CONTROLLED-RELEASE TABLET OF IBUPROFEN AND METHOD FOR PREPARING SAME

Abstract

An ibuprofen controlled-release tablet and a method for preparing same are provided. The controlled-release tablet is composed of a drug-containing immediate-release layer and a drug-containing sustained-release layer, wherein a mass of ibuprofen in the drug-containing sustained-release layer is greater than a mass of ibuprofen in the drug-containing immediate-release layer, and a ratio of the mass of the ibuprofen in the drug-containing sustained-release layer to the mass of the ibuprofen in the drug-containing immediate-release layer is ≤7. The tablet of the present disclosure has an effective analgesic effect for 24 h after administration.

Claims

1. An ibuprofen controlled-release tablet, wherein the controlled-release tablet is composed of a drug-containing immediate-release layer and a drug-containing sustained-release layer, a mass of ibuprofen in the drug-containing sustained-release layer is greater than a mass of ibuprofen in the drug-containing immediate-release layer, and a ratio of the mass of the ibuprofen in the drug-containing sustained-release layer to the mass of the ibuprofen in the drug-containing immediate-release layer fails into a range of 2.2:1-7:1.

2. The ibuprofen controlled-release tablet according to claim 1, wherein the ratio of the mass of the ibuprofen in the drug-containing sustained-release layer to the mass of the ibuprofen in the drug-containing immediate-release layer falls into the range selected from 3:1-7:1, 4:1-7:1, 2.5-7:1, 6:1-7:1, 2.2:1-3:1, 2.2:1-4:1, 2.2:1-5:1, 2.2:1-6:1, 3:1-4:1, 4:1-5:1, and 5:1-6:1.

3. The ibuprofen controlled-release tablet according to claim 1, wherein a sustained-release polymer in the drug-containing sustained-release layer comprises xanthan gum, the xanthan gum takes 5-10 wt % the ibuprofen controlled-release tablet.

4. The ibuprofen controlled-release tablet according to claim 1, wherein the drug-containing immediate-release layer is composed of the following components: ibuprofen, a filler, an adhesive, a disintegrating agent, a lubricant, and a flow aid.

5. The ibuprofen controlled-release tablet according to claim 1, wherein calculated by the ibuprofen controlled-release tablet, the drug-containing immediate-release layer comprises 5.00-30.00 wt % of the ibuprofen and 0.50-5.00 wt % of a disintegrating agent.

6. The ibuprofen controlled-release tablet according to claim 3, wherein the drug-containing sustained-release layer is composed of the following components: ibuprofen, a sustained-release polymer, a filler, a lubricant, and a flow aid.

7. The ibuprofen controlled-release tablet according to according to claim 6, wherein calculated by the ibuprofen controlled-release tablet, the drug-containing sustained-release layer comprises 30.00-65.00 wt % of the ibuprofen and 5.00-25.00 wt % of the sustained-release polymer.

8. The ibuprofen controlled-release tablet according to claim 1, wherein a mass ratio of the drug-containing sustained-release layer to the drug-containing immediate-release layer is 5.6:1 to 1.66:1.

9. The ibuprofen controlled-release tablet according to claim 1, wherein the ibuprofen controlled-release tablet is oval or capsule-shaped; and the drug-containing immediate-release layer and the drug-containing sustained-release layer separately constitute an upper layer and a lower layer of the ibuprofen controlled-release tablet.

10. The ibuprofen controlled-release tablet according to claim 1, wherein the ibuprofen controlled-release tablet further comprises a tablet core layer wrapped between the drug-containing immediate-release layer and the drug-containing sustained-release layer; and the tablet core layer is an immediate-release tablet core layer or a sustained-release tablet core layer.

11. The ibuprofen controlled-release tablet according to claim 10, wherein when the tablet core layer is formed by the sustained-release tablet core layer, the tablet core layer is composed of the following components: the ibuprofen, a sustained-release polymer, a filler, a lubricant, a flow aid, and an enteric coating premix; and when the tablet core layer is the immediate-release tablet core layer, the tablet core layer is composed of the following components: the ibuprofen, the filler, an adhesive, a disintegrating agent, the lubricant, the flow aid, and the enteric coating premix.

12. The ibuprofen controlled-release tablet according to claim 11, wherein when the tablet core layer is the sustained-release tablet core layer, a ratio of a sum of the mass of the ibuprofen in the drug-containing sustained-release layer and a mass of the ibuprofen in the sustained-release tablet core layer to the mass of the ibuprofen in the drug-containing immediate-release layer is 2.2:1 to 7:1, 3:1 to 7:1, 4:1 to 7:1, 2.5 to 7:1, 6:1 to 7:1, 2.2:1 to 3:1, 2.2:1 to 4:1, 2.2:1 to 5:1, 2.2:1 to 6:1, 3:1 to 4:1, 4:1 to 5:1, or 5:1 to 6:1, and a ratio of the mass of the ibuprofen in the drug-containing sustained-release layer to the mass of the ibuprofen in the sustained-release tablet core layer is 27:1 to 3:1 or 19:1 to 4.6:1; when the tablet core layer is the immediate-release tablet core layer, a ratio of the mass of the ibuprofen in the drug-containing sustained-release layer to a sum of a mass of the ibuprofen in the immediate-release tablet core layer and the mass of the ibuprofen in the drug-containing immediate-release layer is 2.2:1 to 7:1, 3:1 to 7:1, 4:1 to 7:1, 2.5 to 7:1, 6:1 to 7:1, 2.2:1 to 3:1, 2.2:1 to 4:1, 2.2:1 to 5:1, 2.2:1 to 6:1, 3:1 to 4:1, 4:1 to 5:1, or 5:1 to 6:1, and a ratio of the mass of the ibuprofen in the drug-containing immediate-release layer to the mass of the ibuprofen in the immediate-release tablet core layer is 11:1 to 1:1 or 10:1 to 2:1.

