Controlled-release tablets of loxoprofen sodium, their preparation and use

Abstract

The present invention belongs to the technical field of pharmaceutical formulations, specifically relates to a controlled-release tablet of loxoprofen sodium, its preparation method, and use. The controlled-release tablet comprises a drug-containing immediate-release layer, a drug-containing core layer, and a drug-containing sustained-release layer, the drug-containing core layer comprising a plain tablet core, an enteric coating film, and a sealing coating film. The preparation method includes granulating the raw materials for the drug-containing immediate-release layer and the drug-containing sustained-release layer, respectively, wet granulating the raw materials for the plain tablet core and compressing them into tablets, followed by sequentially applying a first sealing coating, a second enteric coating, and a third sealing coating to obtain a drug-containing core, placing the drug-containing core on the drug-containing sustained-release layer granules and pre-compressing them, and then placing the drug-containing immediate-release layer granules on the pre-compressed tablet, compressing them, and coating them to obtain the drug-containing core. The present invention achieves the sustained-release effect of the loxoprofen sodium tablet core by designing the single-layer structure, raw materials, and coating layer components of the dry-coated tablet, thereby achieving 12-hour in vivo efficacy and improving patient compliance.

Description

[Technical Field]

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a controlled-release tablet of loxoprofen sodium, its preparation method and use. [Background technology]

[0002] Loxoprofen sodium tablets were first developed by Sankyo Co., Ltd. and launched in Japan in July 1986 under the trade name "Loxonin®." With a dosage of 60 mg, they are one of Japan's top-selling nonsteroidal anti-inflammatory drugs. This drug was first launched in China in 2003 under the trade name "Lexonin®." Compared with clinically similar drugs, loxoprofen sodium has the advantages of a rapid onset of action, a stronger analgesic effect, and a wider range of applications in the treatment of painful conditions.

[0003] Research has shown that the side effects of nonsteroidal anti-inflammatory drugs, such as allergic reactions, bleeding, and kidney damage, are related to the exposure of the unchanged drug or its metabolites in plasma.Generally available loxoprofen sodium preparations must be taken three times a day, which leads to relatively poor patient compliance.At the same time, general preparations are released too quickly in the body, resulting in too high short-term exposure of the unchanged drug or its metabolites in plasma, resulting in unstable blood concentrations and increased drug side effects.

[0004] Chinese patent application CN105168167A discloses an osmotic pump controlled-release tablet containing loxoprofen sodium, which is an osmotic pump formulation comprising a core and a semipermeable membrane with drug release holes, and which can reduce the number of administrations and improve patient compliance, but which needs further improvement in terms of onset speed and efficacy, etc.

[0005] Chinese patent application CN102525989A discloses a skeletal sustained-release tablet of loxoprofen sodium with a regulating layer, which can release stably for 8 hours and has an ideal release effect, but its daily administration frequency and effective duration need to be further improved.

[0006] Chinese Patent Application CN105769773A discloses sustained-release microspheres of loxoprofen sodium, which are composed of three parts: a drug-loaded core, an isolation layer surrounded by the drug-loaded core, and a sustained-release layer surrounded by the isolation layer. The weight ratio of the drug-loaded core, isolation layer, and sustained-release layer is 80:1 to 15:2 to 20. The present invention relates to sustained-release microspheres of loxoprofen sodium, and the combined effects of the concentration of a pH adjuster in the acidic isolation layer, the coating weight of the isolation layer, and the coating weight of the sustained-release layer slow the release rate of the microspheres in vitro and reduce the sudden release phenomenon of loxoprofen sodium. However, the operation to achieve the sustained-release effect is complicated, and the microspheres do not take effect quickly enough to achieve a rapid analgesic effect. DISCLOSURE OF THE INVENTION

[0007] Detailed Description of the Invention In response to the shortcomings of existing technologies, the present invention provides a controlled-release tablet of loxoprofen sodium and a manufacturing method thereof, which utilizes the design of dry-coated tablets to optimize the structure of the dry-coated tablets, creatively designs and adjusts the coating formula, and simultaneously optimizes the dose distribution of immediate release and sustained release, combining the properties of immediate release and sustained release, thereby enabling the tablet to quickly exert its effect after administration to the patient, and also maintain long-term efficacy by stably controlling the drug release, thereby stabilizing blood concentration.

