PREGABALIN SUSTAINED RELEASE COMPOSITION AND METHOD FOR PREPARING THE SAME

Abstract

The present application relates to a pregabalin sustained release composition, comprising: (a) an active ingredient; (b) a matrix-forming agent; (c) a swelling agent; (d) a gelling agent; and optionally a filler. The pregabalin sustained release composition provided in the present application can rapidly swell in volume when exposed to aqueous medium until exceeding the diameter of human gastric pyloric (13 mm). It thereby prolongs the gastric emptying time to increase the retention time of pregabalin in the stomach and enhances absorption of pregabalin in the small intestine and ascending colon. Moreover, the pregabalin sustained release composition provided herein achieves a sustained release for 24 h, which allows QD (once a day) administration, reduces administration number, and improves patient compliance.

Claims

1. A pregabalin sustained release composition comprising: (a) an active ingredient comprising pregabalin or a pharmaceutically acceptable salt or hydrate thereof; (b) a matrix-forming agent; (c) a swelling agent; and (d) a gelling agent; wherein, the swelling agent comprises one or at least two selected from the group consisting of crosslinked carmellose sodium, carmellose calcium, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, and polyoxyethylene.

2. The pregabalin sustained release composition according to claim 1, wherein the swelling agent comprises sodium carboxymethyl starch and at least one of low substituted hydroxypropyl cellulose and polyoxyethylene.

3. The pregabalin sustained release composition according to claim 1, wherein the swelling agent comprises at least one selected from the group consisting of carmellose calcium, low substituted hydroxypropyl cellulose and polyoxyethylene.

4. The pregabalin sustained release composition according to claim 1, wherein the pregabalin or the pharmaceutically acceptable salt or hydrate thereof has a particle size D.sub.90 of 250 to 600 μm.

5. The pregabalin sustained release composition according to claim 1, wherein the composition further comprises a filler.

6. The pregabalin sustained release composition according to claim 5, wherein the weight percentage of the filler is 1%-40%, based on the total weight of the pregabalin sustained release composition.

7. The pregabalin sustained release composition according to claim 1, wherein the matrix-forming agent is a mixture of polyvinyl acetate and polyvinylpyrrolidone.

8. The pregabalin sustained release composition according to claim 1, wherein the gelling agent is one of carbomer and polysaccharides, or combinations thereof.

9. The pregabalin sustained release composition according to claim 1, wherein, the weight percentage of the active ingredient is 5%-55%; the weight percentage of the matrix-forming agent is 5%-45%; the weight percentage of the swelling agent is 5%-70%; and the weight percentage of the gelling agent is 1%-30%, based on the total weight of the pregabalin sustained release composition.

10. The pregabalin sustained release composition according to claim 1, wherein the composition further comprises a lubricant.

11. The pregabalin sustained release composition according to claim 1, wherein the composition further comprises a coating powder.

12. A method for preparing the pregabalin sustained release composition according to claim 1 comprising: mixing the active ingredient, the matrix-forming agent, the swelling agent, the gelling agent, and optionally the filler, and then subjecting the mixture to a shaping process.

13. The method for preparing the pregabalin sustained release composition according to claim 12, wherein the mixing time is 10-30 min.

14. A pregabalin sustained release tablet comprising the pregabalin sustained release composition according to claim 1.

15. The pregabalin sustained release composition according to claim 2, wherein the swelling agent comprises carboxymethyl starch sodium and polyoxyethylene.

16. The pregabalin sustained release composition according to claim 5, wherein the filler is one or at least two selected from the group consisting of microcrystalline cellulose, lactose, starch, pregelatinized starch, calcium phosphate dihydrate, and anhydrous dicalcium phosphate.

17. The pregabalin sustained release composition according to claim 10, wherein the lubricant is one or at least two selected from the group consisting of magnesium stearate, talc powder, micropowder of silica gel, sodium stearyl fumarate, glyceryl behenate and polyethylene glycol.

18. The pregabalin sustained release composition according to claim 10, wherein the weight percentage of the lubricant is 0.1%-1.5%, based on the total weight of the pregabalin sustained release composition.

19. The pregabalin sustained release composition according to claim 11, wherein the coating powder comprises at least one of polyvinyl alcohol and polyethylene glycol, at least one of silica and talc powder, and/or a flavoring agent.

20. The pregabalin sustained release composition according to claim 11, wherein the weight percentage of the coating powder is 2%-6%, based on the total weight of the pregabalin sustained release composition.

Description

DESCRIPTION OF THE DRAWINGS

[0036] In order to illustrate the embodiments of the examples of the present application and the prior art more clearly, the drawings used in the following description of the embodiments and the prior art will be briefly described. It is obvious to those skilled in the art that the accompanying drawings in the following description are only some examples of the application, and other drawings can be obtained from these drawings without any inventive efforts.

[0037] FIG. 1 is a dissolution profile of Examples 1-8 and Comparative Example 1 of the present application;

[0038] FIG. 2 is a dissolution profile of Examples 10-17 of the present application and the control formulation Lyrica® CR;

[0039] FIG. 3 is a graph showing a curve of the average drug concentration-time (Mean±SD) for pregabalin in plasma, after a single oral administration of tested pregabalin sustained release tablet formulation (330 mg/tablet) and a control formulation of Lyrica® CR (330 mg/tablet) to a healthy person after meal.

DETAILED DESCRIPTION OF THE INVENTION

[0040] In order to make the technical problems, technical solutions and effects of the present application more clear, the present application will be further described in conjunction with specific examples as follows. In the following examples, the specific conditions of the experiment methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer, unless otherwise stated. The starting materials and reagents are all commercially available or prepared according to published information.

Preparation Example of a Pregabalin Sustained Release Tablet (an Oval Tablet)

[0041] The English abbreviations used in the following examples are shown in Table 2 below.

