PREGABALIN SUSTAINED-RELEASE PREPARATION

Abstract

Disclosed is a pregabalin sustained-release preparation, wherein the sustained-release tablet contains a pharmaceutically active ingredient containing pregabalin or a salt or hydrate thereof, a gel framework material containing alginic acid, and a swellable material containing polyoxyethylene.

Claims

1. An oral sustained-release preparation comprising pregabalin, a salt or hydrate thereof as an active ingredient, a gel matrix material and a swelling material, wherein the gel matrix material comprises alginate, and the swelling material comprises polyoxyethylene.

2. The oral sustained-release preparation according to claim 1, wherein the preparation is for oral administration once daily.

3. The oral sustained-release preparation according to claim 1, wherein the alginate is at least one selected from the group consisting of sodium alginate, potassium alginate, and ammonium alginate.

4. The oral sustained-release preparation according to claim 1, wherein the amount of the gel matrix material is 5% to 45% by weight, based on a total weight of the sustained-release preparation.

5. The oral sustained-release preparation according to claim 1, wherein the amount of the swelling material is 10% to 75% by weight, based on a total weight of the sustained-release preparation.

6. The oral sustained-release preparation according to claim 1, wherein the average molecular weight of the alginate is 1×10.sup.4to 2×10.sup.5 Da.

7. The oral sustained-release preparation according to claim 1, wherein the average molecular weight of the polyoxyethylene is 1×10.sup.5 to 1×10.sup.7 Da.

8. The oral sustained-release preparation according to claim 1, wherein the gel matrix material further comprises a calcium salt.

9. The oral sustained-release preparation according to claim 8, wherein a weight ratio of the alginate to the calcium salt is 1:1 to 10:1.

10. The oral sustained-release preparation according to claim 1, wherein the swelling agent further comprises crosslinked polyvinylpyrrolidone.

11. The oral sustained-release preparation according to claim 10, wherein the swelling agent consists of polyoxyethylene and crosslinked polyvinylpyrrolidone.

12. The oral sustained-release preparation according to claim 10, wherein the weight ratio of the alginate to the calcium salt is 1:1 to 10:1, the polyoxyethylene is present in an amount of 25% to 55% by weight, based on a total weight of the preparation; and the crosslinked polyvinylpyrrolidone is present in an amount of 5% to 20% by weight, based on the total weight of the preparation.

13. The oral sustained-release preparation according to claim 1, wherein the sustained-release preparation expands to a size of 13 mm or greater when contacted with water.

14. The oral sustained-release preparation according to claim 1, wherein the sustained-release preparation is retained in the stomach of a patient for 3 hours to 14 hours after oral administration.

15. The oral sustained-release preparation according to claim 1, wherein the time to the maximum plasma concentration (T.sub.max) is 8 hours to 12 hours after oral administration of the sustained-release preparation.

16. The oral sustained-release preparation according to claim 4, wherein the amount of the gel matrix material is 20% to 40% by weight, based on the total weight of the sustained-release preparation.

17. The oral sustained-release preparation according to claim 5, wherein the amount of the swelling material is 30% to 60% by weight, based on the total weight of the sustained-release preparation.

18. The oral sustained-release preparation according to claim 8, wherein the calcium salt is at least one selected from the group consisting of calcium hydrogen phosphate, calcium phosphate, calcium bisulfate, calcium sulfate, calcium bicarbonate, calcium carbonate, and calcium chloride.

19. The oral sustained-release preparation according to claim 9, wherein the weight ratio of the alginate to the calcium salt is 2:1 to 5:1.

20. The oral sustained-release preparation according to claim 10, wherein the weight ratio of the alginate to the calcium salt is 2:1 to 5:1, the polyoxyethylene is present in an amount of 30% to 50% by weight, based on a total weight of the preparation; and the crosslinked polyvinylpyrrolidone is present in an amount of 5% to 10% by weight, based on the total weight of the preparation.

Description

DESCRIPTION OF THE DRAWINGS

[0020] FIG. 1 is a graph showing the mean plasma concentration vs. time for the sustained-release tablet prepared according to the present invention (Example 14) in comparison to a commercially available Lyrica® immediate-release capsule.