[0008] The object of the present invention is achieved by the following technical means. The controlled-release tablet of ibuprofen sodium comprises a drug-containing immediate-release layer, a drug-containing core layer and a drug-containing sustained-release layer, the drug-containing core layer comprising a plain tablet core, an enteric coating film and a sealing coating film, and the enteric coating film is not in direct contact with the core, the drug-containing immediate-release layer and the drug-containing sustained-release layer. Preferably, the enteric coating film is in direct contact only with the sealing coating film, and the exterior of the plain tablet core in the drug-containing core layer is in the order of sealing coating film 1, enteric coating film, and sealing coating film 2 from the inside to the outside.

[0009] Preferably, the raw materials of the sealing coating film include one or more sealing coating materials selected from the group consisting of hypromellose, hydroxypropyl cellulose, ethyl cellulose, and polyvinyl alcohol, the content of the sealing coating material in the sealing coating film is 5 to 20%, and the coating weight gain of the sealing coating film is 2 to 10%.

[0010] Preferably, the raw materials for the enteric coating film include an enteric coating material selected from the group consisting of methacrylic acid, acrylates, methacrylates, polymethacrylic acid, polymethacrylic acid esters, methacrylic acid amino ethyl trimesoyl chloride, and polyvinyl acetate phthalate, the content of the enteric coating material in the enteric coating film is 5-35%, and the coating weight gain of the enteric coating film is 5-30%. Preferably, the enteric coating material is a mixture of methacrylic acid and ethyl acrylate in a mass ratio of 1:1, and the coating weight gain is 15-25%, or the enteric coating material is a mixture of methacrylic acid and methyl methacrylate in a mass ratio of 1:2, and the coating weight gain is 6-30%.

[0011] Preferably, the raw materials for the enteric coating film also contain additives, and the additives include a plasticizer and an anti-blocking agent in a mass ratio of 0.25 to 5: 1, preferably a mass ratio of 0.25 to 4: 1. The raw materials for the sealing coating film also contain a plasticizer.

[0012] Preferably, the plasticizer is one or more selected from the group consisting of triethyl citrate, polyethylene glycol 6000, tributyl citrate, and dibutyl sebacate.

[0013] The anti-tack agent is at least one selected from the group consisting of talc, magnesium stearate, and glycerin monostearate.

[0014] Preferably, the raw materials for the plain tablet core include a filler of loxoprofen sodium, a disintegrant, and a lubricant, preferably 20 to 65 parts of loxoprofen sodium, 30 to 70 parts of a filler, 1 to 5 parts of a disintegrant, and 1 to 5 parts of a lubricant.

[0015] Preferably, the raw materials of the drug-containing immediate-release layer include loxoprofen sodium, a filler, a binder, a disintegrant, and a lubricant, and preferably include 5 to 25 parts of loxoprofen sodium, 50 to 80 parts of a filler, 4 to 10 parts of a binder, 2 to 8 parts of a disintegrant, and 0.5 to 8 parts of a lubricant.

[0016] Preferably, the raw materials of the drug-containing sustained-release layer include loxoprofen sodium, a sustained-release polymer, a filler, a binder, and a lubricant, and more preferably contain 10 to 35 parts of loxoprofen sodium, 5 to 60 parts of sustained-release polymer, 25 to 40 parts of filler, 5 to 15 parts of binder, and 0.5 to 8 parts of lubricant.

[0017] Preferably, the sustained release polymer is one or more selected from the group consisting of hydroxypropyl methylcellulose and polysaccharide gums.

[0018] Preferably, the hydroxypropyl methylcellulose is one or more selected from the group consisting of E30LV, E50LV, K100LV, K4M, K15M and K100M.

[0019] Preferably, the polysaccharide gum is one or more selected from the group consisting of sodium alginate, gum arabic, xanthan gum, and locust bean gum.

[0020] Preferably, the sustained-release polymer is 5 to 60% of the sustained-release layer, preferably 7.5 to 40%.

[0021] Preferably, the binder is one or more selected from the group consisting of sodium carboxymethylcellulose, povidone and hydroxypropylmethylcellulose, preferably povidone.

[0022] Preferably, the disintegrant is one or more selected from the group consisting of crosscarboxymethyl starch sodium, croscarmellose sodium, crospovidone PVPP, and low-substituted hydroxypropyl cellulose L-HPC, preferably crosscarboxymethyl starch sodium or croscarmellose sodium.

[0023] Preferably, the filler is one or more selected from the group consisting of lactose, corn starch, pregelatinized starch and microcrystalline cellulose, preferably lactose, pregelatinized starch or microcrystalline cellulose.