TABLE-US-00002 TABLE 2 Kollidon ® SR A mixture of polyvinyl acetate and polyvinyl- pyrrolidone PVPP Crospovidone PEO Polyoxyethylene MCC Microcrystalline cellulose CMS-Na Sodium carboxymethyl starch CC-Na Crosslinked carmellose sodium L-HPC Low substituted hydroxypropyl cellulose

Example 1

[0042] Formulation:

TABLE-US-00003 Drug/adjuvant Dosage (g) Pregbalin 330 Kollidon ® SR 256.5 CMS-Na 150 PEO 313.3 Carbomer 974P 69.6 Magnesium stearate 5.6 Produced into 1125 g/1000 tablets

[0043] Preparation method: according to the formulation dosage, pregabalin, Kollidon® SR, CMS-Na and carbomer 974P was weighed and passed through a 40 mesh sieve together, added with PEO and mixed for 15 min in a mixer, added with magnesium stearate and mixed for 5 min, and tableted.

Example 2

[0044] Formulation:

TABLE-US-00004 Drug/adjuvant Dosage (g) Pregbalin 330 Kollidon ® SR 169 PEO 313 Carbomer 974P 308 Magnesium sterate 5.6 Produced into 1125 g/1000 tablets

[0045] Preparation method: according to the formulation dosage, pregabalin, Kollidon® SR and Carbomer 974P was weighed and passed through a 40 mesh sieve together, added with PEO and mixed for 10 min in a mixer, added with magnesium stearate in half of the formulation dosage and mixed for 5 min. The mixture was subjected to dry granulating, finishing granule by passing through a 20 mesh sieve, then added with the remaining half magnesium stearate, mixed for 10 min and tableted.

Example 3

[0046] Formulation:

TABLE-US-00005 Drug/adjuvant Dosage (g) Pregbalin 330 Kollidon ® SR 257 CMS-Na 225 PEO 239 Carbomer 974P 70 Magnesium stearate 5.6 Produced into 1125 g/1000 tablets

[0047] Preparation method: according to the formulation dosages, pregabalin, Kollidon® SR, CMS-Na and Carbomer 974P was weighed and passed through a 40 mesh sieve together, added with PEO and mixed for 15 min in a mixer, then added with magnesium stearate and mixed fox 5 min, and tableted.

Example 4

[0048] Formulation:

TABLE-US-00006 Drugs/adjuvant Dosage (g) Pregbalin 330 Kollidon ® SR 169 CMS-Na 225 PEO 326 Carbomer 974P 70 Magnesium stearate 5.6 Produced into 1125 g/1000 tablets

[0049] Preparation method: according to the formulation dosage, pregabalin, Kollidon® SR, CMS-Na and Carbomer 974P was weighed and passed together through a 40 mesh sieve, added with PEO and mixed for 15 min in a mixer, then added with magnesium stearate and mixed for 5 min, and tableted.

Example 5

[0050] Formulation:

TABLE-US-00007 Drug/adjuvant Dosage (g) Pregbalin 330 Kollidon ® SR 257 CC-Na 225 PEO 239 Carbomer 974P 70 Magnesium stearate 5.6 Produced into 1125 g/1000 tablets

[0051] Preparation method: according to the formulation dosage, pregabalin, Kollidon® SR, CC—Na and carbomer 974P was weighed and passed together through a 40 mesh sieve, added with PEO, mixed for 15 min in a mixer, then added with magnesium stearate, mixed fear 5 min, and tableted.

Example 6

[0052] Formulation:

TABLE-US-00008 Drug/adjuvant Dosage (g) Pregbalin 330 Kollidon ® SR 257 L-HPC 225 PEO 239 Carbomer 974P 70 Magnesium sterate 5.6 Produced into 1125 g/1000 tablets

[0053] Preparation method: according to the formulation dosage, pregabalin, Kollidon® SR, L-HPC and Carbomer 974P was weighed and passed together through a 40 mesh sieve, added with PEO, mixed for 15 min in a mixer, then added with magnesium stearate, mixed for 5 min, and tableted.

Example 7

[0054] Formulation:

TABLE-US-00009 Drug/adjuvant Dsssge (g) Pregbalin 330 Kollidon ® SR 257 L-HPC 225 PEO 239 Chitosan 70 Magnesium stearate 5.6 Produced into 1125 g/1000 tablets

[0055] Preparation method: according to the formulation dosage, pregabalin, Kollidon® SR, L-HPC and chitosan was weighed and passed together through a 40 mesh sieve, added with PEO, mixed for 15 min in a mixer, then added with magnesium stearate, mixed for 5 min, and tableted.

Example 8

[0056] Formulation:

TABLE-US-00010 Drug/adjuvant Dosage (g) Pregbalin 330 Kollidon ® SR 257 CMS-Na 225 PEO 239 Carbomer 974P 70 Magnesium stearate 5.6 Film coating premix 35 Produced into 1160 g/1000 tablets

[0057] Preparation method: according to the formulation dosage, pregabalin, Kollidon® SR, CMS-Na and Carbomer 974P was weighed and passed together through a 40 mesh sieve, added with PEO and mixed for 15 min in a mixer, then added with magnesium stearate and mixed for 5 min, tableted. The tablet was coated with a film coating premix of 12% (w/w) solid contest, with an increased weight up to 3% by coating. The film coating premix contained polyvinyl alcohol, silica, talc powder, polyethylene glycol and a flavoring agent, and it was obtained by dissolving the above materials in purified water and passing through an 80 mesh sieve.

Example 9

[0058] Formulation:

TABLE-US-00011 Drug/adjuvant Dosage (g) Pregbalin 330 Kollidon ® SR 300 PEO 295 Carbomer 974P 115 Microcrystalline cellulose 80 Magnesium stearate 5 Produced into 1125 g/1000 tablets

[0059] Preparation method: according to the formulation dosage, pregabalin, Kollidon® SR, microcrystalline cellulose and Carbomer 974P was weighed and passed together through a 40 mesh sieve, added with PEO and mixed for 15 min in a mixer, then added with magnesium stearate and mixed for 5 min, and tableted.

