APREMILAST SUSTAINED RELEASE PREPARATION

Abstract

The present invention relates to an apremilast sustained release preparation. Specifically, the present invention relates to an apremilast composition which is a sustained release preparation having a high bioavailability in the body. The present invention provides a sustained release drug preparation containing an apremilast sustained release component and a site-specific release component therefor. Within in vitro release testing, the release speed is steady and constant.

Claims

1. A pharmaceutical formulation, comprising: (i) a sustained release component I of apremilast, and (ii) a site-specific release component II of apremilast.

2. The pharmaceutical formulation according to claim 1, wherein the sustained release component I comprises: A) apremilast or a pharmaceutically acceptable salt or solvate thereof, in an amount of 5-20% by weight, relative to the weight of the sustained release component I; and B) a sustained release material.

3. The pharmaceutical formulation according to claim 2, wherein the site-specific release component II comprises: A) apremilast or a pharmaceutically acceptable salt or solvate thereof, in an amount of 5-20% by weight, relative to the weight of the sustained release component II; and B) a site-specific release coating.

4. The pharmaceutical formulation according to claim 3, wherein the site-specific release coating is an enteric coating or a gastric coating; wherein the enteric coating is at least one selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methylcellulose titanate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, and acrylic resin; wherein the site-specific release coating is present in an amount of 1-40% by weight, relative to the weight of the site-specific release component II.

5. The pharmaceutical formulation according to claim 2, wherein the sustained release material in the sustained release component I is at least one selected from the group consisting of hypromellose, polyoxyethylene, hydroxypropyl cellulose, copolymer of polyalkyl saccharose or polyalkyl pentaerythritol and acrylic cross-linked polymer, and sodium alginate.

6. The pharmaceutical formulation according to claim 3, wherein the site-specific release component II further comprises a sustained release material which is at least one selected from the group consisting of hypromellose, polyoxyethylene, hydroxypropyl cellulose, copolymer of polyalkyl saccharose or polyalkyl pentaerythritol and acrylic cross-linked polymer, and sodium alginate.

7. The pharmaceutical formulation according to claim 6, wherein the sustained release material is present in an amount of 6-60% by weight, relative to the weight of the corresponding sustained release component I or the site-specific release component II in the pharmaceutical formulation.

8. The pharmaceutical formulation according to claim 1, wherein a weight ratio of the sustained release component I to the site-specific release component II is 1:8-8:1.

9. The pharmaceutical formulation according to claim 2, wherein the sustained release component I further comprises a pharmaceutical excipient, wherein the pharmaceutical excipient is at least one selected from the group consisting of a filler, surfactant, glidant, lubricant, and coating agent.

10. The pharmaceutical formulation according to claim 3, wherein the site-specific release component II further comprises a pharmaceutical excipient, wherein the pharmaceutical excipient is at least one selected from the group consisting of a filler, surfactant, glidant, lubricant, and coating agent.

11. The pharmaceutical formulation according to claim 10, wherein the filler is a water-soluble filler or a water-swellable filler, and is at least one selected from the group consisting of microcrystalline cellulose, pregelatinized starch, corn starch, dextrin, lactose, sucrose, mannitol, calcium sulfate, and calcium hydrogen phosphate; and the filler is present in an amount of 10-40% by weight, relative to the weight of the corresponding sustained release component I or the site-specific release component II in the pharmaceutical formulation.

12. The pharmaceutical formulation according to claim 10, wherein the surfactant is one or more of ionic surfactants and nonionic surfactants; the ionic surfactant is stearic acid, sodium lauryl sulfate, lecithin, or amino acid; the nonionic surfactant is glyceryl monostearate, polysorbate, sorbitan fatty acid ester, or polyoxyethylene-polyoxypropylene copolymer; and the surfactant is present in an amount of 0.5%-10% by weight, relative to the weight of the corresponding sustained release component I or the site-specific release component II in the pharmaceutical formulation.

13. The pharmaceutical formulation according to claim 10, wherein the glidant is at least one selected from the group consisting of silica, talc, and micro powder silica gel; and the glidant is present in an amount of 0.1-5% by weight, relative to the weight of the corresponding sustained release component I or the site-specific release component II in the pharmaceutical formulation.

14. The pharmaceutical formulation according to claim 10, wherein the lubricant is one or more selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, polyethylene glycol 6000, sodium stearyl fumarate, talc, hydrogenated castor oil, and glyceryl behenate; and the lubricant is present in an amount of 0.1-5% by weight, relative to the weight of the corresponding sustained release component I or the site-specific release component II in the pharmaceutical formulation.

15. The pharmaceutical formulation according to claim 1, wherein the pharmaceutical formulation is a granule, powder, tablet, capsule, suspension, or pill.

