Controlled release tablet of sodium loxoprofen, preparation method and application

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a controlled-release tablet of sodium loxoprofen, a preparation method and application. The controlled-release tablet comprises a drug-containing immediate-release layer, a drug-containing tablet core layer and a drug-containing sustained-release layer; the drug-containing tablet core layer comprises a blank tablet core, an enteric coating film and an isolation coating film. The preparation method comprises preparing drug-containing immediate-release layer granules from raw materials of the drug-containing immediate-release layer and the drug-containing sustained-release layer; wet granulating raw materials of the blank tablet core, tabletting, and then sequentially performing first isolation coating, second enteric coating and third isolation coating to obtain a drug-containing tablet core; placing the drug-containing tablet core on the drug-containing sustained-release layer granules, pre-compressing, placing the drug-containing immediate-release layer granules on the pre-compressed tablet, tabletting, and coating to obtain the tablet. The tablet core sustained-release effect of the sodium loxoprofen tablet is achieved by designing the tablet type structure of the core tablet and the raw materials, coating and other components, so that the tablet is effective in the body for 12 hours, and the patient compliance is improved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a controlled-release tablet of loxoprofen sodium, its preparation method, and its application. Background Technology

[0002] Loxoprofen sodium tablets were first developed by Sankyo Co., Ltd. of Japan, and were launched in Japan in July 1986 under the brand name... It is available on the market in 60mg form and is a leading-selling nonsteroidal anti-inflammatory drug (NSAID) in Japan. This drug was first launched in my country in 2003 under the brand name [Brand Name Missing]. Compared with similar drugs in clinical practice, loxoprofen sodium has the advantages of faster onset of action, stronger analgesic effect, and wider range of applications in the treatment of painful diseases.

[0003] Studies have shown that the side effects of nonsteroidal anti-inflammatory drugs (NSAIDs), such as allergic reactions, bleeding, and kidney damage, are related to the plasma exposure of the parent drug or its metabolites. Commercially available, readily available loxoprofen sodium formulations require three daily doses, leading to poor patient adherence. Furthermore, the rapid release of the drug from the body in these formulations results in excessively high plasma exposure of the parent drug or its metabolites within a short period, causing unstable blood drug concentrations and increasing the risk of side effects.

[0004] Chinese invention patent application CN105168167A discloses an osmotic pump controlled-release formulation containing loxoprofen sodium and its preparation method. The osmotic pump controlled-release formulation is an osmotic pump controlled-release tablet, which includes a tablet core and a semi-permeable membrane with a drug release pore. It can reduce the frequency of administration and improve patient compliance, but the onset speed and effectiveness need further improvement.

[0005] Chinese invention patent application CN102525989A discloses a loxoprofen sodium matrix sustained-release tablet with a regulating layer, which can release stably for 8 hours with ideal release effect, but its daily dosing frequency and effective duration need further improvement.

[0006] Chinese invention patent application CN105769773A discloses loxoprofen sodium sustained-release microspheres, which consist of three parts: a drug-loaded core, an isolation layer encapsulating the drug-loaded core, and a sustained-release layer encapsulating the isolation layer. The weight ratio of the drug-loaded core, the isolation layer, and the sustained-release layer is 80:1-15:2-20. This invention, a loxoprofen sodium sustained-release microsphere, achieves a slow in vitro release rate by combining the concentration of the pH adjuster in the acidic isolation layer, the coating amount of the isolation layer, and the coating amount of the sustained-release layer, thus reducing the burst release phenomenon of loxoprofen sodium. The operation to achieve a sustained-release effect is complex, and the microspheres cannot take effect rapidly, thus failing to achieve a rapid analgesic effect. Summary of the Invention

[0007] In view of the deficiencies of the prior art, the present application provides a controlled-release tablet of sodium loxoprofen and a preparation method thereof, adopts a core-in-tablet design, optimizes the core-in-tablet structure, creatively designs and adjusts the coating prescription, and simultaneously optimizes the dose distribution of the immediate-release and sustained-release, combines the characteristics of the immediate-release and sustained-release, so that after the patient takes the medicine, the drug can quickly take effect and can also maintain long-term effectiveness through stable control of drug release, thereby keeping the blood drug concentration stable.