13. The ibuprofen controlled-release tablet according to claim 10, wherein a filler in the drug-containing immediate-release layer, the drug-containing sustained-release layer, the immediate-release tablet core layer, and the sustained-release tablet core layer is independently selected from one or more of lactose, corn starch, pregelatinized starch, and microcrystalline cellulose.

14. The ibuprofen controlled-release tablet according to claim 10, wherein an adhesive in the drug-containing immediate-release layer and the immediate-release tablet core layer is independently selected from one or more of sodium carboxymethyl cellulose, polyvinyl pyrrolidone, hydroxypropylmethylcellulose (HPMC), and hydroxypropylcellulose (HPC).

15. The ibuprofen controlled-release tablet according to claim 10, wherein a disintegrating agent in the drug-containing immediate-release layer and the immediate-release tablet core layer is independently selected from one or more of cross-linked sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone (PVPP), and low-substituted hydroxypropyl cellulose (L-HPC).

16. The ibuprofen controlled-release tablet according to claim 10, wherein a lubricant in the drug-containing immediate-release layer, the drug-containing sustained-release layer, the immediate-release tablet core layer, and the sustained-release tablet core layer is independently selected from one or more of magnesium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, hydrogenated castor oil, and sodium dodecyl sulfate.

17. The ibuprofen controlled-release tablet according to claim 10, wherein a flow aid in the drug-containing immediate-release layer, the drug-containing sustained-release layer, the immediate-release tablet core layer, and the sustained-release tablet core layer is independently selected from colloidal silicon dioxide and talc powder.

18. The ibuprofen controlled-release tablet according to claim 10, wherein a sustained-release polymer in the drug-containing sustained-release layer and the sustained-release tablet core layer is a combination of hydroxypropylmethylcellulose and xanthan gum.

19. The ibuprofen controlled-release tablet according to claim 10, wherein an enteric coating premix in the immediate-release tablet core layer and the sustained-release tablet core layer is independently selected from one or more of a methacrylic acid copolymer, polyvinyl acetate phthalate, and Opadry.

20. The ibuprofen controlled-release tablet according to claim 18, wherein the hydroxypropylmethylcellulose in the sustained-release polymer is 1-25 wt % in the ibuprofen controlled-release tablet.

21. The ibuprofen controlled-release tablet according to claim 18, wherein the hydroxypropylmethylcellulose in the sustained-release polymer has a viscosity range of 3-2,000 mpa.Math.s.

22. The ibuprofen controlled-release tablet according to claim 18, wherein the hydroxypropylmethylcellulose in the sustained-release polymer of the ibuprofen controlled-release tablet is selected from one or more of E3LV, E5LV, E6LV, E15LV, E30LV, E50LV, K100LV, SH50, SH400, and SH1500.

23. A method for preparing the ibuprofen controlled-release tablet according to claim 1, comprising the following steps: a. weighing a formulation amount of the ibuprofen and a filler required to prepare the drug-containing immediate-release layer, performing a first wet granulation by using first purified water or a first alcohol solution, passing a first wet particle through a first 1,000-8,000 μm sieve, drying the first wet particle, passing a first dried particle through the first 1,000-8,000 μm sieve, adding an adhesive, a disintegrating agent, and a flow aid to a first sieved particle to obtain a first mixture, pre-mixing the first mixture, and then adding a lubricant to be mixed to prepare a drug-containing immediate-release layer particle for later use; b. weighing a formulation amount of the ibuprofen, a sustained-release polymer, and the filler required to prepare the drug-containing sustained-release layer, performing a second wet granulation by using second purified water or a second alcohol solution, passing a second wet particle through a second 1,000-8,000 μm sieve, drying the second wet particle, passing a second dried particle through the second 1,000-8,000 μm sieve, adding the flow aid to a second sieved particle to obtain a second mixture, pre-mixing the second mixture, and then adding the lubricant to be mixed to prepare a drug-containing sustained-release layer particle for later use; and d. placing a formulation amount of the drug-containing sustained-release layer particle into a punching die of a tablet machine for pre-pressing; and then placing a formulation amount of the drug-containing immediate-release layer particle into the punching die to be pressed into the ibuprofen controlled-release tablet.

24. The method according to claim 23, wherein in step d, a pre-pressure is 0.1-2 KN or 0.1-0.5 KN; and a main pressure is 5-60 KN or 10-50 KN.