[0024] Preferably, the lubricant is one or more selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, hydrogenated castor oil and sodium lauryl sulfate, preferably magnesium stearate or stearic acid.

[0025] Preferably, the ratio of the mass of the drug-containing sustained-release layer to the mass of the drug-containing core is 12.5 to 1:1, more preferably 5 to 1:1, in parts by weight. Preferably, the ratio of the mass of the drug-containing immediate-release layer to the mass of the drug-containing core is 10 to 1:1, preferably 5 to 1:1.

[0026] Another object of the present invention provides a method for preparing the above controlled-release tablet, comprising the steps of: (1) Wet granulating the raw materials for the drug-containing immediate-release layer to obtain drug-containing immediate-release layer granules; (2) wet granulating the raw materials for the drug-containing sustained-release layer to obtain drug-containing sustained-release layer granules; (3) The raw materials for the plain tablet core are wet granulated and compressed into tablets, followed by a first sealing coating layer, a second enteric coating layer, and a third sealing coating layer, to obtain the drug-containing core. (4) The drug-containing core is placed on the drug-containing sustained-release layer granules and pre-pressed to form a tablet, and then the drug-containing immediate-release layer granules are placed on the pre-pressed tablet, pressed, and coated to form a tablet.

[0027] Preferably, in the wet granulation step described in step (1) or (2), the binder is dissolved in water or an ethanol solution, and then the other raw materials except the lubricant are added and wet granulated. The wet whole granules are passed through a sieve with openings of 1000 to 8000 μm and dried. The dried whole granules are passed through a sieve with openings of 1000 to 8000 μm, and the lubricant is added and mixed.

[0028] Preferably, the pre-compression tableting pressure described in step (4) is 0.1 to 2 KN, more preferably 0.1 to 0.5 KN. The tableting pressure is 5 to 25 KN, more preferably 8 to 20 KN.

[0029] Preferably, the coating solution for the first and third sealing coating layers in step (3) is prepared by adding water and stirring to form a vortex, then adding the sealing coating film material to the water and stirring, then adding a plasticizer and stirring for 45 minutes or more. The coating solution required for the second enteric coating layer is prepared by first adding additives to an aqueous solution or a 70% to 95% ethanol solution, and stirring for 8 to 15 minutes at 8,000 to 11,000 revolutions per minute using a high-shear mixer to obtain A. A is then added to the enteric coating material, stirred for 0.3 to 0.8 hours, and then passed through a sieve with openings of 50 to 200 μm.

[0030] Preferably, the dissolution rate of loxoprofen sodium in the controlled-release tablet after 2 hours is 20 to 55%, and the dissolution rate after 10 hours is 80 to 100%.

[0031] Another object of the present invention is to provide a use of the above-mentioned controlled-release loxoprofen sodium tablet or the controlled-release tablet produced by the production method in the manufacture of a medicament for a painful disease.

[0032] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) There is currently no enteric-coated formulation for loxoprofen sodium. Research has shown that loxoprofen sodium is a strong base, weak acid salt, and when dissolved in water, OH - It has been found that the generation of ions increases the local pH, destroying the enteric coating film, causing the core API to be released through the enteric coating film, and the sustained release effect of the core cannot be achieved.The present invention separates the enteric coating film into a specific sealing coating film, and synergistically protects the stability of the enteric coating film through a specific coating sequence process, coating material, coating weight increase, etc., and achieves the sustained release effect by releasing at a specific site. (2) By designing the single-layer structure of the dry-coated tablet, the components of each coating film, and the structure of the controlled-release tablet, the present invention achieves a sustained-release effect for the loxoprofen sodium tablet core, achieving 12 hours of in vivo effectiveness and improving patient compliance.On the other hand, with commercially available coating films, after the core coating is pressed into the dry-coated tablet, the pressed shell applies pressure to the coated core, causing the coating film to break under the force, resulting in premature release of the core and failing to achieve the sustained-release effect of the core. (3) Through multiple experiments, the present invention creatively blends suitable raw materials for the enteric coating film and sealing coating film of the present invention, and at the same time, by combining it with a unique single-layer design, it is possible to achieve the expected drug release effect.