[0008] The object of the present application is achieved by the following technical solutions:

[0009] A controlled-release tablet of sodium loxoprofen, the controlled-release tablet comprising a drug-containing immediate-release layer, a drug-containing tablet core layer and a drug-containing sustained-release layer; wherein the drug-containing tablet core layer comprises a tablet core, an enteric coating film and an isolation coating film; the enteric coating film is not in direct contact with the tablet core, the drug-containing immediate-release layer and the drug-containing sustained-release layer.

[0010] Preferably, the enteric coating film is only in direct contact with the isolation coating film, and the tablet core in the drug-containing tablet core layer has the isolation coating film 1, the enteric coating film and the isolation coating film 2 from inside to outside in sequence outside the tablet core.

[0011] Preferably, the raw material of the isolation coating film comprises an isolation coating material selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose and polyvinyl alcohol; the content of the isolation coating material in the isolation coating film is 5-20%, and the coating weight gain of the isolation coating film is 2%-10%.

[0012] Preferably, the raw material of the enteric coating film comprises an enteric coating material selected from one or more of methacrylic acid, acrylic ester, methacrylic ester, polymethacrylic acid, polymethacrylic ester, chlorinated trimethylamine ethyl methacrylate and polyvinyl alcohol 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 at a mass ratio of 1:1, the coating weight gain is 15-25%; or the enteric coating material is a mixture of methacrylic acid and methacrylic acid methyl ester at a mass ratio of 1:2, the coating weight gain is 6-30%.

[0013] Preferably, the raw material of the enteric coating film further comprises an additive, the additive comprises a plasticizer and an anti-adhesive at a mass ratio of 0.25-5:1, preferably at a mass ratio of 0.25-4:1; the raw material of the isolation coating film further comprises a plasticizer.

[0014] Preferably, the plasticizer is selected from one or more of triethyl citrate, polyethylene glycol 6000, tributyl citrate and dibutyl sebacate;

[0015] Preferably, the anti-adhesion agent is selected from one or more of talc, magnesium stearate and glyceryl monostearate.

[0016] Preferably, the raw materials of the tablet core comprise the following components: sodium loxoprofen, filler, disintegrant and lubricant, preferably 20-65 parts of sodium loxoprofen, 30-70 parts of filler, 1-5 parts of disintegrant and 1-5 parts of lubricant;

[0017] Preferably, the raw materials of the drug-containing immediate release layer comprise the following components: sodium loxoprofen, filler, binder, disintegrant and lubricant, preferably 5-25 parts of sodium loxoprofen, 50-80 parts of filler, 4-10 parts of binder, 2-8 parts of disintegrant and 0.5-8 parts of lubricant;

[0018] Preferably, the raw materials of the drug-containing sustained release layer comprise the following components: sodium loxoprofen, sustained release polymer, filler, binder and lubricant, preferably 10-35 parts of sodium loxoprofen, 5-60 parts of sustained release polymer, 25-40 parts of filler, 5-15 parts of binder and 0.5-8 parts of lubricant.

[0019] Preferably, the sustained release polymer is selected from one or more of hypromellose and polysaccharide gum;

[0020] Preferably, the hypromellose is selected from one or more of E30LV, E50LV, K100LV, K4M, K15M and K100M;

[0021] Preferably, the polysaccharide gum is selected from one or more of sodium alginate, gum arabic, xanthan gum and locust bean gum;

[0022] Preferably, the sustained release polymer accounts for 5-60% of the sustained release layer, preferably 7.5-40%.

[0023] Preferably, the binder is selected from one or more of sodium carboxymethyl cellulose, povidone and hypromellose; preferably povidone.

[0024] Preferably, the disintegrant is selected from one or more of sodium croscarmellose, sodium croscarmellose, cross-linked povidone PVPP and low-substituted hydroxypropyl cellulose L-HPC; preferably sodium croscarmellose or sodium croscarmellose.

[0025] Preferably, the filler is selected from one or more of lactose, corn starch, pre-gelatinized starch and microcrystalline cellulose; preferably lactose, pre-gelatinized starch or microcrystalline cellulose.