25. A method for preparing the ibuprofen controlled-release tablet according to claim 10, comprising the following steps: a. weighing a formulation amount of the ibuprofen and a filler required to prepare the drug-containing immediate-release layer, performing a first wet granulation by using first purified water or a first alcohol solution, passing a first wet particle through a first 1,000-8,000 μm sieve, drying the first wet particle, passing a first dried particle through the first 1,000-8,000 μm sieve, adding an adhesive, a disintegrating agent, and a flow aid to a first sieved particle to obtain a first mixture, pre-mixing the first mixture, and then adding a lubricant to be mixed to prepare a drug-containing immediate-release layer particle for later use; b. weighing a formulation amount of the ibuprofen, a sustained-release polymer, and the filler required to prepare the drug-containing sustained-release layer, performing a second wet granulation by using second purified water or a second alcohol solution, passing a second wet particle through a second 1,000-8,000 μm sieve, drying the second wet particle, passing a second dried particle through the second 1,000-8,000 μm sieve, adding the flow aid to a second sieved particle to obtain a second mixture, pre-mixing the second mixture, and then adding the lubricant to be mixed to prepare a drug-containing sustained-release layer particle for later use; c. placing a part of the drug-containing immediate-release layer particle prepared in step a or a part of the drug-containing sustained-release layer particle prepared in step b into a punching die of a tablet machine to be pressed into a plain tablet core; e. weighing a formulation amount of an enteric coating premix and preparing the enteric coating premix into an enteric coating solution by using a third alcohol solution; and placing the plain tablet core pressed in step c in a coating machine and performing a coating by using the enteric coating solution to prepare a tablet core layer for later use; and f. placing a formulation amount of the drug-containing sustained-release layer particle into the punching die of the tablet machine, placing the tablet core layer on the drug-containing sustained-release layer particle for pre-pressing; and then placing a formulation amount of the drug-containing immediate-release layer particle into the punching die to be pressed into the ibuprofen controlled-release tablet.

26. The method according to claim 25, wherein in step f, a pre-pressure is 0.1-2 KN or 0.1-0.5 KN; and a main pressure is 5-60 KN or 10-50 KN.

27. A method for preparing the ibuprofen controlled-release tablet according to claim 1, comprising the following steps: a. weighing a formulation amount of the ibuprofen and a filler required to prepare the drug-containing immediate-release layer, performing a first wet granulation by using first purified water or a first alcohol solution, passing a first wet particle through a first 1,000-8,000 μm sieve, drying the first wet particle, passing a first dried particle through the first 1,000-8,000 μm sieve, adding an adhesive, a disintegrating agent, and a flow aid to a first sieved particle to obtain a first mixture, pre-mixing the first mixture, and then adding a lubricant to be mixed to prepare a drug-containing immediate-release layer particle for later use; b. weighing a formulation amount of the ibuprofen, a sustained-release polymer, and the filler required to prepare the drug-containing sustained-release layer, performing a second wet granulation by using second purified water or a second alcohol solution, passing a second wet particle through a second 1,000-8,000 μm sieve, drying the second wet particle, passing a second dried particle through the second 1,000-8,000 μm sieve, adding the flow aid to a second sieved particle to obtain a second mixture, pre-mixing the second mixture, and then adding the lubricant to be mixed to prepare a drug-containing sustained-release layer particle for later use; c. placing a part of the drug-containing immediate-release layer particle prepared in step a or a part of the drug-containing sustained-release layer particle prepared in step b into a punching die of a tablet machine to be pressed into a plain tablet core; e. weighing a formulation amount of an enteric coating premix and preparing the enteric coating premix into an enteric coating solution by using a third alcohol solution; and placing the plain tablet core pressed in step c in a coating machine and performing a coating by using the enteric coating solution to prepare a tablet core layer for later use; and f. placing a formulation amount of the drug-containing sustained-release layer particle into the punching die of the tablet machine, placing the tablet core layer on the drug-containing sustained-release layer particle for pre-pressing; and then placing a formulation amount of the drug-containing immediate-release layer particle into the punching die to be pressed into the ibuprofen controlled-release tablet.

28. The method according to claim 27, wherein in step f, a pre-pressure is 0.1-2 KN or 0.1-0.5 KN; and a main pressure is 5-60 KN or 10-50 KN.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0057] FIG. 1 is a structural diagram of the ibuprofen controlled-release tablet of the present application (not containing a tablet core);

[0058] FIG. 2 is a structural diagram of the ibuprofen controlled-release tablet of the present application (containing a tablet core);

[0059] FIG. 3 shows in-vitro dissolution curves of the ibuprofen controlled-release tablets in examples 1-5;

[0060] FIG. 4 shows in-vitro dissolution curves of the ibuprofen controlled-release tablets in examples 7-8;

[0061] FIG. 5 shows in-vitro dissolution curves of formulations I and II;

[0062] FIG. 6 shows in-vivo curves of the ibuprofen controlled-release tablets in examples 2 and 5;

[0063] FIG. 7 shows an in-vivo curve of the ibuprofen controlled-release tablet in example 7;

[0064] FIG. 8 shows in-vitro plasma concentration curves of example 2 and commercially-available ibuprofen products; and

[0065] FIG. 9 shows comparison of stable dissolution of formulations with different xanthan gum proportions.

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0066] The present disclosure will be further described below in detail via examples.

[0067] A dissolution condition used in the following examples are as follows: a paddle method+settling basket, 900 mL of a dissolution medium of a phosphate buffer solution at a pH of 7.2+2% SDS, a rotation speed of 200 rpm, and a solution temperature of 37° C.