DETAILED DESCRIPTION OF THE INVENTION

[0021] The present invention will be described in more detail by the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Examples 1 to 20

[0022] Sustained-release tablets were prepared according to the components and amounts shown in Tables 1 to 3. The amounts in Table 1 to Table 3 represent the weight (mg) of each component in each tablet. For each example, all of the tablet components except magnesium stearate were mixed in a material mixer for about 15 minutes, and then mixed with magnesium stearate that was passed through a 20 mesh sieve for a further 5 minutes to obtain a final blend. The final blend was then compressed in a tablet press to obtain tablets of 1.125 g or 1 g in weight.

TABLE-US-00001 TABLE 1 Example (mg/tablet) Components 1 7 3 4 5 Pregabalin 300 300 300 300 300 Sodium 338 281 225 225 225 alginate polyoxyethylene 476 420 420 363 363 (Polyox 303) CaHPO.sub.4 — — — — 113 CaCO.sub.3 — — — — — Crospovidone — — — — — Lactose — 113 169 226 113 Magnesium 11 11 11 11 11 stearate Total 1125 1125 1125 1125 1125 Com- Example (mg/tablet) ponents 6 7 8 9 Pregabalin 300 300 300 300 Sodium 225 282 282 282 alginate polyoxy- 363 363 363 390 ethylene (Polyox 303) CaHPO.sub.4 113 56 — 86 CaCO.sub.3 — — 56 — Cros- 56 113 113 56 povidone Lactose 56 — — — Mag- 11 11 11 11 nesium stearate Total 1125 1125 1125 1125

TABLE-US-00002 TABLE 2 Example (mg/tablet) Components 10 11 12 13 14 15 Pregabalin 330 330 330 330 330 330 Sodium alginate 225 282 196 225 282 282 polyoxyethylene 363 390 363 390 363 390 (Polyox 303) CaHPO.sub.4 — — 56 113 56 56 Crospovidone 83 113 56 56 83 56 Lactose 113 — 113 — — — Magnesium 11 11 11 11 11 11 stearate Total 1125 1126 1125 1125 1125 1125

TABLE-US-00003 TABLE 3 Example (mg per one tablet) Components 16 17 18 19 20 21 Pregabalin 165 165 165 82.5 82.5 82.5 Sodium alginate 352 260 280 250 300 280 polyoxyethylene 323 410 390 507.5 447.5 467.5 (Polyox 303) CaHPO.sub.4 50 55 55 50 60 60 Crospovidone 100 100 100 100 100 100 Magnesium 10 10 10 10 10 10 stearate Total 1000 1000 1000 1000 1000 1000

Comparative Example 1

[0023] The comparative example was prepared according to patent application publication no. CN101330907A. As shown in Table 4, pregabalin (300 g), Kollidon SR (250 g), Plasdone XL (280 g), Polyox N60K NF (225 g) and Carbopol 71 G (56.5 g) were mixed for 15 minutes. The above mixture was additionally mixed with magnesium stearate (11.5 g) for 5 minutes, and then compressed to obtain tablets.

TABLE-US-00004 TABLE 4 Comparative Example 1 Components %, w/w mg per one tablet pregabalin 26.7 300 KOLLIDON ® SR 22.3 250 PLASDONE ® XL 25.0 282 POLYOX ® WSR N60K NF 20.0 225 CARBOPOL ® 71G 5.0 56.5 Magnesium stearate 1.0 11.5 Total 100.0 1125

Experimental Example 1

In Vitro Dissolution Test

[0024] The tablets prepared in Examples 1 to 21 and Comparative Example 1 were subjected to a dissolution test according to the second method (paddle method) of the dissolution test disclosed in the appendix of volume II of Chinese Pharmacopeia (2010 edition). 1000 ml of a 0.06 N HCl solution was used as a dissolution medium, and the dissolution test was carried out at 37±0.5° C. and at the paddle speed of 50 rpm. Small samples were taken from the dissolution medium at 0.5, 1, 2, 4, 8, 12, 16, 20 and 24 hours, respectively. Each sample was analyzed with HPLC (at 210 nm) to calculate the dissolution rate. The results are shown in Tables 5 to 7.