16. The pharmaceutical formulation according to claim 1, wherein the sustained release component I comprises: A) 5-20% by weight of apremilast or a pharmaceutically acceptable salt or solvate thereof; B) a sustained release material, wherein the sustained release material is one or two selected from the group consisting of polyoxyethylene, hypromellose and hydroxypropyl cellulose; wherein the sustained release material is present in an amount of 6-60% by weight, relative to the weight of the corresponding sustained release component I in the pharmaceutical formulation, C) 10-40% by weight of a filler; D) 0.5-10% by weight of a surfactant; E) 0.1-5% by weight of a glidant; and F) 0.1-5% by weight of a lubricant.

17. The pharmaceutical formulation according to claim 1, wherein the site-specific release component II comprises: A) 5-20% by weight of apremilast or a pharmaceutically acceptable salt or solvate thereof; B) 10-40% by weight of a filler; C) 0.5-10% by weight of a surfactant; D) 0.1-5% by weight of a glidant; E) 0.1-5% by weight of a lubricant; and F) an enteric coating which is at least one selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and acrylic resin; wherein the enteric coating is present in an amount of 1-40% by weight, relative to the weight of the site-specific release component II.

18. The pharmaceutical formulation according to claim 17, wherein the site-specific release component II further comprises a sustained release material which is polyoxyethylene, hypromellose or hydroxypropyl cellulose; the sustained release material is present in an amount of 6-60% by weight, relative to the weight of the corresponding site-specific release component II in the pharmaceutical formulation.

19. The pharmaceutical formulation according to claim 18, wherein the weight ratio of the sustained release component I to the site-specific release component II is 1:8-8:1.

20. A sustained release formulation comprising apremilast, wherein the following dissolution profile is obtained: 10-20% by weight of apremilast is released after 2 hours, 30-60% by weight of apremilast is released after 4 hours, 85-96% by weight of apremilast is released after 8 hours, and 96-100% by weight of apremilast is released after 12 hours; when tested according to a paddle method of a dissolution test of Chinese Pharmacopoeia, wherein 900 mL of dissolution medium is used, the formulation is placed in a medium with pH 1.0 and tested for 2 hours, and then placed in a phosphate buffer solution with pH 6.8, and wherein a temperature of the dissolution medium is 370.5 C., a paddle speed is 75 rpm, and a UV spectrophotometer is used at 230 nm.

21. A pharmaceutical formulation according to claim 1, having the following dissolution profile: 10-20% by weight of apremilast is released after 2 hours, 30-60% by weight of apremilast is released after 4 hours, 85-96% by weight of apremilast is released after 8 hours, and 96-100% by weight of apremilast is released after 12 hours; when tested according to a paddle method of a dissolution test of Chinese Pharmacopoeia, wherein 900 mL of dissolution medium is used, the formulation is placed in a medium with pH 1.0 and tested for 2 hours, and then placed in a phosphate buffer solution with pH 6.8, and wherein a temperature of the dissolution medium is 370.5 C., a paddle speed is 75 rpm, and a UV spectrophotometer is used at 230 nm.

22. The pharmaceutical formulation according to claim 4, wherein the enteric coating is one or more selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and acrylic resin.

23. The pharmaceutical formulation according to claim 4, wherein the site-specific release coating is present in an amount of 2-30% by weight, relative to the weight of the site-specific release component II.

24. The pharmaceutical formulation according to claim 4, wherein the site-specific release coating is present in an amount of 2-20% by weight, relative to the weight of the site-specific release component II.

25. The pharmaceutical formulation according to claim 7, wherein the sustained release material is present in an amount of 10-50% by weight, relative to the weight of the corresponding sustained release component I or the site-specific release component II in the pharmaceutical formulation.

26. The pharmaceutical formulation according to claim 7, wherein the sustained release material is present in an amount of 15-45% by weight, relative to the weight of the corresponding sustained release component I or the site-specific release component II in the pharmaceutical formulation.

27. The pharmaceutical formulation according to claim 8, wherein the weight ratio of the sustained release component I to the site-specific release component II is 1:6-6:1.

28. The pharmaceutical formulation according to claim 8, wherein the weight ratio of the sustained release component I to the site-specific release component II is 1:5-4:1.

29. The pharmaceutical formulation according to claim 16, wherein the sustained release material is present in an amount of 10-50% by weight, relative to the weight of the corresponding sustained release component I in the pharmaceutical formulation.

30. The pharmaceutical formulation according to claim 16, wherein the sustained release material is present in an amount of 15-45% by weight, relative to the weight of the corresponding sustained release component I in the pharmaceutical formulation.

31. The pharmaceutical formulation according to claim 17, wherein the enteric coating is present in an amount of 2-30% by weight, relative to the weight of the site-specific release component II.

32. The pharmaceutical formulation according to claim 17, wherein the enteric coating is present in an amount of 2-20% by weight, relative to the weight of the site-specific release component II.

Description

DESCRIPTION OF THE DRAWINGS

[0042] FIG. 1 shows the dissolution profile of apremilast in embodiments G, I, and H.