Example 1 Preparation of 1,000 Ibuprofen Controlled-Release Tablets (not Containing Tablet Core)

[0068] Taking a preparation of 1,000 ibuprofen controlled-release tablets as an example, each component and dose are shown in the following table:

TABLE-US-00001 Tablet layer Formulation Mass (g) Immediate-release Ibuprofen 100.00 layer Pregelatinized starch 96.20 Cross-linked sodium carboxymethyl 31.20 starch Sodium carboxymethyl cellulose 18.81 Talc powder 2.50 Stearic acid 1.32 Sustained-release Ibuprofen 700.00 layer Xanthan gum 82.50 Hydroxypropylmethylcellulose 280.01 Microcrystalline cellulose 327.03 Colloidal silicon dioxide 3.50 Stearic acid 6.93

[0069] A method for preparing an ibuprofen controlled-release tablet in example 1 of the present disclosure comprised the following steps:

[0070] a. a formulation amount of 100.00 g of ibuprofen and 96.20 g of a filler required to prepare an immediate-release layer were weighed, wet granulation was performed by using purified water or an alcohol solution, a wet particle was passed through a 1,000-8,000 μm sieve and dried, the dried particle was passed through a 1,000-8,000 μm sieve, 18.81 g of an adhesive, 31.20 g of a disintegrating agent, and 2.50 g of a flow aid were added, the materials were pre-mixed, and then 1.32 g of a lubricant was added to be mixed to prepare an immediate-release layer particle for later use;

[0071] b. a formulation amount of 700.00 g of the ibuprofen, 362.51 g of a sustained-release polymer, and 327.03 g of the filler required to prepare a sustained-release layer were weighed, wet granulation was performed by using purified water or an alcohol solution, a wet particle was passed through a 1,000-8,000 μm sieve and dried, the dried particle was passed through a 1,000-8,000 μm sieve, 3.50 g of the flow aid was added, the materials were pre-mixed, and then 6.93 g of the lubricant was added to be mixed to prepare a sustained-release layer particle for later use; and

[0072] c. a formulation amount of the sustained-release layer particle was placed into a punching die of a tablet machine for pre-pressing at 0.5 KN; and then a formulation amount of the immediate-release layer particle was placed into the punching die to be pressed into a tablet at a main pressure of 10 KN.

Example 2 Preparation of 2,000 Ibuprofen Controlled-Release Tablets (not Containing Tablet Core)

[0073] Taking a preparation of 2,000 ibuprofen controlled-release tablets as an example, each component and dose are shown in the following table:

TABLE-US-00002 Tablet layer Formulation Mass (g) Immediate-release Ibuprofen 300.00 layer Pregelatinized starch 114.50 Microcrystalline cellulose 71.40 Cross-linked sodium carboxymethyl 60.00 cellulose Polyvinyl pyrrolidone K30 44.88 Colloidal silicon dioxide 6.12 Magnesium stearate 3.05 Sustained-release Ibuprofen 1300.00 layer Xanthan gum 178.50 Hydroxypropylmethylcellulose 292.50 Microcrystalline cellulose 164.50 Colloidal silicon dioxide 4.85 Magnesium stearate 9.70

[0074] A method for preparing an ibuprofen controlled-release tablet in example 2 of the present disclosure comprised the following steps:

[0075] a. a formulation amount of 300.00 g of ibuprofen and 185.90 g of a filler required to prepare an immediate-release layer were weighed, wet granulation was performed by using purified water or an alcohol solution, a wet particle was passed through a 1,000-8,000 μm sieve and dried, the dried particle was passed through a 1,000-8,000 μm sieve, 44.88 g of an adhesive, 60.00 g of a disintegrating agent, and 6.12 g of a flow aid were added, the materials were pre-mixed, and then 3.05 g of a lubricant was added to be mixed to prepare an immediate-release layer particle for later use;

[0076] b. a formulation amount of 1300.00 g of the ibuprofen, 471.00 g of a sustained-release polymer, and 164.50 g of the filler required to prepare a sustained-release layer were weighed, wet granulation was performed by using purified water or an alcohol solution, a wet particle was passed through a 1,000-8,000 μm sieve and dried, the dried particle was passed through a 1,000-8,000 μm sieve, 4.85 g of the flow aid was added, the materials were pre-mixed, and then 9.70 g of the lubricant was added to be mixed to prepare a sustained-release layer particle for later use; and

[0077] c. a formulation amount of the sustained-release layer particle was placed into a punching die of a tablet machine for pre-pressing at 0.4 KN; and then a formulation amount of the immediate-release layer particle was placed into the punching die to be pressed into a tablet at a main pressure of 20 KN.

Example 3 Preparation of 800 Ibuprofen Controlled-Release Tablets (not Containing Tablet Core)

[0078] Taking a preparation of 800 ibuprofen controlled-release tablets as an example, each component and dose are shown in the following table:

TABLE-US-00003 Tablet layer Formulation Mass (g) Immediate-release Ibuprofen 160.00 layer Microcrystalline cellulose 22.00 Corn starch 35.10 Cross-linked polyvinyl pyrrolidone 19.50 HPMC E4 19.50 Colloidal silicon dioxide 2.60 Sodium stearyl fumarate 1.30 Sustained-release Ibuprofen 480.00 layer Xanthan gum 75.50 Hydroxypropylmethylcellulose 68.40 Microcrystalline cellulose 55.00 Colloidal silicon dioxide 1.70 Hydrogenated castor oil 3.40

[0079] A method for preparing an ibuprofen controlled-release tablet in example 3 of the present disclosure comprised the following steps:

[0080] a. a formulation amount of 160.00 g of ibuprofen and 57.10 g of a filler required to prepare an immediate-release layer were weighed, wet granulation was performed by using purified water or an alcohol solution, a wet particle was passed through a 1,000-8,000 μm sieve and dried, the dried particle was passed through a 1,000-8,000 μm sieve, 19.50 g of an adhesive, 19.50 g of a disintegrating agent, and 2.60 g of a flow aid were added, the materials were pre-mixed, and then 1.30 g of a lubricant was added to be mixed to prepare an immediate-release layer particle for later use;

[0081] b. a formulation amount of 480.00 g of the ibuprofen, 143.90 g of a sustained-release polymer, and 55.00 g of the filler required to prepare a sustained-release layer were weighed, wet granulation was performed by using purified water or an alcohol solution, a wet particle was passed through a 1,000-8,000 μm sieve and dried, the dried particle was passed through a 1,000-8,000 μm sieve, 1.70 g of the flow aid was added, the materials were pre-mixed, and then 3.40 g of the lubricant was added to be mixed to prepare a sustained-release layer particle for later use; and

[0082] c. a formulation amount of the sustained-release layer particle was placed into a punching die of a tablet machine for pre-pressing at 0.4 KN; and then a formulation amount of the immediate-release layer particle was placed into the punching die to be pressed into a tablet at a main pressure of 20 KN.

Example 4 Preparation of 1,000 Ibuprofen Controlled-Release Tablets (not Containing Tablet Core)

[0083] Taking a preparation of 1,000 ibuprofen controlled-release tablets as an example, each component and dose are shown in the following table:

TABLE-US-00004 Tablet layer Formulation Mass (g) Immediate-release Ibuprofen 250.00 layer Lactose 51.00 Low-substituted hydroxypropyl cellulose 17.50 Hydroxypropylmethylcellulose E5 26.26 Colloidal silicon dioxide 3.50 Glyceryl behenate 1.74 Sustained-release Ibuprofen 550.00 layer Xanthan gum 108.50 Hydroxypropylmethylcellulose 17.14 Microcrystalline cellulose 53.82 Colloidal silicon dioxide 1.84 Magnesium stearate 3.70

[0084] A method for preparing an ibuprofen controlled-release tablet in example 4 of the present disclosure comprised the following steps:

[0085] a. a formulation amount of 250.00 g of ibuprofen and 51.00 g of a filler required to prepare an immediate-release layer were weighed, wet granulation was performed by using purified water or an alcohol solution, a wet particle was passed through a 1,000-8,000 μm sieve and dried, the dried particle was passed through a 1,000-8,000 μm sieve, 26.26 g of an adhesive, 17.50 g of a disintegrating agent, and 3.50 g of a flow aid were added, the materials were pre-mixed, and then 1.74 g of a lubricant was added to be mixed to prepare an immediate-release layer particle for later use;

[0086] b. a formulation amount of 550.00 g of the ibuprofen, 125.64 g of a sustained-release polymer, and 53.82 g of the filler required to prepare a sustained-release layer were weighed, wet granulation was performed by using purified water or an alcohol solution, a wet particle was passed through a 1,000-8,000 μm sieve and dried, the dried particle was passed through a 1,000-8,000 μm sieve, 1.84 g of the flow aid was added, the materials were pre-mixed, and then 3.70 g of the lubricant was added to be mixed to prepare a sustained-release layer particle for later use; and

[0087] c. a formulation amount of the sustained-release layer particle was placed into a punching die of a tablet machine for pre-pressing at 0.4 KN; and then a formulation amount of the immediate-release layer particle was placed into the punching die to be pressed into a tablet at a main pressure of 20 KN.

Example 5 Preparation of 500 Ibuprofen Controlled-Release Tablets (not Containing Tablet Core)

[0088] Taking a preparation of 500 ibuprofen controlled-release tablets as an example, each component and dose are shown in the following table:

TABLE-US-00005 Tablet layer Formulation Mass (g) Immediate-release Ibuprofen 150.00 layer Microcrystalline cellulose 15.96 Cross-linked sodium carboxymethyl 4.69 cellulose Hydroxypropyl cellulose 14.07 Talc powder 1.89 Sodium dodecyl sulfate 0.90 Sustained-release Ibuprofen 250.00 layer Xanthan gum 56.10 Hydroxypropylmethylcellulose 5.10 Microcrystalline cellulose 8.87 Colloidal silicon dioxide 0.80 Magnesium stearate 1.62

[0089] A method for preparing an ibuprofen controlled-release tablet in example 5 of the present disclosure comprised the following steps:

[0090] a. a formulation amount of 150.00 g of ibuprofen and 15.96 g of a filler required to prepare an immediate-release layer were weighed, wet granulation was performed by using purified water or an alcohol solution, a wet particle was passed through a 1,000-8,000 μm sieve and dried, the dried particle was passed through a 1,000-8,000 μm sieve, 14.07 g of an adhesive, 4.69 g of a disintegrating agent, and 1.89 g of a flow aid were added, the materials were pre-mixed, and then 0.90 g of a lubricant was added to be mixed to prepare an immediate-release layer particle for later use;

[0091] b. a formulation amount of 250.00 g of the ibuprofen, 61.20 g of a sustained-release polymer, and 8.87 g of the filler required to prepare a sustained-release layer were weighed, wet granulation was performed by using purified water or an alcohol solution, a wet particle was passed through a 1,000-8,000 μm sieve and dried, the dried particle was passed through a 1,000-8,000 μm sieve, 0.80 g of the flow aid was added, the materials were pre-mixed, and then 1.62 g of the lubricant was added to be mixed to prepare a sustained-release layer particle for later use; and

[0092] c. a formulation amount of the sustained-release layer particle was placed into a punching die of a tablet machine for pre-pressing at 0.4 KN; and then a formulation amount of the immediate-release layer particle was placed into the punching die to be pressed into a tablet at a main pressure of 20 KN.