[0025] As shown in Tables 5 to 7, the pregabalin preparations prepared according to the present invention showed excellent sustained-release dissolution patterns. The pregabalin sustained-release preparations had essentially no burst-release effect at 1 hour, the dissolution amount was 50% to 70% at 8 hours, and the release amount was more than 80% at 16 hours by adjusting the components and ratios of the sustained-release preparations. The tablets prepared in Comparative Example 1 had a cumulative dissolution rate of about 20% at 1 hour, which showed a certain burst-release effect, whereas the tablets prepared according to the present invention significantly weakened this burst-release effect, thereby releasing pregabalin more slowly, and increasing the safety of the drug.

TABLE-US-00005 TABLE 5 Example (dissolution rate, %) Comparative Time (h) 1 2 1 4 5 6 7 8 9 Example 1 0.5 6.0 6.9 7.3 7.6 8.9 6.8 6.9 8.5 6.1 11.6 1 10.3 15.3 18.2 19.1 18.4 12.4 11.1 13.6 10.9 19.3 2 16.9 19.7 25.4 24.7 23.7 20.3 20.2 23.3 23.9 29.1 4 28.7 30.4 34.1 36.4 35.0 35.9 39.6 38.4 41.2 43.8 8 52.1 55.6 56.8 58.8 54.6 59.1 64.6 62.6 68.1 67.6 12 69.8 73.6 75.2 76.3 76.8 79.9 80.8 83.3 85.3 79.5 16 78.9 81.3 85.3 87.2 88.4 88.8 90.8 94.5 92.5 88.6 20 86.1 87.3 89.5 91.9 91.3 95.1 94.8 98.2 95.0 92.7 24 90.6 91.7 93.6 96.0 95.7 97.3 96.6 98.5 96.2 96.8

TABLE-US-00006 TABLE 6 Time Example (dissolution rate, %) (h) 10 11 12 13 14 15 0.5 8.1 8.0 8.5 7.3 10.5 7.7 1 13.2 12.8 13.4 12.5 16.5 11.6 2 20.6 23.6 22.5 21.2 24.2 21.2 4 37.6 42.5 39.2 35.5 38.7 34.2 8 63.2 65.6 61.3 59.3 60.9 58.1 12 81.5 80.3 79.1 77.5 78.8 76.3 16 89.6 91.1 88.5 86.5 87.2 85.0 20 95.5 94.5 92.2 91.1 91.2 90.0 24 96.6 96.0 94.5 94.0 94.2 95.2

TABLE-US-00007 TABLE 7 Time Example (dissolution rate, %) (h) 16 17 18 19 20 21 0.5 4.3 8.5 6.3 12.4 5.9 9.1 1 8.4 14.5 12.7 19.1 10.6 13.9 2 13.9 23.9 21.7 28.2 18.7 23.1 4 27.1 39.4 35.0 45.4 32.7 38.4 8 49.2 61.9 61.0 66.0 61.1 61.4 12 67.3 73.6 77.1 79.6 77.9 75.5 16 81.3 84.4 86.9 87.4 90.5 83.7 20 86.4 88.7 93.2 89.0 92.0 88.8 24 91.4 93.8 97.0 90.6 93.2 93.3

Experimental Example 2

Measurement of Swelling Size

[0026] The tablets prepared in the above Examples and Comparative Example were subjected to a dissolution test according to the second method (paddle method) of the dissolution test disclosed in the appendix of volume II of Chinese Pharmacopeia (2010 edition). 1000 ml of a 0.06 N HCl solution was used as a dissolution medium, and the dissolution test was carried out at 37±0.5° C. and at a paddle speed of 50 rpm. The drug samples were taken out from the dissolution medium at 1, 2, 6, 8 and 24 hours after the start of the dissolution test and then their sizes were measured. The results are shown in Tables 8 and 9. The size of the tablets prepared according to the present invention swelled to 13 mm or more at 1 hour (the “size” corresponds to the longest linear size of the cross-section having the smallest area of the dosage form), and the residence time of the sustained-release tablet in the stomach can be effectively prolonged by mechanical retardation of the size. The size of the tablets prepared in Comparative Example 1 swelled to only 11.4 mm at 1 hour, and the possibility of passing through the pylorus could not be excluded according to the aastrointestinal condition of the patient.

