wherein step (d) is carried out by coating the film coated tablet obtained in step (c) with a film coating solution obtained by dissolving polyvinyl alcohol in water.

15. The process according to claim 11, wherein step (c) is carried out by coating the tablet obtained in step (b) with a film coating solution obtained by dissolving hydroxypropyl methylcellulose in a mixed solvent of anhydrous ethanol and methylene chloride.

16. The process according to claim 13, wherein step (d) is carried out by coating the film coated tablet obtained in step (c) with a film coating solution obtained by dissolving polyvinyl alcohol in water.

Description

DESCRIPTION OF DRAWINGS

(1) FIG. 1 shows the appearances of the film coated tablets obtained by forming a film coating layer with hydroxypropyl methylcellulose, the tablets of which were stored at room temperature condition (i.e., the condition of 25 C., 60% relative humidity) for 72 hours.

(2) FIG. 2 shows the appearances of the film coated tablets obtained by forming a film coating layer with polyvinyl alcohol.

(3) FIG. 3 shows the appearances of the film coated tablets obtained according to the present invention [i.e., the film coated tablets having both a film coating layer comprising hydroxypropyl methylcellulose and a film coating layer comprising polyvinyl alcohol (Example 2-3)], the tablets of which were stored at room temperature condition (i.e., the condition of 25 C., 60% relative humidity) for 72 hours.

BEST MODE

(4) The present invention provides a film coated tablet comprising a first film coating layer comprising hydroxypropyl methylcellulose and a second film coating layer comprising polyvinyl alcohol, on a tablet containing choline alfoscerate as an active ingredient and magnesium aluminometasilicate as an additive.

(5) In the film coated tablet according to the present invention, the active ingredient (i.e., choline alfoscerate) may be used in a therapeutically effective amount, for example in an amount of 200 mg, 400 mg and so on per 1 tablet, but not limited thereto.

(6) The uncoated tablet used in the present invention includes magnesium aluminometasilicate as one of the additives. Magnesium aluminometasilicate, which is a pharmaceutically compatible additive with choline alfoscerate, enables the tablet-preparation according to conventional methods for preparing a tablet such as wet-granulation methods, as described below. Magnesium aluminometasilicate is a white powder having chemical formula Al.sub.2O.sub.2.2Mg.3O.sub.3Si, and also referred to as Silodrate or Simaldrate. It is water-insoluble and has hygroscopicity under the condition of relative humidity of not less than 70%. In addition, commercially available Neusilin (Fuji Chemical Industry) may be used.

(7) The magnesium aluminometasilicate may be used in an amount of preferably 0.35 to 0.45 part by weight, more preferably 0.4 to 0.43 part by weight, most preferably about 0.425 part by weight, based on 1 part by weight of the choline alfoscerate. When magnesium aluminometasilicate is used in an amount of not more than 0.3 part by weight based on 1 part by weight of the choline alfoscerate, sticking problems may occur during the compression. In addition, when magnesium aluminometasilicate is used in an amount of not less than 0.5 part by weight based on 1 part by weight of the choline alfoscerate, the bulk-density of the resulting granules gets very low. Thus, since significant amounts of the granules escape from a compression die during the compression, it may be difficult to prepare tablets with desired weight.

(8) The film coated tablet according to the present invention includes a first film coating layer comprising hydroxypropyl methylcellulose and a second film coating layer comprising polyvinyl alcohol. The hydroxypropyl methylcellulose in the first film coating layer may be present in an amount of preferably 0.02 to 0.1 part by weight, more preferably 0.03 to 0.05 part by weight, based on 1 part by weight of the choline alfoscerate. The polyvinyl alcohol in the second film coating layer may be present in an amount of preferably 0.02 to 0.2 part by weight, more preferably 0.04 to 0.07 part by weight, based on 1 part by weight of the choline alfoscerate.

(9) The present invention also provides a process for preparing the film coated tablet. In other words, the present invention provides a process for preparing a film coated tablet comprising: (a) wet-granulating a mixture of choline alfoscerate, magnesium aluminometasilicate, and a pharmaceutically acceptable excipient, (b) mixing the granules obtained in step (a) with a pharmaceutically acceptable excipient, followed by compressing to form a tablet, (c) forming a first film coating layer comprising hydroxypropyl methylcellulose on the tablet obtained in step (b), and (d) forming a second film coating layer comprising polyvinyl alcohol on the film coating layer obtained in step (c).