[0026] Preferably, the lubricant is selected from one or more of magnesium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, hydrogenated castor oil and sodium lauryl sulfate; preferably magnesium stearate or stearic acid.

[0027] Preferably, the ratio of the mass of the drug-containing sustained-release layer to the mass of the drug-containing core layer is 12.5-1:1, preferably 5-1:1, by weight.

[0028] Preferably, the ratio of the mass of the drug-containing sustained-release layer to the mass of the drug-containing core layer is 12.5-1:1, preferably 5-1:1, by weight.

[0029] It is another object of the present application to provide a method for preparing the above-mentioned controlled-release tablet, comprising the following steps:

[0030] (1) wet granulating the raw materials of the drug-containing immediate-release layer to obtain drug-containing immediate-release layer granules;

[0031] (2) wet granulating the raw materials of the drug-containing sustained-release layer to obtain drug-containing sustained-release layer granules;

[0032] (3) wet granulating the raw materials of the core, tabletting, and then sequentially performing first layer isolation coating, second layer enteric coating and third layer isolation coating to obtain the drug-containing core;

[0033] (4) placing the drug-containing core on the drug-containing sustained-release layer granules, pre-compressing, placing the drug-containing immediate-release layer granules on the pre-compressed tablet, tabletting, and coating to obtain the controlled-release tablet.

[0034] Preferably, the wet granulation process in step (1) or (2) is to dissolve the binder in water or ethanol solution, then add other raw materials except lubricant, wet granulate through 1000-8000 μm sieve, dry, dry granulate through 1000-8000 μm sieve, and then add lubricant to mix.

[0035] Preferably, the pre-compression pressure in step (4) is 0.1-2 KN, preferably 0.1-0.5 KN; and the tabletting pressure is 5-25 KN, preferably 8-20 KN.

[0036] Preferably, the preparation method of the coating solution for the first layer isolation coating and the third layer isolation coating in step (3) comprises: stirring to form a vortex, then adding the isolation coating film material into the water, stirring, and then adding the plasticizer and stirring for more than 45 min; and the preparation method of the coating solution for the second layer enteric coating comprises: first adding the additive into water solution or 70%-95% ethanol solution, stirring at 8000-11000 rpm for 8-15 min using a high-shear stirrer to obtain A; and then adding A into the enteric coating material, stirring for 0.3-0.8 h, and then passing through a 50-200 μm sieve to obtain the coating solution.

[0037] Preferably, the dissolution of loxoprofen sodium in the controlled-release tablet is 20-55% at 2 h and 80-100% at 10 h.

[0038] The present application also aims to provide the use of the above-mentioned controlled release tablets of sodium loxoprofen or the controlled release tablets prepared by the preparation method in the preparation of a medicament for treating a painful disease.

[0039] Compared with the prior art, the present application has the following beneficial effects:

[0040] (1) There is no enteric-coated preparation of sodium loxoprofen at present. It is found that sodium loxoprofen is a strong base weak acid salt, and OH - ions are generated after it is dissolved in water, which can increase the local pH, destroy the enteric-coated film, and make the API of the tablet core release through the enteric-coated film, so that the effect of sustained release of the tablet core cannot be achieved. In the present application, the enteric-coated film is separated in a specific isolation coating film, and the stability of the enteric-coated film is protected by the specific coating sequence process, coating material, coating weight, etc., and the sustained release effect is achieved by releasing at a specific site.

[0041] (2) The present application achieves the effect of sustained release of the tablet core of sodium loxoprofen by designing the tablet type structure of the core-coated tablet, the components of each coating film and the structure of the controlled release tablet, achieves 12h effectiveness in vivo, and improves the compliance of patients. After the coating film of the commercially available coating film is coated and pressed into a core-coated tablet, the pressure of the pressed shell will cause damage to the coated tablet core, so that the coating film is damaged under stress, and the tablet core is released in advance, so that the effect of sustained release of the tablet core cannot be achieved.