TABLE-US-00008 TABLE 8 Time Comparative (h) Example 1 Example 7 Example 1 0 19.6 × 10.0 × 8.5  19.6 × 10.0 × 8.5  19.4 × 9.7 × 8.8  1 22.5 × 13.0 × 11.5 23.4 × 13.7 × 12.4 20.5 × 11.4 × 9.9  2 23.4 × 13.7 × 12.8 24.8 × 14.3 × 13.0 21.1 × 12.2 × 11.4 6 25.0 × 14.6 × 14.3 25.9 × 14.8 × 14.4 22.7 × 13.3 × 12.5 8 26.2 × 15.0 × 14.6 26.8 × 15.6 × 14.9 23.1 × 13.5 × 12.6 24 26.9 × 15.8 × 15.3 27.6 × 16.2 × 15.6 23.7 × 14.0 × 12.8

TABLE-US-00009 TABLE 9 Time (h) Example 14 Example 17 Example 20 0 19.6 × 10.0 × 8.5  19.5 × 10.3 × 7.8  19.5 × 10.3 × 7.9  1 23.4 × 13.6 × 12.0 23.4 × 13.3 × 11.6 23.0 × 13.8 × 11.8 7 23.8 × 14.5 × 13.0 24.3 × 13.7 × 13.0 24.2 × 13.5 × 13.0 6 25.7 × 14.8 × 14.0 25.1 × 14.5 × 13.7 25.0 × 14.3 × 13.6 8 264 × 15.3 × 14.5 25.8 × 14.8 × 14.0 25.9 × 14.6 × 13.9 24 27.0 × 16.2 × 15.1 27.1 × 14.9 × 14.0 27.0 × 15.0 × 14.0

Experimental Example 3

Comparison of Changes in Size and Water Content of Tablets

[0027] The tablets prepared in Examples 6, 7 and Comparative Example 1 were subjected to a dissolution test according to the second method (paddle method) of the dissolution test disclosed in the appendix of volume II of Chinese Pharmacopeia (2010 edition). 1000 ml of a 0.06 N HCl solution was used as a dissolution medium, and the dissolution test was carried out at 37±0.5° C. and at the paddle speed of 50 rpm. The dnig samples were taken out from the dissolution medium at 1, 2, 6, 8 and 24 hours after the start of the dissolution test, their sizes were measured, and the weight change of each tablet was obtained by measuring its water content. The results are shown in Table 10.

[0028] As shown in Table 10, the tablets prepared in Examples 1 and 7 exhibited better properties regarding size change and water content, in comparison to the tablet of Comparative Example 1. These results indicate that the tablets of the present invention can more effectively increase the residence time in the stomach, thereby achieving a long-lasting release and absorption effect of the drug and improving the bioavailability of the drug.

TABLE-US-00010 TABLE 10 Comparative Example 1 Example 7 Example 1 Weight Size Weight Size Weight Size Time change change change change change change (h) (%) (%) (%) (%) (%) (%) 1 163 202 179 239 108 139 2 191 246 226 277 136 177 6 236 313 252 331 170 228 8 258 344 286 374 183 237 24 277 366 318 419 197 256

Experimental Example 4

Comparison of Drug Rigidity

[0029] The tablets prepared in Example 7 and Comparative Example 1 were subjected to a dissolution test according to the second method (paddle method) of the dissolution test disclosed in the appendix of volume II of the Chinese Pharmacopeia (2010 edition). 1000 ml of a 0.06 N HCl solution was used as a dissolution medium, and the dissolution test was carried out at 37±0.5° C. and at a paddle speed of 50 rpm. The drug samples were taken out from the dissolution medium at 1, 2, 6, 8 and 24 hours after the start of the dissolution test, and their rigidity was measured using a TA-Plus texture analyzer under the following setting conditions: 5 kg load unit; P/0.5 cylindrical probe; 1.0 g trigger force; 1.0 mm/s test speed; and 15 mm distance. The results are shown in Table 11.