(10) In the process according to the present invention, the magnesium aluminometasilicate in the mixture of step (a) may be used in an amount of preferably 0.35 to 0.45 part by weight, more preferably 0.4 to 0.43 part by weight, most preferably about 0.425 part by weight, based on 1 part by weight of the choline alfoscerate. The mixture in step (a) may further comprise an additive conventionally used in the preparation of granules, for example, low substituted hydroxypropyl cellulose, and microcrystalline cellulose, etc., but not limited thereto. In an embodiment, the mixture of step (a) may consist of 0.35 to 0.45 part by weight of magnesium aluminometasilicate, 0.01 to 0.04 part by weight of low substituted hydroxypropyl cellulose, and 0.1 to 0.4 part by weight of microcrystalline cellulose, based on 1 part by weight of the choline alfoscerate. In another embodiment, the mixture of step (a) may consist of 400 mg of choline alfoscerate, 170 mg of magnesium aluminometasilicate, 10 mg of low substituted hydroxypropyl cellulose, and 25 mg of microcrystalline cellulose, per 1 tablet of the film coated tablet.

(11) The wet granulation of step (a) may be carried out by using a granulator conventionally used in the art, e.g., a high-shear mixer. The wet granulation may be carried out by using either only a kneading solvent (e.g., water, ethanol, or a mixture of water and ethanol) or a binder solution obtained by dissolving a binder in a solvent. In an embodiment, the wet-granulation of step (a) may be carried out by using a hydroxypropyl cellulose solution as a binder solution. For example, the binder solution may be obtained by dissolving hydroxypropyl cellulose in water or a mixed solvent of water and ethanol. The hydroxypropyl cellulose used as a binder may be used in an amount ranging from 0.05 to 0.08 part by weight based on 1 part by weight of the choline alfoscerate. In an embodiment, about 25 mg of hydroxypropyl cellulose may be used as a binder, based on 400 mg of choline alfoscerate. The obtained granules (i.e., wet granules) may be dried by using a conventional dryer, such as a hot-water circulating dryer or a fluidized bed dryer. Preferably, the resulting granules have water content ranging from 1.0 weight % to 2.0 weight %. If necessary, a sifting step may be also carried out to obtain granules having uniform size distribution.

(12) Step (b) is carried out by mixing the granules obtained in step (a) with a pharmaceutically acceptable excipient, followed by compressing to form a tablet. The pharmaceutically acceptable excipient of step (b) comprises a disintegrant selected from the group consisting of silicified microcrystalline cellulose (Prosolv), croscarmellose sodium, sodium starch glycolate, and crospovidone, an additive selected from the group consisting of microcrystalline cellulose, lactose, and mannitol, and a lubricant selected from the group consisting of magnesium stearate, calcium stearate, and talc, but not limited thereto. The excipients (such as disintegrant, additive) and the amount thereof may be adequately adjusted to exhibit equivalent dissolution pattern to the commercially available soft capsule formulation.

(13) Step (c) is carried out by forming a first film coating layer comprising hydroxypropyl methylcellulose on the tablet obtained in step (b). The hydroxypropyl methylcellulose of step (c) may be used in an amount of preferably 0.02 to 0.1 part by weight, more preferably 0.03 to 0.05 part by weight, based on 1 part by weight of the choline alfoscerate. And also, a commercially available hydroxypropyl methylcellulose-based hydrophilic matrix system (e.g., Opadray 03B28796 (Colorcon, Inc, USA)) may be used for the hydroxypropyl methylcellulose to form a first film coating layer. The hydroxypropyl methylcellulose-film coating may be carried out according to an organic coating method conventionally used in the field of pharmaceutics. In an embodiment, step (c) is carried out by coating the tablet obtained in step (b) with a film coating solution obtained by dissolving hydroxypropyl methylcellulose (or Opadray 03B28796) in a mixed solvent of anhydrous ethanol and methylene chloride.