Example 6 Preparation of 500 Ibuprofen Controlled-Release Tablets (not Containing Tablet Core)

[0093] Taking a preparation of 500 ibuprofen controlled-release tablets as an example, each component and dose are shown in the following table:

TABLE-US-00006 Tablet layer Formulation Mass (g) Immediate-release Ibuprofen 75.00 layer Pregelatinized starch 28.62 Microcrystalline cellulose 17.85 Cross-linked sodium carboxymethyl 14.98 cellulose Polyvinyl pyrrolidone K30 11.22 Colloidal silicon dioxide 1.54 Magnesium stearate 0.78 Sustained-release Ibuprofen 325.00 layer Xanthan gum 76.50 Hydroxypropylmethylcellulose 73.13 Microcrystalline cellulose 9.24 Colloidal silicon dioxide 1.22 Magnesium stearate 2.42

[0094] A method for preparing an ibuprofen controlled-release tablet in example 6 of the present disclosure comprised the following steps:

[0095] a. a formulation amount of 75.00 g of ibuprofen and 46.47 g of a filler required to prepare an immediate-release layer were weighed, wet granulation was performed by using purified water or an alcohol solution, a wet particle was passed through a 1,000-8,000 μm sieve and dried, the dried particle was passed through a 1,000-8,000 μm sieve, 11.22 g of an adhesive, 14.98 g of a disintegrating agent, and 1.54 g of a flow aid were added, the materials were pre-mixed, and then 0.78 g of a lubricant was added to be mixed to prepare an immediate-release layer particle for later use;

[0096] b. a formulation amount of 325.00 g of the ibuprofen, 149.63 g of a sustained-release polymer, and 9.27 g of the filler required to prepare a sustained-release layer were weighed, wet granulation was performed by using purified water or an alcohol solution, a wet particle was passed through a 1,000-8,000 μm sieve and dried, the dried particle was passed through a 1,000-8,000 μm sieve, 1.22 g of the flow aid was added, the materials were pre-mixed, and then 2.42 g of the lubricant was added to be mixed to prepare a sustained-release layer particle for later use; and

[0097] c. a formulation amount of the sustained-release layer particle was placed into a punching die of a tablet machine for pre-pressing at 0.4 KN; and then a formulation amount of the immediate-release layer particle was placed into the punching die to be pressed into a tablet at a main pressure of 20 KN.

[0098] A structure diagram of the tablets in examples 1-5 are shown in FIG. 1. An in-vitro release of the ibuprofen controlled-release tablets in examples 1-5 and a fasting plasma concentration of the ibuprofen controlled-release tablets in examples 2 and 5 were detected by the aforementioned dissolution method. The results are shown in FIG. 3 and FIG. 6 respectively.

[0099] The plasma concentrations of the tablets of examples 1˜4 can all reach 5.0 μg/mL within 1-24 h, all higher than 4.0 μg/mL. The plasma concentration of the tablet of example 5 at 24 h is only 3.25 μg/mL, and thus a 24 h long-term analgesic effect cannot be achieved.

Example 7 Preparation of 1,000 Ibuprofen Controlled-Release Tablets (Containing Tablet Core)

[0100] Taking a preparation of 1,000 ibuprofen controlled-release tablets as an example, each component and dose are shown in the following table:

TABLE-US-00007 Tablet layer Formulation Mass (g) Immediate-release Ibuprofen 100.00 layer Corn starch 59.12 Microcrystalline cellulose 37.02 Cross-linked sodium carboxymethyl starch 31.25 Sodium carboxymethyl cellulose 18.76 Colloidal silicon dioxide 2.50 Magnesium stearate 1.33 Sustained- Ibuprofen 50.00 release tablet Xanthan gum 5.98 core layer Hydroxypropylmethylcellulose 19.92 Microcrystalline cellulose 23.45 Colloidal silicon dioxide 0.20 Magnesium stearate 0.50 Enteric coating premix 9.96 Sustained-release Ibuprofen 650.00 layer Xanthan gum 76.70 Hydroxypropylmethylcellulose 260.00 Microcrystalline cellulose 303.65 Colloidal silicon dioxide 3.16 Magnesium stearate 6.50

[0101] A method for preparing an ibuprofen controlled-release tablet in example 7 of the present disclosure comprised the following steps:

[0102] a. a formulation amount of 100.00 g of ibuprofen and 96.14 g of a filler required to prepare an immediate-release layer were weighed, wet granulation was performed by using purified water or an alcohol solution, a wet particle was passed through a 1,000-8,000 μm sieve and dried, the dried particle was passed through a 1,000-8,000 μm sieve, 18.76 g of an adhesive, 31.25 g of a disintegrating agent, and 2.50 g of a flow aid were added, the materials were pre-mixed, and then 1.33 g of a lubricant was added to be mixed to prepare an immediate-release layer particle for later use;