[0030] As shown in Table 11, the tablets prepared according to the present invention (Example 1 and Example 7) had better rigidity and still showed good rigidity after swelling for 8 hours and 24 hours, in comparison to the tablets of Comparative Example 1. The excellent rigidity provided good gastric retention characteristics, but was also effective in controlling the release of pregabalin.

TABLE-US-00011 TABLE 11 Time Gel Rigidity (g mm) (h) Example 1 Example 7 Comparative Example 1 1 4923 4876 4654 2 4205 4135 4023 6 2783 2568 1734 8 2457 1934 1086 24 1363 876 105

Experimental Example 5

Measurement of Dissolution Rate According to Paddle Speed

[0031] The tablets prepared in Examples 1, 7 and Comparative Example 1 were subjected to a dissolution test according to the second method (paddle method) of the dissolution test disclosed in the appendix of volume II of the Chinese Phaimacopeia (2010 edition). 1000 ml of a 0.06 N HCl solution was used as a dissolution medium, and the dissolution test was carried out at 37±0.5° C. and at paddle speeds of 50 rpm and 100 rpm, respectively. Small samples were taken from the dissolution medium at 0.5, 1, 2, 4 and 8 hours, respectively. Each sample was analyzed with HPLC (at 210 nm) to calculate the dissolution rate. The results are shown in Table 12.

TABLE-US-00012 TABLE 12 Dissolution rates at 50 rpm and 100 rpm Example 1 Example 7 Comparative Example 1 50 rpm 100 rpm 50 rpm 100 rpm 50 rpm 100 rpm 0.5 6.0 6.8 6.9 8.1 11.6 19.6 1 10.3 12.1 11.1 14.4 18.3 26.5 2 16.9 18.8 20.2 22.5 29.1 37.8 4 28.7 30.5 39.6 41.8 43.8 51.0 8 52.1 55.2 64.6 67.3 67.6 76.2

[0032] As shown in Table 12, the tablets of Example 1 and Example 7 showed relatively small differences in the dissolution rate when the paddle speed was increased. In contrast, the dissolution rate, particularly the initial dissolution rate, of the tablet of Comparative Example 1 was significantly increased when the paddle speed was increased. These results indicate that the tablets of the present invention are less affected by the rotational speed of the paddle plate. Therefore, the tablets of the present invention are less affected by gastrointestinal motility, thereby minimizing individual differences.

Experimental Example 6

Pharmacokinetic Study

[0033] The pharmacokinetic study of the tablet prepared in Example 14 was carried out using beagle dogs. The commercially available Lyricat Capsule 300 mg (Pfizer Pharmaceutical Co., Ltd.) was used as a reference preparation. The concentration of pregabalin in plasma was determined by liquid chromatography-tandem mass spectrometry. The plasma concentration curve is shown in FIG. 1; and the pharmacokinetic parameters are shown in Table 13.

TABLE-US-00013 TABLE 13 Pharmacokinetic Reference preparation Example parameters (Lyrica ® Cap. 300 mg) 14 AUC.sub.0-24 h (μg .Math. h/ml) 320.8 318.2 C.sub.max (μg/ml) 30.3 17.7 T.sub.max (h) 1.9 10.5

[0034] The sustained-release tablet of Example 14 showed delayed absorption in comparison to the immediate release tablet of the reference preparation. In Example 14, the average peak time T.sub.max to the maximum plasma concentration of the prototype drug pregabalin in dogs was 10.5 h, which was significantly later than that of the reference preparation group (1.9 h); the peak concentration (C.sub.max) was approximately 60% of that of the reference preparation after administration; and the relative bioavailability was 99.2%. Since pregabalin is absorbed in the upper part of the small intestine, the sustained-release tablets of the present invention can remain in the stomach for a longer period of time, but can still effectively control the release of pregabalin.