[0042] (3) Through multiple experiments, the raw materials suitable for the enteric-coated film and the isolation film of the present application are creatively compounded, and the unique tablet type design is used to make the drug release achieve the expected release effect. BRIEF DESCRIPTION OF DRAWINGS

[0043] Figure 1 is the dissolution curve of Example 4;

[0044] Figure 2 is the dissolution curve of Example 5;

[0045] Figure 3 is the dissolution curve of Example 6;

[0046] Figure 4 is the dissolution curve of Example 2 and Comparative Example 1;

[0047] Figure 5 is the RSD curve of Example 2 and Comparative Example 2;

[0048] Figure 6 is the dissolution curve of Example 1 and Comparative Example 3;

[0049] Figure 7 is the dissolution curve of Example 3 and Comparative Example 4;

[0050] Figure 8 Dissolution curves for Example 1 and Comparative Example 5;

[0051] Figure 9 Dissolution curves for Example 3 and Comparative Example 6;

[0052] Figure 10 Dissolution curves for Example 1 and Comparative Example 9;

[0053] Figure 11 Dissolution curves for Example 2 and Comparative Example 10;

[0054] Figure 12 Dissolution curves for Example 5 and Comparative Example 11. DETAILED DESCRIPTION

[0055] The application will be further described below in conjunction with specific examples.

[0056] In the following examples, unless otherwise specified, all materials are commercially available and conventional.

[0057] The dissolution method conditions used in the following examples and comparative examples are as follows: 2020 edition of Chinese Pharmacopoeia General 0931 Dissolution and Release Determination Method Second Method Slurry Method 50 rpm, pH 4.5, 500 ml.

[0058] The dissolution determination method used in the following examples and comparative examples is as follows: after sampling, the absorbance of sodium loxoprofen dihydrate is detected at 222 nm by high performance liquid chromatograph, and the dissolution is calculated.

[0059] The EUDRAGIT is a mixture of methacrylic acid and ethyl acrylate in a mass ratio of 1:1; EUDRAGIT is a mixture of methacrylic acid, methyl methacrylate in a mass ratio of 1:2.

[0060] Example 1

[0061] The formulation of the loxoprofen sodium-containing tablet core layer of this example is as shown in Table 1 below.

[0062] Table 1

[0063]

[0064] The preparation method is as follows:

[0065] 1) Tablet core layer granule preparation: 24 g of sodium loxoprofen dihydrate, 1.6 g of cross-linked sodium carboxymethyl cellulose, 22 g of lactose G200, and 11.2 g of microcrystalline cellulose PH101 are premixed to obtain a mixture; the mixture is wet granulated, dried, and then mixed with 1.2 g of magnesium stearate and sieved to obtain tablet core layer total mixture granules, which are ready for use.

[0066] 2) tablet core compression: the total mixed granules of the tablet core layer are used as the raw material of the tablet core, a round punch die with a proper diameter is selected, and conventional tablet compression is performed to obtain the tablet core;

[0067] 3) tablet core coating: a separating coating solution is prepared (the raw materials of the separating coating film are added to water, stirred, and then the plasticizer is added and stirred for more than 45 min), the tablets are preheated in the coating pan until the tablet bed temperature reaches 45°C, and then the coating is started, the tablet bed temperature is controlled at 44°C, the tablet core is coated with the separating film for the first time, and the target weight gain is 5%; after the separating coating is completed, an enteric coating solution is prepared (the anti-adhesion agent and the plasticizer are first added to the aqueous solution, a high-shear stirrer is used at a speed of 8000 rpm for 15 min to obtain A; A is added to the enteric coating material, and stirring is performed for 0.5 h before being sieved through a 60-80 mesh sieve), the tablet core coated with the separating film is preheated until the tablet bed temperature reaches 35°C, and then the enteric coating is started, the tablet bed temperature is controlled at 30°C, and after the target weight gain of 16% is reached, the second separating film coating is performed, and the coating process is the same as that of the first separating film coating. After the coating is completed, the tablet core is prepared for use.

[0068] Example 2

[0069] The tablet core layer of the losoxofen sodium in this example has the following formulation shown in Table 2.

[0070] Table 2

[0071]

[0072] The preparation method is as follows:

[0073] 1) tablet core layer granule preparation: the preparation method is the same as that of Example 1.