[0103] b. a formulation amount of 50.00 g of the ibuprofen, 25.90 g of a sustained-release polymer, and 23.45 g of the filler required to prepare a sustained-release tablet core layer were weighed, wet granulation was performed by using purified water or an alcohol solution, a wet particle was passed through a 1,000-8,000 μm sieve and dried, the dried particle was passed through a 1,000-8,000 μm sieve, 0.20 g of the flow aid was added, the materials were pre-mixed, and then 0.50 g of the lubricant was added to be mixed to prepare a sustained-release layer particle for later use;

[0104] c. a formulation amount of 650.00 g of the ibuprofen, 336.70 g of a sustained-release polymer, and 303.65 g of the filler required to prepare a sustained-release layer were weighed, wet granulation was performed by using purified water or an alcohol solution, a wet particle was passed through a 1,000-8,000 μm sieve and dried, the dried particle was passed through a 1,000-8,000 μm sieve, 3.16 g of the flow aid was added, the materials were pre-mixed, and then 6.50 g of the lubricant was added to be mixed to prepare a sustained-release layer particle for later use;

[0105] d. the prepared sustained-release tablet core layer particle was placed into a punching die of a tablet machine to be pressed into a plain tablet core;

[0106] e. a formulation amount of 9.96 g of the enteric coating premix was weighed and prepared into an enteric coating solution with a solid content of 9.9% by using a 95% alcohol solution; and the plain tablet core pressed in step d was placed in a coating machine to be coated with the prepared enteric coating solution to prepare a tablet core layer for later use; and

[0107] f. a formulation amount of the sustained-release layer particle was placed into the punching die of the tablet machine and the tablet core layer was placed on the sustained-release layer for pre-pressing at 0.5 KN; and then a formulation amount of the immediate-release layer particle was placed into the punching die to be pressed into a tablet at a main pressure of 10 KN.

Example 8 Preparation of 800 Ibuprofen Controlled-Release Tablets (Containing Tablet Core)

[0108] Taking a preparation of 800 ibuprofen controlled-release tablets as an example, each component and dose are shown in the following table:

TABLE-US-00008 Tablet layer Formulation Mass (g) Immediate-release Ibuprofen 120.00 layer Microcrystalline cellulose 85.32 Cross-linked sodium carboxymethyl starch 5.82 Polyvinyl pyrrolidone K30 17.28 Colloidal silicon dioxide 2.36 Magnesium stearate 1.18 Immediate- Ibuprofen 80.00 release tablet Microcrystalline cellulose 8.46 core layer Cross-linked sodium carboxymethyl starch 2.46 Polyvinyl pyrrolidone K30 7.55 Magnesium stearate 1.00 Magnesium stearate 0.45 Enteric coating premix 9.64 Sustained-release Ibuprofen 440.00 layer Xanthan gum 89.87 Hydroxypropylmethylcellulose 14.20 Microcrystalline cellulose 19.37 Colloidal silicon dioxide 1.46 Magnesium stearate 3.18

[0109] A method for preparing ibuprofen controlled-release tablets in example 8 of the present disclosure comprised the following steps:

[0110] a. a formulation amount of 120.00 g of ibuprofen and 85.32 g of a filler required to prepare an immediate-release layer were weighed, wet granulation was performed by using purified water or an alcohol solution, a wet particle was passed through a 1,000-8,000 μm sieve and dried, the dried particle was passed through a 1,000-8,000 μm sieve, 17.28 g of an adhesive, 5.82 g of a disintegrating agent, and 2.36 g of a flow aid were added, the materials were pre-mixed, and then 1.18 g of a lubricant was added to be mixed to prepare an immediate-release layer particle for later use;

[0111] b. a formulation amount of 80.00 g of ibuprofen and 8.46 g of a filler required to prepare an immediate-release tablet core layer were weighed, wet granulation was performed by using purified water or an alcohol solution, a wet particle was passed through a 1,000-8,000 μm sieve and dried, the dried particle was passed through a 1,000-8,000 μm sieve, 7.55 g of an adhesive, 2.46 g of a disintegrating agent, and 1.00 g of a flow aid were added, the materials were pre-mixed, and then 0.45 g of a lubricant was added to be mixed to prepare an immediate-release tablet core layer particle for later use;

[0112] c. a formulation amount of 440.00 g of the ibuprofen, 104.07 g of a sustained-release polymer, and 19.37 g of the filler required to prepare a sustained-release layer were weighed, wet granulation was performed by using purified water or an alcohol solution, a wet particle was passed through a 1,000-8,000 μm sieve and dried, the dried particle was passed through a 1,000-8,000 μm sieve, 1.46 g of the flow aid was added, the materials were pre-mixed, and then 3.18 g of the lubricant was added to be mixed to prepare a sustained-release layer particle for later use;

[0113] d. the prepared immediate-release tablet core layer particle was placed into a punching die of a tablet machine to be pressed into a plain tablet core;

[0114] e. a formulation amount of 9.64 g of the enteric coating premix was weighed and prepared into an enteric coating solution with a solid content of 9.9% by using a 95% alcohol solution; and the plain tablet core pressed in step d was placed in a coating machine to be coated with the prepared enteric coating solution to prepare a tablet core layer for later use; and

[0115] f. a formulation amount of the sustained-release layer particle was placed into the punching die of the tablet machine and the tablet core layer was placed on the sustained-release layer for pre-pressing at 0.1 KN; and then a formulation amount of the immediate-release layer particle was placed into the punching die to be pressed into a tablet at a main pressure of 50 KN.