Example 10

[0060] Formulation:

TABLE-US-00012 Drug/adjuvant Dosage (g) Pregbalin 330 Kollidon ® SR 250 CMS-Na 225 PEO 245 Carbomer 69 Magnesium stearate 6 Produced into 1125 g/1000 tablets

[0061] Preparation method: according to the formulation dosage, pregabalin, Kollidon® SR, CMS-Na and Carbomer was weighed and passed together through an 18 mesh sieve, added with PEO and mixed for 15 min in a mixer, then added with magnesium stearate and mixed for 5 min, and tableted.

Example 11

[0062] Formulation:

TABLE-US-00013 Drug/adjuvant Dosage (g) Pregbalin 330 Kollidon ® SR 250 Carmellose calcium 225 PEO 245 Carbomer 69 Magnesium stearate 6 Produced into 1125 g/1000 tablets

[0063] Preparation method: according to the formulation dosage, prepremarin, Kollidon® SR, carmellose calcium and Carbomer was weighed and passed together through a 18 mesh sieve, added with PEO and mixed for 10 min in a mixer, then added with magnesium stearate in half of the formulation dosage and mixed for 5 min. The mixture was subjected to dry granulating, finishing granule by passing through a 20 mesh sieve, then added with the remaining half magnesium stearate, mixed for 10 min and tableted.

Example 12

[0064] Formulation:

TABLE-US-00014 Drug/adjuvant Dosage (g) Pregbalin 330 Kollidon ® SR 250 L-HPC 225 PEO 245 Carbomer 69 Magnesium stearate 6 Produced into 1125 g/1000 tablets

[0065] Preparation method: according to the formulation dosage, pregabalin, Kollidon® SR, L-HPC and Carbomer was weighed and passed together through an 18 mesh sieve, added with PEO and mixed for 15 min in a mixer, then added with magnesium stearate and mixed for 5 min, and tableted.

Example 13

[0066] Formulation:

TABLE-US-00015 Drug/adjuvant Dosage (g) Pregbalin 330 Kollidon ® SR 250 Microcrystalline cellulose 225 PEO 245 Carbomer 69 Magnesium stearate 6 Produced into 1125 g/1000 tablets

[0067] Preparation method: according to the formulation dosage, pregabalin, Kollidon® SR, microcrystalline cellulose and carbomer was weighed and passed together through an 18 mesh sieve, added with PEO and mixed for 15 min in a mixer, then added with magnesium stearate and mixed for 5 min, and tableted.

Example 14

[0068] Formulation:

TABLE-US-00016 Drug/adjuvant Dosage (g) Pregbalin 330 Kollidon ® SR 250 CC-Na 225 PEO 245 Carbomer 69 Magnesium stearate 6 Produced into 1125 g/1000 tablets

[0069] Preparation method: according to the formulation dosage, pregabalin, Kollidon® SR, CC—Na and Carbomer was weighed and passed together through a 18 mesh sieve, added with PEO and mixed for 15 min in a mixer, then added with magnesium stearate and mixed for 5 min, and tableted.

Example 15

[0070] Formulation:

TABLE-US-00017 Drug/adjuvant Dosage (g) Pregbalin 330 Kollidon ® SR 270 Pregelatinized starch 227 PEO 180 Carbomer 113 Magnesium stearate 6 Produced into 1125 g/1000 tablets

[0071] Preparation method: according to the formulation dosage, pregabalin, Kollidon® SR, pregelatinized starch and Carbomer was weighed and passed together through an 13 mesh sieve, added with PEO and mixed for 20 min in a mixer, then added with magnesium stearate and mixed for 5 min, and tableted.

Example 16

[0072] Formulation:

TABLE-US-00018 Drug/adjuvant Dosage (g) Pregbalin 330 Kollidon ® SR 281 Microcrystalline cellulose 169 PEO 284 Carbomer 56 Magnesium stearate 6 Produced into 1125 g/1000 tablets

[0073] Preparation method: according to the formulation dosage, pregabalin, Kollidon® SR, micro-crystalline cellulose and Carbomer was weighed and passed together through an 18 mesh sieve, added with PEO and mixed for 15 min in a mixer, then added with magnesium stearate and mixed for 5 min, and tableted.

Example 17

[0074] Formulation:

TABLE-US-00019 Drug/adjuvant Dosage (g) Pregbalin 330 Kollidon ® SR 281 Microcrystalline cellulose 169 PEO 284 Carbomer 56 Magnesium stearate 6 Film coating premix 35 Produced into 1160 g/1000 tablets

[0075] Preparation method: according to the formulation dosage, pregabalin, Kollidon® SR, microcrystalline cellulose and Carbomer was weighed and passed together through an 18 mesh sieve, added with PEO and mixed for 20 min in a mixer, then added with magnesium stearate and mixed for 5 min, and tableted. The tablet was coating with a film coating premix of 20% (w/w) solid content, with an increased weight of 3% by coating. The film coating premix contained polyvinyl alcohol, silica, talc powder, polyethylene glycol and a flavoring agent and it was obtained by dissolving the above materials in purified water and passing through an 80 mesh sieve.

Example 18-26

[0076] Examples 18-26 were performed with reference to the preparation method of Example 8 and the formulation in Table 3 below.