[0074] 2) tablet core compression: the total mixed granules of the tablet core layer are used as the raw material of the tablet core, a round punch die with a proper diameter is selected, and conventional tablet compression is performed to obtain the tablet core;

[0075] 3) tablet core coating: a separating coating solution is prepared (the same as in Example 1), the tablets are preheated in the coating pan until the tablet bed temperature reaches 43°C, and then the coating is started, the tablet bed temperature is controlled at 43°C, the tablet core is coated with the separating film for the first time, and the target weight gain is 2%; after the separating coating is completed, an enteric coating solution is prepared (the same as in Example 1), the tablet core coated with the separating film is preheated until the tablet bed temperature reaches 33°C, and then the enteric coating is started, the tablet bed temperature is controlled at 28°C, and after the target weight gain of 15% is reached, the second separating film coating is performed, and the coating process is the same as that of the first separating film coating. After the coating is completed, the tablet core is prepared for use.

[0076] Example 3

[0077] The tablet core layer of the losoxofen sodium in this example has the following formulation shown in Table 3.

[0078] Table 3

[0079]

[0080] The preparation method is as follows:

[0081] 1) Preparation of tablet core layer granules: the preparation method is the same as that in Example 1.

[0082] 2) Tablet core compression: the total mixed granules of the tablet core layer are used as the raw material of the tablet core, a round punch die with a suitable diameter is selected, and conventional tablet compression is performed to obtain tablet core blanks;

[0083] 3) Tablet core coating: prepare the separating coating solution (the same as in Example 1), preheat the blanks in the coating pan until the tablet bed temperature reaches 47°C, start the coating, control the tablet bed temperature at 45°C, and perform the first separating coating on the tablet core, with a target weight gain of 10%; after the separating coating is completed, prepare the enteric coating solution (the same as in Example 1), preheat the tablet core coated with the separating coating until the tablet bed temperature reaches 37°C, start the enteric coating, control the tablet bed temperature at 33°C, and after the target weight gain of 25% is reached, perform the second separating film coating, with the same coating process as the first separating coating, and the tablet core is obtained after the coating is completed.

[0084] Example 4

[0085] The formula of the loxoprofen sodium controlled-release tablet in this example is shown in Table 4 below.

[0086] Table 4

[0087]

[0088] The preparation method is as follows:

[0089] 1) Preparation of immediate-release layer granules: 24 g of loxoprofen sodium dihydrate, 11 g of cross-linked sodium carboxymethyl cellulose, 81 g of lactose G200,

[0090] 68 g of microcrystalline cellulose PH101, and 13 g of PVP-30 are premixed to obtain a mixture; the mixture is wet granulated using purified water, dried, and then mixed with 3 g of sieved magnesium stearate to obtain total mixed granules of the immediate-release layer, which is reserved.

[0091] 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 are premixed to obtain a mixture; 6 g of PVP-K30 is added to an ethanol solution, and the mixture is wet granulated, dried, and then mixed with 3 g of sieved magnesium stearate to obtain total mixed granules of the sustained-release layer, which is reserved.

[0092] 3) tabletting: put the granules of the immediate release layer of the prescription amount into the punch die of the tablet machine, put the tablet core obtained in Example 1 on the immediate release layer, pre-press; then put the granules of the sustained release layer of the prescription amount into the punch die of the tablet machine, adjust the main pressure to press into tablets.

[0093] 4) film coating: the tablets obtained in step 3) are subjected to ordinary and conventional film coating with Opadry, with a weight gain of 2%, and then obtained. The dissolution curve of the controlled release tablets obtained in this example is shown in Figure 2. Figure 1 .

[0094] Example 5

[0095] The formula of the controlled release tablets of loxoprofen sodium in this example is shown in Table 5 below.

[0096] Table 5

[0097]

[0098] The preparation method is as follows:

[0099] 1) preparation of the granules of the immediate release layer: 36 g of loxoprofen sodium dihydrate, 12 g of cross-linked sodium carboxymethyl cellulose, 60 g of pregelatinized starch, and 70 g of microcrystalline cellulose PH101 are premixed to obtain a mixture; 15 g of sodium carboxymethyl cellulose is added to purified water to form a solution, and the mixture is subjected to wet granulation, dried, and then mixed with 7 g of magnesium stearate to obtain the total mixed granules of the immediate release layer, which is ready for use.