(14) Step (d) is carried out by forming a second film coating layer comprising polyvinyl alcohol on the film coating layer obtained in step (c). The polyvinyl alcohol may be used in an amount of preferably 0.02 to 0.2 part by weight, more preferably 0.04 to 0.07 part by weight, based on 1 part by weight of the choline alfoscerate. And also, a commercially available poly(vinyl alcohol)-based film forming agent (e.g., Opadray Yellow 85F92177 (Colorcon, Inc, USA)) may be used for the polyvinyl alcohol to form a second film coating layer. The polyvinyl alcohol-film coating may be carried out according to an organic coating method or an aqueous coating method. It has been found by the present invention that the polyvinyl alcohol-film coating can be carried out according to an aqueous coating method which is eco-friendly and enables ensuring great safety. In an embodiment, step (d) may be carried out by coating the film coated tablet obtained in step (c) with a film coating solution obtained by dissolving polyvinyl alcohol (or Opadray Yellow 85F92177) in water (e.g., purified water).

(15) If necessary, the process according to the present invention may further comprise forming an additional film coating layer (a third film coating layer) to improve polishing property. Opadray 97W19196 (Colorcon, Inc, USA) may be used as a coating agent to form a third film coating layer, but not limited thereto. Forming a third film coating layer may be carried out by using a coating solution prepared by dissolving Opadray 97W19196 in purified water.

(16) The present invention will be described in further detail with reference to the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example 1

Selection and Evaluation of Additives

(17) Various excipients were studied in order to select pharmaceutically compatible additives with choline alfoscerate, which make it possible to prepare a tablet according to a conventional method for preparing a tablet. Briefly, preliminary tests were performed by preparing choline alfoscerate-containing tablets with various excipients through wet granulation method and then evaluating the respective compressibility thereof. From the results of the preliminary tests, it was identified that magnesium aluminometasilicate showed relatively excellent compressibility. Additional studies were carried out on the tablets prepared with various contents as presented in the following table 1.

(18) In other words, choline alfoscerate, magnesium aluminometasilicate, low substituted hydroxypropyl cellulose, and microcrystalline cellulose were sieved with 24 mesh and then mixed each other. A binder solution was prepared by dissolving hydroxypropyl cellulose in a mixed solvent of purified water and ethanol. The binder solution was added to the mixture in a high shear mixer to form wet granules, which was then dried using a fluidized bed dryer. The obtained granules were sifted with 24 mesh, mixed with silicified microcrystalline cellulose (Prosolv), croscarmellose sodium, microcrystalline cellulose, and magnesium stearate, and then compressed to form a tablet having about 20 kp of hardness.

(19) TABLE-US-00001 TABLE 1 Example Example Example Components (mg/tablet) 1-1 1-2 1-3 Choline alfoscerate 400 400 400 Magnesium aluminometasilicate 170 120 200 Low substituted hydroxypropyl 10 10 10 cellulose Microcrystalline cellulose 100 100 100 (added when granulating) Hydroxypropyl cellulose 25 25 25 Purified water 25 25 25 Anhydrous ethanol 250 250 250 Prosolv 15 15 15 Croscarmellose sodium 33 33 33 Microcrystalline cellulose 55 55 55 (added when compressing) Magnesium stearate 7 7 7 Total weight (mg/tablet) 815 765 845

(20) All of the tablets prepared in Example 1-1 to 1-3 showed appropriate hardness ranges and dissolution patterns. However, the tablet of Example 1-2 exhibits sticking problems during the compression. The tablet of Example 1-3 showed too low bulk-density to prepare tablets with desired weight, because significant amounts of the granules escaped from the compression die during the compression. Therefore, it can be seen that magnesium aluminometasilicate is used in an amount of preferably 0.35 to 0.45 part by weight, more preferably 0.4 to 0.43 part by weight, most preferably about 0.425 part by weight, based on 1 part by weight of the choline alfoscerate.

Example 2

Selection and Evaluation of Coating Agents

(21) When the tablets of Example 1-1 to 1-3 were stored at the condition of 25 C., 60% relative humidity, all the tablets showed deteriorated appearances such as moisture-adsorption on the tablet surface (i.e., deliquescence and/or hygroscopicity). In order to evaluate potential inhibition against deliquescence/hygroscopicity, suitability was evaluated on various film coating agents. Any appearance change of the resulting film coated tablets was evaluated and the possibility for employing an aqueous coating method which is eco-friendly and enables ensuring great safety was also evaluated.