TABLE-US-00020 TABLE 3 Example 18 19 20 21 22 23 24 25 26 in the in the in the in the in the in the in the in the in the Ingredient formulation formulation formulation formulation formulation formulation formulation formulation formulation name (%) (%) (%) (%) (%) (%) (%) (%) (%) Pregabalin 5 10 15 20 35 40 25 30 55 Kollidon ® SR 30 10 15 25 5 35 40 40 35 CMS-Na 0 0 20 0 0 0 5 5 5 CC-Na 0 0 0 40 40 10 0 0 0 L-HPC 0 0 0 0 0 0 0 0 0 PEO 60 70 34 0 0 0 0 0 0 Carbomer 974P 2 5 5 10 10 5 20 3 3 0 0 0 0 0 0 0 0 0 Microcrystalline 3 3 8 0 0 0 0 0 0 cellulose Magnesium 1 0.5 1.5 1 10 7 7 0.5 0.5 stearate Film coating 0 2.5 1.5 4 0 3 3 1.5 1.5 premix Tablet weight 1000 1000 1125 1125 1125 1125 1125 1125 1125 indicates data missing or illegible when filed

Example 27-34

[0077] Examples 27-34 were performed with reference to the preparation method of Example 17 and the formulation in Table 4 below.

TABLE-US-00021 TABLE 4 Example 27 28 29 30 31 32 33 34 in the in the in the in the in the in the in the in the Ingredient formulation formulation formulation formulation formulation formulation formulation formulation name (%) (%) (%) (%) (%) (%) (%) (%) Pregabalin 5 10 10 20 35 30 25 50 Kollidon ® SR 30 12.5 15 25 5 35 40 40 CMS-Na 0 0 10 0 0 0 0 0 Carmellose 0 0 0 40 0 0 10 0 calcium Microcrystalline 35 0 40 0 30 0 10 0 cellulose Pregelatinized 0 0 0 0 0 5 0 0 starch PEO 25 70 19 0 9 25 5 6.5 Carbomer 4 7 5 14 20 4.5 9.5 3 Magnesium 1 0.5 1 1 1 0.5 0.5 0.5 stearate Film coating 0 2.5 1.5 4 2 3 3 1.5 premix 100 100 100 100 100 100 100 100 indicates data missing or illegible when filed

Comparative Example 1

[0078] Refer to Example 30 in CN101330907A.

Comparative Example 2

[0079] Formulation:

TABLE-US-00022 Drug/adjuvant Dosage (g) Pregbalin 330 Kollidon ® SR 257 PEO 533 Magnesium stearate 5.6 Produced into 1125 g/1000 tablets

[0080] Preparation method: according to the formulation dosage, pregabalin and Kollidon® SR was weighed and passed together through a 40 mesh sieve, added with PEO and mixed for 15 min in a mixer, then added with magnesium stearate and mixed for 5 min, and tableted.

Comparative Example 3

[0081] Formulation:

TABLE-US-00023 Drug/adjuvant Dosage (g) Pregbalin 330 PEO 790 Magnesium stearate 5.6 Produced into 1125 g/1000 tablets

[0082] Preparation method: according to the formulation dosage, pregabalin and PEO was weighed, mixed for 15 min in a mixer, then added with magnesium stearate, mixed for 5 min, and tableted.

Comparative Example 4

[0083] Formulation:

TABLE-US-00024 Drug/adjuvant Dosage (g) Pregbalin 330 Kollidon ® SR 257 Carbomer 974P 533 Magnesium stearate 5.6 Produced into 1125 g/1000 tablets

[0084] Preparation method: according to the formulation dosage, pregabalin, Kollidon® SR and Carbomer 974P was weighed and passed together through a 40 mesh sieve, mixed for 10 min in a mixer, then added with magnesium stearate in half of the formulation dosage and mixed for 5 min. The mixture was subjected to dry granulating, finishing granule by passing through a 20 mesh sieve, then added with the remaining magnesium stearate, mixed for 10 min and tableted.

[0085] Drug Dissolution and Swelling Test

[0086] Test I

Dissolution Test of the Tablets of Examples 1-8 and Comparative Example 1

[0087] 1. Dissolution Method: [0088] 1) Method: Dissolution assay (Chinese Pharmacopoeia, 2015, Vol. IV, General Rules “0931 Dissolution And Release Assay” The Second Method (Paddle Method), with a sinker); [0089] 2) Dissolution medium: 0.06 mol/L HCl, 900 ml; [0090] 3) Rotate Speed: 50 rpm; [0091] 4) Sampling time: 1 h, 2 h, 4 h, 6 h, 9 h, 12 h, 16 h, and 24 h; [0092] 5) Detection method: high performance liquid phase chromatography, with a detection wavelength of 210 nm; [0093] 6) Preparation of tested solution: 10 ml of the solution was taken at each time point and filtered; [0094] 7) Preparation of the control solution: pregabalin control sample was prepared into a control solution with a concentration of about 360 μg/ml in 0.06 mol/L HCl.

[0095] 2. Instrument Model:

Smart Dissolution Tester (Model: DT820, Manufacturer: Erweka, Ltd., Germany)

[0096] 3. Dissolution Results

The dissolution results of Examples 1-8 and Comparative Example 1 in 0.06 mol/L HCl medium are shown in Table 5 and FIG. 1:

TABLE-US-00025 TABLE 5 Batch number 1 h 2 h 4 h 6 h 9 h 12 h 16 h 24 h f.sub.2 Compar- 18.4 28.6 44.0 55.8 69.1 79.6 90.2 100.4 NA ative Example 1 Example 1 17.3 27.1 41.3 52.4 64.8 74.3 83.5  96.5 69 Example 2 18.0 27.2 39.7 48.9 59.2 67.4 77.5  90.9 54 Example 3 17.8 27.1 40.9 51.7 64.1 73.7 83.4  95.8 67 Example 4 16.2 25.7 39.8 51.4 65.1 75.7 86.4  97.1 69 Example 5 19.8 29.8 41.1 53.1 65.2 76.4 86  99.7 74 Example 6 15.7 25.8 38.1 51.0 63.1 72.4 84.1  97.1 64 Example 7 15.9 25.8 36.5 48.5 61.1 73.1 81.4  94.2 58 Example 8 16.4 28.1 37.4 51.2 63.4 75.7 85.1 100.7 65 Note: All of the dissolution results in the table we expressed in percentage.