[0033] Term definition Coating Weight Gain, the term "coating weight gain" in the context of the present invention means the ratio of the weight of the coating material to the weight of the tablet before coating. [Brief explanation of the drawings]

[0034] [Figure 1] FIG. 1 shows the dissolution curve of Example 4. [Figure 2] Figure 2 shows the dissolution curve of Example 5. [Figure 3] Figure 3 shows the dissolution curve of Example 6. [Figure 4] FIG. 4 shows the dissolution curves of Example 2 and Comparative Example 1. [Figure 5] FIG. 5 shows the dissolution curves of Example 2 and Comparative Example 2. [Figure 6] FIG. 6 shows the dissolution curves of Example 1 and Comparative Example 3. [Figure 7] FIG. 7 shows the dissolution curves of Example 3 and Comparative Example 4. [Figure 8] FIG. 8 shows the dissolution curves of Example 1 and Comparative Example 5. [Figure 9] FIG. 9 shows the dissolution curves of Example 3 and Comparative Example 6. [Figure 10] FIG. 10 shows the dissolution curves of Example 1 and Comparative Example 9. [Figure 11] FIG. 11 shows the dissolution curves of Example 2 and Comparative Example 10. [Figure 12] FIG. 12 shows the dissolution curves of Example 5 and Comparative Example 11. DETAILED DESCRIPTION OF THE INVENTION

[0035] The present invention will be further described below with reference to specific examples. Unless otherwise specified, all of the following examples are made using commercially available materials. The dissolution conditions used in the following examples and comparative examples are as follows: 2020 edition of the Chinese Pharmacopoeia, General Rule 0931, Dissolution and Release Test Method, Method 2, Paddle Method, 50 rpm, pH 4.5, 500 ml.

[0036] The dissolution rate measurement method used in the following Examples and Comparative Examples is as follows: after sampling, the absorbance of loxoprofen sodium dihydrate at 222 nm is measured using a high performance liquid chromatograph, and the dissolution rate is calculated. EUDRAGIT L30D-55® below is a mixture of methacrylic acid and ethyl acrylate in a 1:1 weight ratio, and EUDRAGIT S100® is a mixture of methacrylic acid and methyl methacrylate in a 1:2 weight ratio.

[0037] Example 1 The formulation of the loxoprofen sodium-containing core layer in this example is shown in Table 1 below. Table 1 [Table 1]

[0038] The manufacturing method is as follows. 1) Preparation of core layer granules: 24 g of loxoprofen sodium dihydrate, 1.6 g of croscarmellose sodium, 22 g of lactose G 200, and 11.2 g of microcrystalline cellulose PH101 are premixed to obtain a mixture, which is then wet-granulated, dried, mixed with 1.2 g of magnesium stearate, and sieved to obtain the fully mixed granules for the core layer plain tablet core. 2) Core tableting: The entire mixed granules of the core layer are used as the raw material for the core tablet, and a circular punch of an appropriate diameter is selected and subjected to normal tableting to produce the core tablet. 3) Core coating: Prepare the sealing coating solution (add the raw materials of the sealing coating film to water, stir, add plasticizer and stir for 45 minutes or more), place the plain tablets in a coating pan, preheat the temperature of the tablet bed to 45°C, start coating, control the temperature of the tablet bed to 44°C, and apply the first coating to the core, with the target weight gain being 5%. After the sealing coating was completed, the enteric coating solution was prepared (first, the anti-sticking agent and plasticizer were added to the aqueous solution and stirred for 15 minutes at 8000 RPM using a high-shear mixer to obtain A; then A was added to the enteric coating material, stirred for 0.5 hours, and then passed through a sieve with 60-80 μm openings to obtain the enteric coating solution). The sealing-coated cores were preheated to a temperature of 35°C on the tablet bed, and enteric coating began. The temperature of the tablet bed was controlled at 30°C, and after the target weight gain reached 16%, a second sealing coating was performed, and the coating process was the same as the first sealing coating, and the coating was completed to obtain the cores.

[0039] The elution curves of this example are shown in Figures 6, 8 and 10.

[0040] Example 2 The formulation of the loxoprofen sodium-containing core layer in this example is shown in Table 2 below. Table 2 [Table 2]

[0041] The manufacturing method is as follows. 1) Preparation of core layer granules: The preparation method is the same as in Example 1. 2) Core tableting: The entire mixed granules of the core layer are used as the raw material for the core tablet, and a circular punch of an appropriate diameter is selected and subjected to normal tableting to produce the core tablet. 3) Core coating: Prepare a sealing coating solution (same as in Example 1), place the plain tablets in a coating pan, preheat the tablet bed to 43°C, start coating, and control the tablet bed temperature at 43°C. The cores are coated for the first time, with a target weight gain of 2%. After sealing coating is complete, prepare an enteric coating solution (same as in Example 1), preheat the sealing-coated cores to 33°C, start enteric coating, and control the tablet bed temperature at 28°C. After a target weight gain of 15%, a second sealing coating is performed. The coating process is the same as the first sealing coating, and the cores are obtained. The elution curves of this example are shown in Figures 4, 5 and 11.