(22) (1) Evaluation on Hydroxypropyl Methylcellulose-Film Coating

(23) Hydroxypropyl methylcellulose-film coating was employed using water as a solvent. However, the tablet surface was dissolved upon directly contacting with water, which makes it impossible to proceed with the aqueous coating. Therefore, a film coating layer comprising hydroxypropyl methylcellulose was formed on the tablet obtained in Example 1-1 through an organic coating method, according to the components and contents shown in the following table 2. In other words, the film coated tablet was prepared by dissolving the hydroxypropyl methylcellulose-based coating agent (Opadray 03B28796 (Colorcon, Inc, USA)) in a mixed solvent of anhydrous ethanol and methylene chloride to obtain a coating solution and then film-coating with the coating solution to form a film coating layer on the tablet obtained in Example 1-1.

(24) TABLE-US-00002 TABLE 2 Components (mg) Example 2-1 Opadray 03B28796 15 Anhydrous ethanol 75 Methylene chloride 75 Total coating amount (mg) 15

(25) When the resulting film coated tablet was stored at room temperature condition (the condition of 25 C., 60% relative humidity), the appearance thereof was deteriorated after about 8 hours (FIG. 1). When the resulting film coated tablet was stored at accelerated condition (the condition of 40 C., 75% relative humidity), the appearance thereof was deteriorated in less than 1 hour (see Tables 5 and 6 below).

(26) (2) Evaluation on Polyvinyl Alcohol-Film Coating

(27) Polyvinyl alcohol-film coating was employed using water as a solvent. However, the tablet surface was dissolved upon directly contacting with water, which makes it impossible to proceed with the aqueous coating. Therefore, a film coating layer comprising polyvinyl alcohol was formed on the tablet obtained in Example 1-1 through an organic coating method, according to the components and contents shown in the following table 3. In other words, the film coated tablet was prepared by dissolving the poly(vinyl alcohol)-based coating agent (Opadray Yellow 85F92177 (Colorcon, Inc, USA)) in a mixed solvent of anhydrous ethanol and methylene chloride to obtain a coating solution and then film-coating with the coating solution to form a film coating layer on the tablet obtained in Example 1-1.

(28) TABLE-US-00003 TABLE 3 Components (mg) Example 2-2 Opadray Yellow 85F92177 25 Anhydrous ethanol 125 Methylene chloride 125 Total coating amount (mg) 25

(29) The resulting film coated tablet exhibited inappropriate appearances having powders stuck on the surface of the tablet (FIG. 2). When the resulting film coated tablet was stored at room temperature condition (the condition of 25 C., 60% relative humidity) and at accelerated condition (the condition of 40 C., 75% relative humidity), the appearances thereof were deteriorated greater than the hydroxypropyl methylcellulose-based coating agent-containing film coated tablet (see Tables 5 and 6 below). In other words, the polyvinyl alcohol-based coating agent was not appropriate for employing an organic coating method.

(30) (3) Evaluation of Two Layer-Film Coating

(31) Both a film coating layer comprising hydroxypropyl methylcellulose and a film coating layer comprising polyvinyl alcohol were formed on the tablet obtained in Example 1-1, according to the components and contents shown in the following Table 4. In other words, the film coated tablet having a first film coating layer was prepared by dissolving Opadray 03B28796 (Colorcon, Inc, USA) in a mixed solvent of anhydrous ethanol and methylene chloride to obtain a first coating solution and then film-coating with the first coating solution to form a film coating layer on the tablet obtained in Example 1-1. Subsequently, the film coated tablet having two coating layers was prepared by dissolving Opadray Yellow 85F92177 (Colorcon, Inc, USA) in purified water to obtain a second coating solution and then film-coating with the second coating solution to additionally form a film coating layer on the tablet having the first film coating layer.

(32) TABLE-US-00004 TABLE 4 Components (mg) Example 2-3 First film coating layer Opadray 03B28796 15 Anhydrous ethanol 75 Methylene chloride 75 Second film coating layer Opadray Yellow 85F92177 25 Purified water 166.67 Total coating amount (mg) 40

(33) The tablet of Example 1-1 (uncoated tablet) and the resulting film coated tablets in the above (Example 2-1 to 2-3) were exposed to air at room temperature condition (the condition of 25 C., 60% relative humidity) or at accelerated condition (the condition of 40 C., 75% relative humidity). The appearance changes are presented in the following tables 5 and 6.