[0097] As can be seen from Table 5 and FIG. 1, the pregabalin sustained release tablets prepared in Examples 1-8 of the present application were sustained released over 24 h, with release amount of <30% at 2 h and 60% to 80% at 12 h. A complete release can be observed at 24 h. The dissolution characteristics are substantially the same as those of the sustained release tablets (Comparative Example 1) described in CN101330907A, thus QD administration can be achieved.

[0098] Test II

Test for Swelling Size of the Tablets of Examples 1-8 and Comparative Examples 1-4

[0099] The tablets prepared in the above examples were subjected to a dissolution test accords to Chinese Pharmacopoeia, 2015, Vol. IV, General Rules “0931 Dissolution And Release Assay”, The Second Method (Paddle Method). 900 ml 0.06 N HCl solution was used as a dissolution medium at a rotation speed of 50 rpm. The drug was collected from the dissolution medium at 1 h, 2 h, and 6 h of the dissolution test. The size was measured with an electronic vernier calliper, and compared with the size of the tablet at 0 h (the tablet before test). The results are shown in Table 6 below:

TABLE-US-00026 TABLE 6 Length * Width * Thickness Sample 0 h 1 h 2 h 6 h Example 1 20.7 × 10.1 × 7.3 22.7 × 12.9 × 9.7  24.3 × 14.2 × 13.6 25.7 × 15.2 × 14.8 Example 2 20.7 × 10.1 × 9.2 22.1 × 12.1 × 11.2 23.1 × 13.2 × 12.2 25.7 × 14.8 × 13.9 Example 3 20.6 × 10.1 × 7.9 23.6 × 13.5 × 12.1 25.2 × 14.2 × 13.3 27.2 × 15.8 × 14.9 Example 4 20.6 × 10.1 × .4 23.8 × 14.2 × 12.9 25.4 × 14.7 × 13.7 27.4 × 15.9 × 15.2 Example 5 20.7 × 10.1 × 8.6 22.7 × 12.9 × 10.6 24.9 × 14.1 × 12.1 27.7 × 15.7 × 14.8 Example 6 20.7 × 10.1 × 9.1 22.1 × 12.1 × 11.1 24.7 × 13.8 × 12.9 27.5 × 15.1 × 14.9 Example 7 20.6 × 10.1 × 8.7 22.6 × 12.4 × 10.7 25.9 × 13.5 × 13.0 28.9 × 14.5 × 13.7 Example 8 20.7 × 10.1 × 8.3 23.7 × 13.1 × 12.3 25.3 × 14.0 × 13.1 27.3 × 14.9 × 14.6 Comparative Example 1 17.1 × 17.7 × 6.7 18.2 × 19.3 × 9.5  19.8 × 20.1 × 11.4 23.8 × 22.1 × 13.4 Comparative Example 2 20.6 × 10.1 × 7.5 23.6 × 13.4 × 10.5 25.2 × 16.1 × 11.5 27.2 × 18.1 × 8.5  Comparative Example 3 20.6 × 10.1 × 7.4 22.1 × 12.4 × 8.3  — — Comparative Example 4 20.7 × 10.1 × 9.1 24.8 × 12.1 × 10.8 27.1 × 13.0 × 11.4 1.  × 14.5 × 12.6 Note: For the Comparative Example 2, the swelled sample first became larger, and then as the swelling continued, the tablet became soft with poor mechanical strength and low thickness of the tablet, which collapsed on the test table after taking out. The sample of Comparative Example 3 was deformed after swelling for 6 h, so that the length, width and thickness of the tablet cannot be measured. indicates data missing or illegible when filed

[0100] As can be seen from Table 6, the tablets prepared in Examples 1, 3, 4, and 8 of the present application had a size of more than 13 mm after 2 h swelling (this size corresponds to the longest linear dimension of the smallest cross section of the formulation), which was obviously superior to that of Comparative Example 1. In other examples, the swelling size also reached 13 mm or more after 6 h. This size can effectively prolong the retention time of the sustained release tablet in the stomach by mechanical retardation. The pharmaceutical composition can continuously release pregabalin in the stomach, resulting in a much wider absorption window of pregabalin and enhanced absorption thereof in the small intestine and ascending colon. QD administration of the pharmaceutical composition can be achieved. Further, in comparison with Comparative Examples 2-4 without at least one of the matrix-forming agent, the swelling agent, and the gelling agent, the swelling size is greater in Examples 1-8.

[0101] Test III

Dissolution Test of Examples 10-17 and a Control Formulation (Lyrica® CR)

[0102] The dissolution method can be referred to test I. The sampling time was 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 16 h, and 24 h. The smart dissolution tester was the same as that in test I.

[0103] The dissolution results of Examples 10-17 and control formulation (Lyrica® CR) with 0.06 mol/L HCl medium are shown in Table 7 and FIG. 2:

TABLE-US-00027 TABLE 7 Batch number 1 h 2 h 4 h 6 h 8 h 10 h 12 h 16 h 24 h f.sub.2 Lyrica ® CR 18.8 30.0 45.7 57.5 66.7 74.0 79.7 88.2 97.4 NA Example 10 19.5 30.1 42.4 54.4 64.2 71.9 78.4 85.6 96.7 81 Example 11 22.5 33.5 51.1 63.0 71.5 79.2 84.1 90.5 101.1 67 Example 12 17.1 27.1 39.5 53.3 65.2 73.4 78.5 83.5 96.5 72 Example 13 17.5 28.1 44.1 55.3 65.3 73.4 79.2 88.4 100.2 88 Example 14 17.6 27.2 39.7 53.9 64.4 73.5 80.2 88.4 99.5 76 Example 15 17.8 26.8 41.6 54.5 63.4 72.5 78.3 85.3 98.1 77 Example 16 19.8 27.2 40.8 52.6 64.1 71.2 77.1 85.3 99.6 73 Example 17 17.8 27.1 39.5 51.7 61.2 70.1 75.7 84.5 100.8 67 Note: All of the dissolution results in the table we expressed in percentage.