[0042] Example 3 The formulation of the loxoprofen sodium-containing core layer in this example is shown in Table 3 below. Table 3 [Table 3]

[0043] The manufacturing method is as follows. 1) Preparation of core layer granules: The preparation method is the same as in Example 1. 2) Core tableting: The entire mixed granules of the core layer are used as the raw material for the core tablet, and a circular punch of an appropriate diameter is selected and subjected to normal tableting to produce the core tablet. 3) Core coating: Prepare a sealing coating solution (same as in Example 1), place the plain tablets in a coating pan, preheat the tablet bed to 47°C, start coating, control the tablet bed temperature at 45°C, and apply the first coating to the cores with a target weight gain of 10%. After sealing coating is completed, prepare an enteric coating solution (same as in Example 1), preheat the sealing-coated cores to 37°C, start enteric coating, control the tablet bed temperature at 33°C, and apply a second sealing coating after a target weight gain of 25% is reached. The coating process is the same as the first sealing coating, and the cores are obtained. The elution curve of this example is shown in FIG.

[0044] Example 4 The formulation of the controlled-release tablets of loxoprofen sodium in this example is shown in Table 4 below. Table 4 [Table 4]

[0045] The manufacturing method is as follows. 1) Preparation of immediate-release layer granules: 24 g of loxoprofen sodium dihydrate, 11 g of croscarmellose sodium, 81 g of lactose G 200, 68 g of microcrystalline cellulose PH101, and 13 g of PVP-30 are premixed to obtain a mixture, which is then wet-granulated with purified water, dried, and mixed with 3 g of sieved magnesium stearate to obtain the complete immediate-release layer granule mixture. 2) Preparation of sustained-release layer granules: 55 g of loxoprofen sodium dihydrate, 30 g of HPMC-K4M, 30 g of HPMC-K100M, and 8 g of PVP-K30 were premixed to obtain a mixture. 6 g of PVP-K30 was added to an ethanol solution, and the mixture was wet-granulated. After drying, the mixture was mixed with 3 g of sieved magnesium stearate to obtain the fully mixed granules for the sustained-release layer. 3) Tableting: The prescribed amount of immediate-release layer granules is placed in the die of a tablet press, the core obtained in Example 1 is placed on the immediate-release layer, and pre-pressurized tableting is performed. Further, the prescribed amount of sustained-release layer granules is placed in the die of a tablet press, and the tablet is formed by adjusting the main pressure appropriately. 4) Film coating: The tablets produced in step 3) are conventionally film coated with Opadry to a weight gain of 2%. The dissolution curve of the controlled-release tablets produced in this example is shown in FIG.

[0046] Example 5 The formulation of the controlled-release tablets of loxoprofen sodium in this example is shown in Table 5 below. Table 5 [Table 5]

[0047] The manufacturing method is as follows. 1) Preparation of immediate-release layer granules: 36 g of loxoprofen sodium dihydrate, 12 g of croscarmellose sodium, 60 g of pregelatinized starch, and 70 g of microcrystalline cellulose PH101 are mixed in advance to obtain a mixture. 15 g of carmellose sodium is added to purified water to prepare a solution, and the mixture is wet-granulated. After drying, the mixture is mixed with 7 g of magnesium stearate to obtain immediate-release layer fully mixed granules. 2) Preparation of sustained-release layer granules: 60 g of loxoprofen sodium dihydrate, 25 g of HPMC-K15M, 28 g of sodium alginate, 68 g of microcrystalline cellulose, and 16 g of carmellose sodium are premixed to obtain a mixture, which is wet-granulated, dried, and then mixed with 3 g of magnesium stearate to obtain fully mixed granules for the sustained-release layer. 3) Tableting: The prescribed amount of immediate-release layer granules is placed in the die of a tablet press, the core obtained in Example 2 is placed on the immediate-release layer, and pre-pressurized tableting is performed. Further, the prescribed amount of sustained-release layer granules is placed in the die of a tablet press, and the tablet is formed by adjusting the main pressure appropriately. 4) Film coating: The tablets produced in step 3) are conventionally film coated with Opadry to a weight gain of 2%. The elution curve of this example is shown in FIG.