[0043] FIG. 2 shows the dissolution profile of apremilast in embodiments J, I, and K.

DETAILED DESCRIPTION OF THE INVENTION

[0044] The invention is further illustrated in detail by the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the invention.

Example 1

[0045] Preparation of Sustained Release Component I

[0046] Apremilast, a filler, sustained release material, surfactant, glidant, and lubricant were mixed according to the ratio in Table 1, and then directly compressed into tablets using a powder direct tabletting technology. Dies with any diameters can be selected when tabletting, including any circular dies with a diameter from 2 mm to 6 mm. The tablet weight was from 10 mg to 100 mg.

TABLE-US-00002 TABLE 1 (6 mm circular die, each tablet weight of 100 mg) Formula A B C Dosage Ratio Dosage Ratio Dosage Ratio (mg) (%) (mg) (%) (mg) (%) Apremilast 15 15 15 15 15 15 Pregelatinized 10 10 10 10 30 30 starch Microcrystalline 30 30 30 30 30 30 cellulose HPMC-K100LV 40 40 / / / / Polyoxyethylene / / 40 40 20 20 1105 Sodium dodecyl 3 3 3 3 3 3 sulfate Silica 1 1 1 1 1 1 Magnesium 1 1 1 1 1 1 stearate Total Core 100 100 100 100 100 100

Example 2

[0047] Preparation of Site-Specific Release Component II

[0048] Apremilast, a filler, sustained release material, surfactant, glidant, and lubricant were mixed according to the ratio in Table 2, and then directly compressed into tablets using a powder direct tabletting technology. The compressed tablet was then coated with a highly effective coating agent. Dies with any diameters can be selected when tabletting, including any circular dies with a diameter from 2 mm to 6 mm. The tablet weight was from 10 mg to 100 mg.

TABLE-US-00003 TABLE 2 (6 mm circular die, each tablet weight of 100 mg) Formula D E F Dosage Ratio Dosage Ratio Dosage Ratio (mg) (%) (mg) (%) (mg) (%) Apremilast 15 15 15 15 15 15 Pregelatinized 30 10 10 10 30 30 starch Microcrystalline 30 30 30 30 30 30 cellulose HPMC-K100LV 20 20 / / / / Polyoxyethylene / / 10 10 / / 1105 Polyoxyethylene / / 30 30 40 40 N60K Sodium dodecyl 3 3 3 3 3 3 sulfate Silica 1 1 1 1 1 1 Magnesium 1 1 1 1 1 1 stearate Total core 100 100 100 100 100 100 Opadry 2 / 2 / 2 / 85F23718 Eudragit 10 / 10 / 10 / (L100-55)

Example 3

[0049] Preparation of Apremilast Sustained Release Formulation

[0050] The sustained release component I and the site-specific release component II were filed into 00# capsules according to different ratios to provide sustained release formulations with different dissolution profiles. The specific embodiments are shown in Table 3.

TABLE-US-00004 TABLE 3 Embodiment G H I J K Dosage Ratio Dosage Ratio Dosage Ratio Dosage Ratio Dosage Ratio Component (mg) (%) (mg) (%) (mg) (%) (mg) (%) (mg) (%) Formula A 400 80 / / / / / / / / Formula B / / 400 80 / / / / / / Formula C / / / / 400 80 300 60 300 60 Formula D 100 20 / / / / / / / / Formula E / / 100 20 / / / / 200 40 Formula F / / / / 100 20 200 40 / /

[0051] The in vitro dissolution rate of the apremilast sustained release capsules of embodiments G to K were tested according to the second method, i.e., paddle method of the dissolution test of Chinese Pharmacopoeia, wherein 900 mL of dissolution medium was used. Firstly, the formulation was placed in a medium with pH 1.0 and tested for 2 hours, and then placed in a phosphate buffer solution with pH 6.8 to determine the dissolution rate. The temperature of the dissolution medium was 370.5 C., and the paddle speed was 75 rpm. Samples were taken at 2, 4, 6, 8, and 12 hours and measured by a UV spectrophotometer at 230 nm. The results are shown in Table 4.

TABLE-US-00005 TABLE 4 Results of dissolution rate of different embodiments Dissolution Rate (%) Time (h) G H I J K 2 14.7 11.3 15.0 12.0 12.0 4 43.3 28.4 44.0 35.0 31.0 6 67.3 66.0 75.0 65.0 60.0 8 92.0 94.8 93.0 90.0 88.0 12 99.8 99.6 100.1 99.6 99.9

[0052] From the results shown in the above table, it can be seen that the apremilast sustained release formulation prepared according to the method of the present invention releases slowly within 2 hours, and can achieve the therapeutic effect while the side effects caused by excessive rapid release after oral administration are avoided. The release is moderate within 2-12 hours, which can ensure a constant plasma concentration and a lasting effect.