[0104] As can be seen from Table 7 and FIG. 2, the pregabalin sustained release tablets prepared in Examples 10-17 of the present application were slowly released over 24 h, with a release amount of <25% at 1 h and above 60% at 8 h. Nearly 100% release can be observed at 24 h. The dissolution characteristics are substantially the same as those of the sustained release tablets in Comparative Example 1 and Lyrica® CR, thus QD administration can be achieved.

[0105] Test IV

Test for Swelling Size of the Tablets of Examples 10-17 and Lyrica® CR

[0106] The test method can be referred to Test II. The results are shown in Table 8 below:

TABLE-US-00028 TABLE 8 Length * Width * Thickness Sample 0 h 1 h 2 h 6 h Lyrica ®CR 22.3 × 11.0 × 6.9 24.3 × 13.  × 7.1  24.4 × 13.2 × 9.7  26.5 × 13.8 × 10.6 Example 10 20.7 × 10.1 × 7.8 22.7 × 12.9 × 9.1  24.3 × 14.2 × 12.6 25.7 × 15.2 × 13.1 Example 11 20.7 × 10.1 × 7.8 / / / Example 12 20.7 × 10.1 × 7.9 23.5 × 13.5 × 11.2 24.1 × 14.3 × 12.5 27.2 × 15.8 × 13.9 Example 13 20.7 × 10.1 × 7.4 23.4 × 14.2 × 11.5 25.1 × 14.7 × 12.7 27.4 × 15.9 × 14.1 Example 14 20.7 × 10.1 × 7.8 22.4 × 12.9 × 11.4 24.4 × 14.1 × 12.5 27.7 × 15.7 × 14.1 Example 15 20.7 × 10.1 × 8.8 22.1 × 12.1 × 11.5 24.7 × 13.8 × 13.0 27.5 × 15.1 × 14.6 Example 16 20.7 × 10.1 × 8.3 22.5 × 12.4 × 11.3 25.4 × 13.5 × 12.5 28.1 × 14.5 × 13.7 Example 17 20.7 × 10.1 × 8.3 23.7 × 13.1 × 11.4 25.3 × 14.0 × 12.6 27.3 × 14.9 × 13.6 Note: After the sample of Example 11 was dissolved for 1 h, the sample was dispersed, and the size could not be measured. indicates data missing or illegible when filed

[0107] As can be seen from Table 8, the tablets prepared in the examples of the present application have a size of 13 mm or more after swelling for 2 h (this size corresponds to the longest linear dimension of the smallest cross section of the formulation), similar to the Lyrica® CR (in this study, the difference in initial tablet size was due to the difference in tablet form). The increase in thickness of the tablet was greater than that in the comparative example and Lyrica® CR tablets. This size can effectively prolong the retention time of the sustained release tablet in the stomach by mechanical retardation. The pharmaceutical composition can continuously release pregabalin in the stomach, resulting in a much wider absorption window of pregabalin, and enhanced absorption thereof in the small intestine and ascending colon. QD administration of the pharmaceutical composition can be achieved.

[0108] Drug Rigidity Assay

Dissolution Test of Tablets of Examples 10-16 and Lyrica® CR

[0109] 1. Test Method:

[0110] The tablets prepared in Examples 10 to 16 were subjected to a dissolution test with a sinker, according to Chinese Pharmacopoeia, 2015, Vol. IV, General Rules “0931 Dissolution And Release Assay”, The Second Method (Paddle Method). 900 ml of 0.06 mol/L HCl solution was used as the dissolution medium, and the dissolution test was carried out at 37±5° C. at a paddle speed of 50 rpm. The drug was collected from the medium at 2 h, 6 h and 24 h after the test started. The sample rigidity was measured under the following predetermined conditions. The test results are shown in Table 9.

[0111] Instrument: Texture Tester (EZ Test)

Load unit: 5 kg
Probe: ¼ sphere probe
Trigger force: 0.5 g
Test speed: 0.2 m/s
Acquisition rate: 10 samples/s
Test distance: 8-10 mm

TABLE-US-00029 TABLE 9 Time (h) Ex- Ex- Ex- Ex- Ex- Ex- Ex- ample ample ample ample ample ample ample Lyrica ® 10 11 12 13 14 15 16 CR 2 3580 3802 3750 4480 3211 4108 4753 4450 6 850 1250 1009 1912 998 1909 1981 1760 24 485 635 601 708 604 681 698 800

[0112] As can be seen from Table 9, the tablets prepared in Examples 10, 11, 12 and Example 14 of the present application were less rigid than the tablets of Lyrica® CR after 2 h, 6 h and 24 h. The tablets containing a filler in Examples 13, 15 and 16 were significantly more rigid and significantly superior than the tablets of Lyrica® CR. The rigidity of the tablets during dissolution can protect the tablets from being destroyed by food in the gastrointestinal tract, thereby prolonging the retention time of the tablets in the stomach to widen the absorption window. The absorption of pregabalin in the small intestine and ascending colon is increased to allow QD administration. From the results of the measurement, the use of filler in the present application are effective in increasing the rigidity of the formulation, maintaining the shape of the drug, and ensuring sustained release of the drug.

[0113] Drug Stability Test

[0114] The influencing factors of Example 17 and the control formulation Lyrica® CR were investigated. The appearance traits, weight gain or loss, dissolution, content and related substances of the samples in 30 days are shown in Table 10 to Table 14.