[0100] 2) preparation of the granules of the sustained release layer: 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 sodium carboxymethyl cellulose are premixed to obtain a mixture; wet granulation is performed, and then dried and mixed with 3 g of magnesium stearate to obtain the total mixed granules of the sustained release layer, which is ready for use.

[0101] 3) tabletting: put the granules of the immediate release layer of the prescription amount into the punch die of the tablet machine, put the tablet core obtained in Example 2 on the immediate release layer, pre-press; then put the granules of the sustained release layer of the prescription amount into the punch die of the tablet machine, adjust the main pressure to press into tablets.

[0102] 4) film coating: the tablets obtained in step 3) are subjected to ordinary and conventional film coating with Opadry, with a weight gain of 2%, and then obtained.

[0103] The dissolution curve of this example is shown in Figure 3. Figure 2 .

[0104] Example 6

[0105] The formula of the controlled release tablets of loxoprofen sodium in this example is shown in Table 6 below.

[0106] Table 6

[0107]

[0108] Preparation method:

[0109] 1) Preparation of immediate-release layer granules: 26 g of sodium loxoprofen dihydrate, 8 g of cross-linked sodium carboxymethyl cellulose, 72 g of lactose G200, 70 g of microcrystalline cellulose PH101, and 20 g of hydroxypropyl methyl cellulose were premixed to obtain a mixture; the mixture was granulated by wet method using purified water, and after drying, 8 g of sieved magnesium stearate was mixed to obtain the total mixed granules of the immediate-release layer, which was ready for use.

[0110] 2) Preparation of sustained-release layer granules: 70 g of sodium loxoprofen dihydrate, 20 g of HPMC-E30LV, 36 g of HPMC-K100LV, 60 g of lactose G200, and 8 g of hydroxypropyl methyl cellulose were premixed to obtain a mixture; the mixture was granulated by wet method, and after drying, 6 g of sieved magnesium stearate was mixed to obtain the total mixed granules of the sustained-release layer, which was ready for use.

[0111] 3) Tablet compression: the prescription amount of the immediate-release layer granules was placed in the die of the tablet press, the tablet core obtained in Example 3 was placed on the immediate-release layer, and pre-compression was performed; then the prescription amount of the sustained-release layer granules was placed in the die of the tablet press, and the main compression pressure was adjusted to compress the tablets.

[0112] 4) Film coating: the tablets obtained in step 3) were subjected to ordinary and conventional film coating with Opadry, and the weight was increased by 2%, and the process was completed.

[0113] The dissolution curve of this example is shown in Figure 3 .

[0114] Comparative Example 1

[0115] The difference between this comparative example and Example 2 is that the tablet core coating is different, and this comparative example does not perform isolation coating, but only enteric coating on the plain tablet core, and the rest is the same as Example 2. The dissolution curves of Comparative Example 1 and Example 2 are shown in Figure 4 .

[0116] Result analysis: the tablet core dissolution results in the table are required to be complete or less than 10% in 0-4 h. In 0-4 h, in the medium of pH 4.5, Example 2 is complete and qualified; Comparative Example 1 releases 102.6% at 1 h, and has been completely released, which is unqualified.

[0117] Comparative Example 2

[0118] The difference between this comparative example and Example 2 is that the second isolation coating is not performed in the drug-containing tablet core layer process, and the rest is the same as Example 2.

[0119] The RSD of Comparative Example 2 and Example 2 is shown in Figure 5 .

[0120] Result analysis: the RSD of Example 2 is less than 10%, which is stable and qualified; the RSD of Comparative Example 2 is up to 16.6% and as low as 2.6%, which has large difference and is unqualified in consistency.

[0121] Comparative Example 3

[0122] This comparative example is different from Example 1 in that the enteric coating weight gain is 7.03%, and the rest is consistent with Example 1.

[0123] The dissolution curve of Comparative Example 3 and Example 1 is shown in Figure 6 .

[0124] Result analysis: 0-4h, in the medium of pH4.5, Example 1 is complete and qualified; Comparative Example 3 releases 9.3% at 1h, and the dissolution reaches 102.3% at 2h, which has been completely released and is unqualified.

[0125] Comparative Example 4

[0126] This comparative example is different from Example 3 in that the enteric coating weight gain is 4.50%, and the rest is consistent with Example 3.