[0116] A structure diagram of the tablet prepared by the method is shown in FIG. 2. In-vitro dissolution data of the tablets of example 7-8 and in-vivo data of the tablet of example 7 are shown in FIG. 4 and FIG. 7 respectively.

[0117] The present example verified in-vivo plasma concentrations of different formulations (example 2, example 3, and commercially available products). Basic information of the commercially available products is shown in the following table:

TABLE-US-00009 Trade name Factory Batch No. Specification remarks Advil Pfizer Consumer Healthcare, L50926 Immediate-release 200 mg a division of Pfizer Canada Inc Advil ®12 Hour Pfizer Consumer Healthcare, W61840 Immediate-release 200 mg + a division of Pfizer Canada Inc Sustained-release 400 mg Brufen ®Retard Mylan Products Ltd. 85068PC Sustained-release 800 mg IBU ™ Dr. Reddy's Laboratories LA LLC. L700164 Immediate-release 800 mg

[0118] At present, ibuprofen on the market is divided into two types, an immediate-release type (Advil, IBU™) and a sustained-release type (Brufen® Retard). The immediate-release dosage releases rapidly. But since the ibuprofen has a short half-life period (t.sub.1/2 about 2 h), the drug is quickly eliminated in the body, such that the drug efficacy cannot be sustained and a patient needs to be administered many times. At present, the sustained-release dosage on the market can take effect continuously for a certain period of time, reduce the number of times of administration, and improve compliance of a patient, but the drug cannot take effect quickly after the administration and cannot rapidly reduce pain of the patient. An only immediate-release and sustained-release preparation (Advil® 12 Hour) on the current market can take effect quickly after the administration, but cannot be continuously effective for 24 h. and still needs to be administered 2 times a day.

[0119] Test results are shown in FIG. 8. It can be seen that the plasma concentration of the tablet of example 2 within 0-4 h was higher than that commercially available preparations of Advil, Advil® 12 Hour, and Brufen® Retard, and the tablet of example 2 can take effect quickly. The plasma concentration of the tablet of example 2 within 12-24 h is all higher than that of 800 mg of an immediate-release tablet IBU™ and effective time is prolonged from 12 h to 24 h.

Example 10

[0120] The present example verified a stable dissolution of formulations with different xanthan gum proportions (examples 2 and 6). The results are shown in FIG. 9. It can be seen that when the proportion of the xanthan gum in the formulation is greater than 10%, a dissolution rate in vitro will increase significantly after an accelerated stability test of the tablet for a period of time.

[0121] Hardness and fragility of the controlled-release tablets with different xanthan gum proportions (examples 2, 4, and 5) were detected. The results are shown in the following table:

TABLE-US-00010 Xanthan gum Hardness Fragility Cracked Example proportion N % or not Example 2  7% 150-230 0.02 No Example 4 10% 120-170 0.09 No Example 5 11%  70-100 0.12 Yes

[0122] It can be seen that when the proportion of the xanthan gum in the formulation was greater than 10%, the hardness is low and the fragility is non-conformity (the tablet is cracked).

[0123] In conclusion, when the proportion of the xanthan gum in the formulation was greater than 10%, a plasma concentration cannot reach an analgesic effect (fasting plasma drug test data in example 5) and the formulation was not suitable for mass production.

Example 11

[0124] The present example verified effects of formulations I and II of a combination of an immediate-release layer and a sustained-release layer. Specific compositions of the formulations I and II are as follows:

TABLE-US-00011 Tablet layer/ proportion Specification/tablet weight/formulation Formulation I Formulation II Immediate-release Specification 200 mg 200 mg layer Tablet weight 400 mg 400 mg Ibuprofen 20.00%  20.00%  Filler (microcrystalline cellulose) 14.40%  14.40%  Disintegrating agent (cross-linked sodium 2.00% 2.00% carboxymethyl cellulose) Adhesive (polyvinyl pyrrolidone K30) 3.00% 3.00% Flow aid (colloidal silicon dioxide) 0.20% 0.40% Lubricant (magnesium stearate) 0.40% 0.20% Sustained-release Specification 400 mg 400 mg layer Tablet weight 600 mg 600 mg Ibuprofen 40.00%  40.00%  Sustained-release polymer (HPMC-K100LV) 12.00%  / Sustained-release polymer (HPMC-K100M) / 18.00   Filler (microcrystalline cellulose) 6.00% / Flow aid (colloidal silicon dioxide) 1.40% 1.40% Lubricant (magnesium stearate) 0.60% 0.60%

[0125] In the formulation I, the sustained-release polymer is HPMC-K100LV with a content of 12% and a ratio of ibuprofen in a sustained-release layer to that in an immediate-release layer is 2. An in-vitro dissolution test was performed. Results are shown in FIG. 5. It can be seen that the drug in the sustained-release layer of the formulation I was completely released within 12 h and thus a long-acting analgesic effect within 24 h cannot be realized.

[0126] In the formulation II, the sustained-release polymer is HPMC-K100M with a content of 18% and a ratio of the ibuprofen in the sustained-release layer to that in an immediate-release layer is 2. An in-vitro dissolution test was performed. Results are shown in FIG. 5. It can be seen that although the formulation II continuously released for 24 h, but a release dissolution rate was only 66%. The release was incomplete, an ideal plasma concentration cannot be realized, namely the long-acting analgesic effect cannot be realized.