[0048] Example 6 The formulation of the controlled-release tablets of loxoprofen sodium in this example is shown in Table 6 below. Table 6 [Table 6]

[0049] Manufacturing method: 1) Preparation of immediate-release layer granules: 26 g of loxoprofen sodium dihydrate, 8 g of croscarmellose sodium, 72 g of lactose G 200, 70 g of microcrystalline cellulose PH101, and 20 g of hydroxypropyl methylcellulose are mixed in advance to obtain a mixture. The mixture is wet-granulated with purified water, dried, and then mixed with 8 g of sieved magnesium stearate to obtain the complete mixture for the immediate-release layer. 2) Preparation of sustained-release layer granules: 70 g of loxoprofen sodium dihydrate, 20 g of HPMC-E30LV, 36 g of HPMC-K100LV, 60 g of lactose G200, and 8 g of hydroxypropyl methylcellulose were premixed to obtain a mixture, which was wet-granulated and dried, and then mixed with 6 g of sieved magnesium stearate to obtain the fully mixed granules for the sustained-release layer. 3) Tableting: The prescribed amount of immediate-release layer granules is placed in the die of a tablet press, the core obtained in Example 3 is placed on the immediate-release layer, and pre-pressurized tableting is performed. Further, the prescribed amount of sustained-release layer granules is placed in the die of a tablet press, and the tablet is formed by adjusting the main pressure appropriately. 4) Film coating: The tablets prepared in step 3) were conventionally film coated with Opadry to increase the weight by 2%. The dissolution curve for this example is shown in Figure 3.

[0050] Comparative Example 1 The difference between this Comparative Example and Example 2 is the core coating; in this Comparative Example, no sealing coating was applied, and only the plain tablet core was enteric coated; the rest was the same as in Example 2. The dissolution curves of Comparative Example 1 and Example 2 are shown in Figure 4. Results analysis: The table shows the core dissolution results, and requires that the core is completely released or the dissolution rate is less than 10% within 0 to 4 hours. In a pH 4.5 medium for 0 to 4 hours, Example 2 is completely released and passes the test. Comparative Example 1 shows 102.6% release within 1 hour, indicating complete release and therefore fails the test.

[0051] Comparative Example 2 This comparative example differs from Example 2 in that the second sealing coating was not performed in the process for forming the drug-containing core layer, and the rest of the process was the same as Example 2. The RSDs of Comparative Example 2 and Example 2 are shown in FIG. Result analysis: The RSD of Example 2 was stable and less than 10%, which is acceptable. The RSD of Comparative Example 2 was 16.6% at the highest and 2.6% at the lowest, which is a large difference and indicates that the consistency is unacceptable.

[0052] Comparative Example 3 The difference between this comparative example and Example 1 is that the weight gain of the enteric coating was 7.03%, but the rest is the same as Example 1. The dissolution curves of Comparative Example 3 and Example 1 are shown in FIG. Results analysis: In the medium of pH 4.5 for 0-4 hours, Example 1 was completely released and passed the test. Comparative Example 3 showed 9.3% release in 1 hour, and the dissolution rate reached 102.3% in 2 hours, indicating complete release and failing the test.

[0053] Comparative Example 4 The difference between this comparative example and Example 3 is that the weight gain of the enteric coating was 4.50%, but the rest is the same as Example 3. The dissolution curves of Comparative Example 4 and Example 3 are shown in FIG. Results analysis: In the medium of pH 4.5 from 0 to 4 hours, Example 3 was completely released, and Comparative Example 4 was released at 25.1% in 1 hour, and the dissolution rate was 105.9% in 2 hours, indicating complete release.

[0054] Comparative Example 5 The difference between this comparative example and Example 1 is that the sealing coating material used is commercially available OPADRY® II, which is a mixture of polyvinyl alcohol and polyethylene glycol 3350; otherwise, the comparative example is identical to Example 1. The dissolution curves of Comparative Example 5 and Example 1 are shown in FIG. Analysis of results: Comparative Example 5 had a dissolution rate of 90.6% in 2 hours, which was too fast to pass the test.

[0055] Comparative Example 6 The difference between this comparative example and Example 3 is the blending ratio of the plasticizer and anti-blocking agent in the enteric coating raw materials, but the rest is the same as Example 3. The detailed ingredients are shown in Table 7. Table 7 [Table 7]

[0056] The dissolution curves of Comparative Example 6 and Example 3 are shown in FIG. Analysis of results: Comparative Example 6 had a dissolution rate of 48.6% after 4 hours, which was too rapid for the release and was therefore unacceptable.