[0127] The dissolution curve of Comparative Example 4 and Example 3 is shown in Figure 7 .

[0128] Result analysis: 0-4h, in the medium of pH4.5, Example 3 is complete, and Comparative Example 4 releases 25.1% at 1h, and the dissolution reaches 105.9% at 2h, which has been completely released.

[0129] Comparative Example 5

[0130] This comparative example is different from Example 1 in that the isolation coating material uses commercially available II isolation coating material, II is a mixture of polyvinyl alcohol and polyethylene glycol 3350, and the rest is consistent with Example 1.

[0131] o

[0132] The dissolution curve of Comparative Example 5 and Example 1 is shown in Figure 8 .

[0133] Result analysis: the dissolution of Comparative Example 5 is 90.6% at 2h, which is too fast and unqualified.

[0134] Comparative Example 6

[0135] This comparative example is different from Example 3 in that the ratio of plasticizer and anti-adhesive in the enteric coating raw material is different, and the rest is the same as Example 3. The specific ingredients are shown in Table 7.

[0136] Table 7

[0137]

[0138] The dissolution curves of Comparative Example 6 and Example 3 are shown in Figure 9 .

[0139] Analysis of dissolution results: the dissolution of Comparative Example 6 was 48.6% at 4h, which was too fast and unqualified.

[0140] Comparative Example 7

[0141] This comparative example is different from Example 4 in that the type of adhesive in the drug-containing sustained-release layer is different, specifically HPC-EF, and the rest is the same as Example 4.

[0142] For Example 4 and Comparative Example 7, the appearance and friability were investigated, and the experimental data are shown in Table 8.

[0143] Table 8

[0144]

[0145] Result analysis: under the condition that the type of adhesive in the drug-containing sustained-release layer is different, the appearance of Example 4 is smooth and qualified, and the appearance of Comparative Example 7 is chipped and unqualified.

[0146] Comparative Example 8

[0147] This comparative example is different from Example 4 in that there is no adhesive in the drug-containing immediate-release layer, as shown in Table 9.

[0148] Table 9

[0149]

[0150] For Example 4 and Comparative Example 8, the appearance and friability were investigated, and the experimental data are shown in Table 10.

[0151] Table 10

[0152]

[0153] Result analysis: under the condition that there is no adhesive in the immediate-release layer, the friability of Example 4 is 0.19%, which is qualified, and the friability of Comparative Example 8 reaches 91%, which is unqualified.

[0154] Comparative Example 9

[0155] This comparative example is different from Example 1 in that the enteric coating material is Kollidon 930, which is a mixture of methacrylic acid and ethyl acrylate copolymer, and the rest is the same as Example 1.

[0156] The dissolution curves of Comparative Example 9 and Example 1 are shown in Figure 10 .

[0157] Result analysis: 0-4h, in the medium of pH 4.5, the comparative example 9 released 87.2% at 1h, and the dissolution reached 102.5% at 2h, which was all released, unqualified.

[0158] Comparative example 10

[0159] The difference between the present comparative example and example 2 is the coating sequence, specifically, the tablet core is coated twice for isolation, and then enteric film coating is performed, and the specific coating parameters are the same as those of example 2.

[0160] The dissolution curve of comparative example 10 and example 2 is shown in Figure 11 .

[0161] Result analysis: 0-4h, in the medium of pH 4.5, the comparative example 10 released 98.7% at 1h, and the dissolution reached 103.1% at 3h, which was all released.

[0162] Comparative example 11

[0163] The difference between the present comparative example and example 5 is that the tablet core layer is inconsistent, and the tablet core used in the present comparative example is the tablet core prepared in comparative example 2, and the rest is the same as that of example 5.

[0164] The dissolution curve of comparative example 11 and example 5 is shown in Figure 12 .

[0165] Result analysis: under the condition of inconsistent tablet core layer, the dissolution of comparative example 11 was 100.6% at 8h, which was all released, and did not achieve the effect of 12h sustained release, unqualified; the dissolution of example 5 was 93.5% at 12h, which achieved the effect of 12h sustained release, qualified.