(34) TABLE-US-00005 TABLE 5 Storage at the condition of 25 C., 60% relative humidity Example 1-1 Example 2-1 Example 2-2 Example 2-3 After 6 hours After 12 hours X X After 18 hours X X X After 24 hours X X X After 48 hours X X X After 72 hours X X X : no significant change of appearance, X: significant change of appearance

(35) TABLE-US-00006 TABLE 6 Storage at the condition of 40 C., 75% relative humidity Example 1-3 Example 2-1 Example 2-2 Example 2-3 After 1 hour X X X After 2 hours X X X After 3 hours X X X After 4 hours X X X After 5 hours X X X X : no significant change of appearance, X: significant change of appearance

(36) The uncoated tablet (Example 1-1) showed no appearance change up to 6 hours to 12 hours when stored at room temperature condition. In contrast, the film coated tablet containing only a HPMC-based coating agent (Example 2-1) and the film coated tablet containing only a PVA-based coating agent (Example 2-2) showed the stabilities similar to the uncoated tablet, when stored at room temperature condition. However, the film coated tablet having two coating layers according to the present invention (Example 2-3) maintained favorable appearance even after 72 hours (FIG. 3). And also, when stored at accelerated condition, all the tablets except for the film coated tablet having two coating layers according to the present invention (Example 2-3) showed significant appearance changes. Especially, it can be seen that the coating methods of the present invention as in Example 2-3 makes it possible to form a PVA coating layer (which requires employing an aqueous coating method) for improving the stability of the tablet, in spite of deliquescence and hygroscopicity of the active ingredient (choline alfoscerate).

Example 3

Comparative Dissolution Test

(37) According to the components and contents presented in Table 7 below, an additional film coating layer was formed on the film coated tablet obtained in Example 2-3 in order to improve polishing property. In other words, the film coated tablet having two coating layers (i.e., tablet of Example 3-1) was prepared by dissolving Opadray 97W19196 (Colorcon, Inc, USA) in purified water to obtain a third coating solution and then film-coating with the third coating solution to additionally form a film coating layer on the tablet obtained in Example 2-3. The components and contents of each film coating layer of Example 3-1 are presented in Table 7.

(38) TABLE-US-00007 TABLE 7 Components (mg) Example 3-1 First film coating layer Opadray Clear 03K19229 15 Anhydrous ethanol 75 Methylene chloride 75 Second film coating OpadrayYellow 85F92177 25 layer Purified water 166.67 Third film coating layer Opadry 97W19196 1 Purified water 14.28 Total coating amount (mg) 41

(39) Comparative dissolution tests were performed on the uncoated tablets of Example 1-1 (n=6), the film coated tablets of Example 3-1 (n=6) and the commercially available soft capsule formulation [Gliatilin Soft Capsule (Daewoong Pharmaceutical Co., Ltd), choline alfoscerate 400 mg, Comparative Example) (n=6). Purified water was used as a dissolution medium and the dissolution tests were performed at 37 C. and at the paddle rotation speed of 50 rpm. An aliquot was taken from the dissolution medium at the time of 15, 20, 30, 45, and 60 minutes, followed by filtering for analysis. Separately, 22 mg of choline alfoscerate (reference standard) was added to a 100 ml volumetric flask and a mixed solution of water and acetonitrile (1:1, v/v) was added thereto (up to the mark of the volumetric flask) to prepare a standard solution. Each aliquot was analyzed with HPLC under the following conditions.

(40) <HPLC Analysis Condition>

(41) Column: Inertsil NH.sub.2 Column

(42) Mobile phase: Water:Acetonitrile=40:60 (v/v)

(43) Detector: Refractive Index Detector

(44) Flow rate: 1.5 ml/min

(45) Injection volume: 50 ul

(46) The results of the comparative dissolution tests are shown in Table 8 below.

(47) TABLE-US-00008 TABLE 8 Comparative dissolution test Dissolution rate (%) Example 1-1 Example 3-1 Comparative Example 15 minutes 94.36 95.96 100.2 20 minutes 100.88 99.35 101.36 30 minutes 100.80 101.87 102.11 45 minutes 100.75 102.29 102.08 60 minutes 101.17 102.25 102.15

(48) Comparative Example (soft capsule) showed immediate drug release of more than 100% at the time of 15 minutes. The two test formulations (i.e., Examples 1-1 and 3-1) also showed immediate drug release profiles in 15 minutes. From the results of Table 8, it can be seen that both of the uncoated tablet of Example 1-1 and the film coated tablet of Example 3-1 show equivalent dissolution patterns to the comparative example (i.e., the commercially available soft capsule formulation), without exhibiting significant difference in drug release profile.