TABLE-US-00030 TABLE 10 Results of appearance traits Trait Time Sample Test condition 0 d 5 d 10 d 30 d Lyrica ®CR High temperature test Pink film-coated tablets, — Same as 0 d Same as 0 d (° C.): 60 ± 2 white after removal of the coating High temperature test Pink film-coated tablets, — Same as 0 d Same as 0 d (° C.): 40 ± 2 white after removal of the coating Intense light Pink film-coated tablets, — Same as 0 d Same as 0 d illumination test (Lx): white after removal of the 5000 ± 500 coating High humidity test: Pink film-coated tablets, — Same as 0 d Same as 0 d RH 75% white after removal of the coating Example 17 High temperature test Pink film-coated tablets, Same as 0 d Same as 0 d Same as 0 d (° C.): 60 ± 2 white after removal of the coating High temperature test Pink film-coated tablets, Same as 0 d Same as 0 d Same as 0 d (° C.): 40 ± 2 white after removal of the coating Intense light Pink film-coated tablets, Same as 0 d Same as 0 d Same as 0 d illumination test (Lx): white after removal of the 5000 ± 500 coating High humidity test: Pink film-coated tablets, Same as 0 d Same as 0 d Same as 0 d RH 75% white after removal of the coating Note: “—” means not studied.

TABLE-US-00031 TABLE 11 Results of weight gain or loss assay Weight gain Weight gain Condition Sample or loss (%) Sample or loss (%) High temperature Example 17-5 d −0.8 — — 60° C. Example 17-10 d −0.1 Lyrica ®CR-10 d −1.7 Example 17-30 d −0.9 Lyrica ®CR-30 d −1.7 High temperature Example 17-5 d −0.1 — — 40° C. Example 17-10 d −0.3 Lyrica ®CR-10 d −0.6 Example 17-30 d −0.3 Lyrica ®CR-30 d −0.9 High temperature Example 17-5 d 2.9 — — RH 75% Example 17-10 d 3.9 Lyrica ®CR-10 d  5.0 Example 17-30 d 5.0 Lyrica ®CR-30 d  9.1 Light illumination Example 17-5 d 0.3 — — 5000LX Example 17-10 d 0.2 Lyrica ®CR-10 d  0.0 Example 17-30 d 0.3 Lyrica ®CR-30 d −0.5 Note: “—” means not studied.

TABLE-US-00032 TABLE 12 Results of dissolution study Cumulative release of pregabalin sustained release tablets in 0.06N HCl (%) Sample 0 1 h 2 h 4 h 8 h 12 h 16 h 24 h f.sub.2 Lyrica ® CR 0 d 18.8 30.0 45.7 66.7 79.7 88.2 97.4 80 Example 17 19.0 29.6 43.9 63.3 76.3 85.8 97.2 Lyrica ® CR 40° C. 10 d 19.2 30.7 46.7 67.8 81.1 89.5 98.4 78 Example 17 18.7 29.1 43.8 63.8 78.0 88.4 101.6 Lyrica ® CR 40° C. 30 d 19.2 30.9 47.6 70.2 84.3 93.3 102.2 65 Example 17 18.7 29.1 43.5 63.2 77.7 87.9 101.2 Lyrica ® CR 60° C. 10 d 19.3 30.7 46.9 68.1 81.4 89.8 98.4 93 Example 17 19.5 30.6 46.3 67.8 82.1 91.8 102.2 Lyrica ® CR 60° C. 30 d 19.8 31.1 47.5 69.0 82.1 90.5 97.9 72 Example 17 19.9 30.1 44.0 63.4 77.8 87.9 101.1 Lyrica ® CR Light illumination 19.8 31.3 47.7 69.6 83.3 91.8 100.3 60 Example 17 10 d 18.5 28.9 42.8 61.4 74.1 83.3 95.0 Lyrica ® CR Light illumination 19.2 30.8 47.3 69.2 82.8 92.2 100.6 59 Example 17 30 d 18.5 28.6 42.4 60.9 73.6 83.0 94.4 Lyrica ® CR RH75% 10 d 20.4 32.1 49.0 69.9 83.9 91.8 100.7 65 Example 17 19.4 30.0 44.4 64.2 76.9 86.0 95.6 Lyrica ® CR RH75% 30 d 18.9 30.2 46.1 67.1 80.1 89.2 98.5 67 Example 17 18.6 28.7 42.4 61.1 73.8 83.3 94.9

TABLE-US-00033 TABLE 13 Light High High High illumination humidity temperature temperature Test 5000 LX RH75% 40° C. 60° C. Item Sample Impurities 0 d 10 d 30 d 10 d 30 d 10 d 30 d 10 d 30 d Related Example Degraded 0.08 0.08 0.08 0.06 0.06 0.12 0.19 0.52 1.08 material 17 impurity C: Maximum N.D. N.D. N.D. N.D. N.D. N.D. N.D. N.D. 0.33 unknown impurity: Total 0.08 0.08 0.08 0.06 0.06 0.12 0.19 0.52 1.65 impurities: Lyrica ® Degraded 0.31 0.27 0.27 0.26 0.26 0.32 0.38 0.89 1.67 CR impurity C: Maximum N.D. N.D. N.D. N.D. N.D. N.D. N.D. N.D. 0.48 unknown impurity: Total 0.31 0.27 0.27 0.26 0.26 0.32 0.38 0.89 3.20 impurities:

[0115] Note:

[0116] Impurity C of 4-isobutylpyrrolidin-2-one is a degradation impurity of the active substance of pregabalin, with a molecular formula of C.sub.8H.sub.15NO, and molecular weight of 141.21. The structure is as follows:

##STR00002##

TABLE-US-00034 TABLE 14 Results of content measurement Light High High High illumination humidity temperature temperature Test 5000 LX RH75% 40° C. 60° C. Item Sample 0 d 10 d 30 d 10 d 30 d 10   30 d 10 d 30 d Content Example 17 98.1 98.6 97.6 98.2 97.7 97.0 98.5 97.8 99.2 (%) Lyrica ® CR 100.0 98.7 98.7 99.2 98.7 97.4 98.5 98.0 98.4

[0117] The remits of influencing factors test showed no significant change in appearance traits of the samples of Example 17 and Lyrica® CR was observed in 30 days under each condition. The pregabalin sustained release tablet was hygroscopic. The hygroscopic weight gain of Example 17 under high humidity (RH75%) condition is significantly lower than that of Lyrica® CR. That is, the hygroscopicity of the sample in Example 17 was significantly improved compared with Lyrica® CR. There was no significantly change in dissolution rate under each condition. The dissolution profile of Example 17 was similar to that of Lyrica® CR. The degraded impurity C of pregabalin sustained release tablets increased under high temperature conditions. The samples in Example and Lyrica® CR increased significantly at 60° C., and Lyrica® CR increased more. That is, the stability of the sample in Example 17 was better.