[0057] Comparative Example 7 The difference between this comparative example and Example 4 is that the type of binder in the drug-containing sustained-release layer is a specific HPC-EF, and the rest is the same as Example 4. The appearance and friability of Example 4 and Comparative Example 7 were examined, and the experimental data are shown in Table 8 below. Table 8 [Table 8]

[0058] Results analysis: When the binder type of the drug-containing sustained-release layer was different, Example 4 had a smooth appearance and passed the test, while Comparative Example 7 had broken edges and failed the test.

[0059] Comparative Example 8 The difference between this comparative example and Example 4 is that the drug-containing immediate-release layer does not contain a binder, as specifically shown in Table 9 below. Table 9 [Table 9]

[0060] The appearance and friability of Example 4 and Comparative Example 8 were examined, and the experimental data are shown in Table 10 below. Table 10 [Table 10] Result analysis: When the immediate-release layer does not contain a binder, the friability of Example 4 is 0.19%, which is acceptable. The friability of Comparative Example 8 reaches 91%, which is unacceptable.

[0061] Comparative Example 9 The difference between this comparative example and Example 1 is that Colorcon 930 is the enteric coating material, and Colorcon 930 is a mixture of methacrylic acid and ethyl acrylate copolymer, while the rest is the same as Example 1. The dissolution curves of Comparative Example 9 and Example 1 are shown in FIG.

[0062] Result analysis: In the medium of pH 4.5 for 0 to 4 hours, Comparative Example 9 released 87.2% in 1 hour, and the dissolution rate reached 102.5% in 2 hours, indicating complete release and failing the test.

[0063] Comparative Example 10 The difference between this comparative example and Example 2 is the coating sequence, specifically, the plain tablet core was first subjected to two sealing coats and then enteric coating, and the detailed coating parameters were the same as those in Example 2. The dissolution curves of Comparative Example 10 and Example 2 are shown in FIG. Result analysis: In a medium of pH 4.5 for 0 to 4 hours, Comparative Example 10 released 98.7% in 1 hour, and the dissolution rate reached 103.1% in 3 hours, indicating complete release.

[0064] Comparative Example 11 The difference between this comparative example and Example 5 is that the core layers do not match, and the core used in this comparative example is the core manufactured in Comparative Example 2, but the rest is the same as Example 5. The dissolution curves of Comparative Example 11 and Example 5 are shown in FIG. Results analysis: In the case of mismatched core layers, the dissolution rate of Comparative Example 11 after 8 hours was 100.6%, which was completely released and failed to achieve the sustained release effect of 12 hours, so it was rejected. The dissolution rate of Example 5 after 12 hours was 93.5%, which achieved the sustained release effect of 12 hours, so it was accepted.

[0065] The above are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. The controlled-release tablet of ibuprofen sodium comprises a drug-containing immediate-release layer, a drug-containing core layer and a drug-containing sustained-release layer, the drug-containing core layer comprising a plain tablet core, an enteric coating film and a sealing coating film, and the enteric coating film is not in direct contact with the core, the drug-containing immediate-release layer and the drug-containing sustained-release layer.

2. The controlled-release tablet according to claim 1, characterized in that the enteric coating film is in direct contact only with the sealing coating film, and the exterior of the plain tablet core in the drug-containing core layer is in the order of sealing coating film 1, enteric coating film, and sealing coating film 2 from the inside to the outside.

3. 2. The controlled-release tablet according to claim 1, wherein the raw material of the sealing coating film comprises one or more sealing coating materials selected from the group consisting of hypromellose, hydroxypropyl cellulose, ethyl cellulose, and polyvinyl alcohol, the content of the sealing coating material in the sealing coating film is 5-20%, and the coating weight gain of the sealing coating film is 2-10%.

4. 2. The controlled-release tablet according to claim 1, wherein the raw materials of the enteric coating film include one or more enteric coating materials selected from the group consisting of methacrylic acid, acrylic acid salts, methacrylic acid salts, polymethacrylic acid, polymethacrylic acid esters, trimethylaminoethyl methacrylate chloride, and polyvinyl acetate phthalate, the content of the enteric coating material in the enteric coating film is 5-35%, and the coating weight gain of the enteric coating film is 5-30%.