[0118] In summary, the prepared tablet of Example 17 significantly more stable than that of Lyrica® CR according to the result of the stability.

[0119] Bioequivalence Test of Drug in Human Body

[0120] 1. Purpose

[0121] A single oral administration of a control formulation of pregabalin sustained release tablet (R, LYRICA® CR, sustained release tablet, batch number T73417, specification 330 mg tablet) and test formulation (T, Example 17, specification of 330 mg/tablet) were investigated to evaluate the bioequivalence thereof.

[0122] 2. Instruments, Drugs and Agents

[0123] 2.1 Instrument

TABLE-US-00035 Name Manufacturer Device Number Balance MSA225S-CE, Sartorius, II 051-021 Germany Vortex mixer Wiggens Vortex II 050-477 Multi-tube vortex VX-II, Beijing Targin II 050-490 oscillator Technology Co., Ltd Desktop high speed Sigma 3K15 II 050-494 refrigerated centrifuge Desktop high speed Sigma 3-18KS II 050-693 refrigerated centrifuge UPLC-MS/MS ACQUITY UPLC H-class/ II 050-503 XEVO TQD, Waters Milli Q UltraPure MilliPore Advantage A10 II 050-325 Water System

[0124] 2.2 Drugs and Agent

TABLE-US-00036 Name Manufacturer Batch Number Pregabalin NICPBP 101106-201001 Pregbalin-d4 TLC 2904-018A1 Dimethyl sulfoxide McLean C10102428 Methanol Merck I0953707 820 Formic Acid ROE 5C2017 Acetonitrile Merck JA050030 Isopropanol Merck 1.01040.4008 Blank, plasma of human Purchased from Beijing 180305 Kemengda Technology Development Co., Ltd.

[0125] 3. Sample Preparation

[0126] To 40 μL of unknown plasma sample, 40 μL of acetonitrile-water solution (1:1, v/v) and 40 μL of internal standard solution (pregabalin-d4 1000 ng.Math.mL.sup.−1) were added followed by 120 μL of methanol. The mixture obtained was vortexed for 2 min, centrifuging under 15000 rpm at 4° C. for 10 min. 50 μL of the supernatant was aspirated, added with 150 μL of 0.1% formic acid aqueous solution, and homogenously mixed, 5 μL was taken for LC-MS/MS quantitative analysis.

[0127] 4. Test Result

[0128] 4.1 Human Plasma Sample Test

[0129] The human plasma samples to be tested were divided into 6 batches for analysis. Each of the analyzed batch has a linear correlation coefficient greater than 0.9900. Each concentration point on the standard curve of pregabalin sustained release tablets of different batches has an average RE % within ±15%. FIG. 3 shows plasma drug concentration-time curve of a single orally administration after meal to a healthy subject for a tested pregabalin sustained release tablet formulation and control formulation.

[0130] 4.2 Human Plasma Pharmacokinetic Parameters

[0131] After single orally administration after meal to a healthy subject of tested and control formulation of HPR, HPR has an average elimination half-life t.sub.1/2 of 6.08±0.718 h and 6.08±1.05 h, respectively, an average peak time T.sub.max of 8.80±3 08 h and 9.90±3.35 h, respectively, an average C.sub.max of 4381±1107 ng.Math.mL.sup.−1 and 4370±870 ng.Math.mL.sup.−1, respectively, an average AUC.sub.0.fwdarw.t of 71361±12040 h.Math.ng.Math.mL.sup.−1 and 72243±17132 h.Math.ng.Math.mL.sup.−1, respectively, and an average AUC.sub.0.fwdarw.∞ of 72053±12163 h.Math.ng.Math.mL.sup.−1 and 73131±17371 h.Math.ng.Math.mL.sup.−1, respectively.

[0132] 4.3 Statistical Results of Human Plasma

[0133] For these two formulations, 90% confidence intervals of the ratios of Ln(AUC.sub.0.fwdarw.t), Ln(AUC.sub.0.fwdarw.∞) and Ln(C.sub.max) is 90.72%-111.45%, 90.39%-111.29% and 88.54%-110.80%, respectively. T.sub.max has a P value <0.05 by two-sided t test. The above results show that the two formulations are bioequivalent. Table 15 shows the statistical results of bioequivalence confidence interval for single orally administration of tested and control formulation after meal to a healthy person.

TABLE-US-00037 TABLE 15 Parameter Confidence interval P Value Ln (C ) 88.54~110.80 — L (AUC ) 90.72~111.45 — Ln(AUC.sub.0 90.39~111.29 — Treatment|(SEQ1 = SEQ2) — 0.246 Treatment & Residual — 0.463 (simultaneous) Note: Equivalence determination standard of AUC.sub.0-t, AUC.sub.0-∞ and C.sub.max 90% confidence interval: 80.00%-125.00%. Equivalence determination standard of T.sub.max: p ≥ 0.05 indicates data missing or illegible when filed

[0134] The above examples are intended to illustrate substantial of the present application, rather than limit the scope thereof. A person skilled in the art should understand that the technical solutions of the present application may be modified or equivalently altered, without departing from the spirit and scope thereof.