5. 2. The controlled-release tablet according to claim 1, wherein the enteric coating material is a mixture of methacrylic acid and ethyl acrylate, and the coating weight gain is 15-25%, or the enteric coating material is a mixture of methacrylic acid and methyl methacrylate, and the coating weight gain is 6-30%.

6. The controlled-release tablet according to claim 1, wherein the raw materials of the enteric coating film also contain additives, and the additives include a plasticizer and an anti-adherent in a mass ratio of 0.25 to 5:

1.

7. 7. The controlled-release tablet according to claim 6, wherein the additives include a plasticizer and an anti-adherent agent in a mass ratio of 0.25 to 4:

1.

8. 2. The controlled-release tablet according to claim 1, characterized in that the raw materials of the sealing coating film also contain a plasticizer.

9. 6. The controlled-release tablet according to claim 5, wherein the plasticizer is one or more selected from the group consisting of triethyl citrate, polyethylene glycol 6000, tributyl citrate, and dibutyl sebacate, and the anti-adhesive agent is one or more selected from the group consisting of talc, magnesium stearate, and glycerin monostearate.

10. The raw materials of the uncoated tablet core include loxoprofen sodium, a filler, a disintegrant and a lubricant. The raw materials of the drug-containing immediate-release layer include loxoprofen sodium, a filler, a binder, a disintegrant, and a lubricant. The raw materials of the drug-containing sustained-release layer include loxoprofen sodium, a sustained-release polymer, a filler, a binder, and a lubricant.

2. The controlled-release tablet according to claim 1.

11. The raw materials for the core tablet include 20 to 65 parts of loxoprofen sodium, 30 to 70 parts of a filler, 1 to 5 parts of a disintegrant, and 1 to 5 parts of a lubricant. The raw materials of the drug-containing immediate-release layer include 5 to 25 parts of loxoprofen sodium, 50 to 80 parts of a filler, 4 to 10 parts of a binder, 2 to 8 parts of a disintegrant, and 0.5 to 8 parts of a lubricant. The controlled-release tablet according to claim 10, characterized in that the raw materials of the drug-containing sustained-release layer comprise 10 to 35 parts of loxoprofen sodium, 5 to 60 parts of sustained-release polymer, 25 to 40 parts of filler, 5 to 15 parts of binder, and 0.5 to 8 parts of lubricant.

12. 11. The controlled-release tablet according to claim 10, wherein the sustained-release polymer is one or more selected from the group consisting of hydroxypropyl methylcellulose and polysaccharide gums; the hydroxypropyl methylcellulose is one or more selected from the group consisting of E30LV, E50LV, K100LV, K4M, K15M and K100M; the polysaccharide gums are one or more selected from the group consisting of sodium alginate, gum arabic, xanthan gum and locust bean gum; the sustained-release polymer accounts for 5 to 60% or 7.5 to 40% of the sustained-release layer; and the binder is one or more selected from the group consisting of sodium carboxymethylcellulose, povidone and hydroxypropyl methylcellulose, preferably povidone.

13. 2. The controlled-release tablet according to claim 1, wherein the ratio of the mass of the drug-containing sustained-release layer to the mass of the drug-containing core is 12.5 to 1:1 in parts by weight, and the ratio of the mass of the drug-containing immediate-release layer to the mass of the drug-containing core is 10 to 1:

1.

14. The steps include: (1) wet granulating the raw materials for the drug-containing immediate-release layer to obtain drug-containing immediate-release layer granules; (2) wet granulating the raw materials for the drug-containing sustained-release layer to obtain drug-containing sustained-release layer granules; (3) The raw materials for the plain tablet core are wet granulated and compressed into tablets, and then a first layer of sealing coating, a second layer of enteric coating, and a third layer of sealing coating are sequentially applied to obtain the drug-containing core. (4) A drug-containing core is placed on top of drug-containing sustained-release layer granules, and pre-pressed and compressed into tablets. Then, drug-containing immediate-release layer granules are placed on top of the pre-pressed tablets, and the tablets are compressed and coated. The method for producing the controlled-release tablet according to any one of claims 1 to 13.

15. 15. The method of claim 14, wherein the pre-compression tableting pressure in step (4) is 0.1-2 KN or 0.1-0.5 KN, and the tableting pressure is 5-25 KN or 8-20 KN.

16. Use of a controlled-release tablet of loxoprofen sodium according to any one of claims 1 to 13 or a controlled-release tablet produced by the production method according to any one of claims 14 to 15 in the manufacture of a therapeutic agent for a painful disease.

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