[0166] The above only describes the preferred embodiments of the present application and is not intended to limit the present application, and any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A controlled release tablet of sodium loxoprofen, characterized by, The controlled release tablet comprises a drug-containing fast release layer, a drug-containing tablet core layer and a drug-containing slow release layer; wherein the drug-containing tablet core layer comprises a tablet core, an enteric coating film and an isolation coating film; The drug-containing tablet core layer is sequentially coated with the isolation coating film 1, the enteric coating film and the isolation coating film 2 from inside to outside; The raw material of the isolation coating film comprises an isolation coating material, which is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose and polyvinyl alcohol; The content of the isolation coating material in the isolation coating film is 5-20%, and the coating weight gain of the isolation coating film is 2%-10%; The raw material of the enteric coating film comprises an enteric coating material, which 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%; The raw material of the enteric coating film further comprises an additive, which comprises a plasticizer and an anti-adhesion agent in a mass ratio of 0.25-5:

1.

2. The controlled release tablet according to claim 1, wherein 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%.

3. The controlled release tablet according to claim 1, wherein The mass ratio of the plasticizer and the anti-adhesion agent is 0.25-4:

1.

4. The controlled release tablet according to claim 3, wherein The plasticizer is selected from one or more of triethyl citrate, polyethylene glycol 6000, tributyl citrate and dibutyl sebacate; and the anti-adhesion agent is selected from one or more of talc, magnesium stearate and glycerol monostearate.

5. The controlled release tablet according to claim 1, wherein The raw material of the tablet core comprises the following components: sodium loxoprofen, a filler, a disintegrant and a lubricant; The raw material of the drug-containing fast release layer comprises the following components: sodium loxoprofen, a filler, a binder, a disintegrant and a lubricant; The raw material of the drug-containing slow release layer comprises the following components: sodium loxoprofen, a slow release polymer, a filler, a binder and a lubricant.

6. The controlled release tablet according to claim 1, wherein The raw material of the tablet core comprises the following components in the following weight proportions: sodium loxoprofen 20-65 parts, a filler 30-70 parts, a disintegrant 1-5 parts and a lubricant 1-5 parts.

7. The controlled release tablet according to claim 1, wherein The raw material of the drug-containing fast release layer comprises the following components in the following weight proportions: sodium loxoprofen 5-25 parts, a filler 50-80 parts, a binder 4-10 parts, a disintegrant 2-8 parts and a lubricant 0.5-8 parts.

8. The controlled release tablet according to claim 1, wherein The raw material of the drug-containing slow release layer comprises the following components in the following weight proportions: sodium loxoprofen 10-35 parts, a slow release polymer 5-60 parts, a filler 25-40 parts, a binder 5-15 parts and a lubricant 0.5-8 parts.

9. The controlled release tablet according to claim 8, wherein The slow release polymer is selected from one or more of hydroxypropyl methylcellulose and polysaccharide gum; the hydroxypropyl methylcellulose is selected from one or more of E30LV, E50LV, K100LV, K4M, K15M and K100M; the polysaccharide gum is selected from one or more of sodium alginate, gum arabic, xanthan gum and locust bean gum; the slow release polymer accounts for 5-60% of the slow release layer; and the binder is selected from one or more of sodium carboxymethylcellulose, povidone and hydroxypropyl methylcellulose.

10. The controlled release tablet according to claim 9, wherein The slow release polymer accounts for 7.5-40% of the slow release layer; and the binder is povidone.

11. 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 layer is 12.5-1:1 by weight fraction; the ratio of the mass of the drug-containing immediate release layer to the mass of the drug-containing core layer is 10-1:

1.

12. A process for the preparation of the controlled release tablet according to any one of claims 1 to 11, characterized in that, The method comprises the following steps: (1) wet granulating the raw materials of the drug-containing immediate release layer to obtain drug-containing immediate release layer granules; (2) wet granulating the raw materials of the drug-containing sustained release layer to obtain drug-containing sustained release layer granules; (3) wet granulating the raw materials of the core, compressing the granules into tablets, and then sequentially performing first layer isolation coating, second layer enteric coating, and third layer isolation coating to obtain a drug-containing core; (4) placing the drug-containing core on the drug-containing sustained release layer granules, pre-compressing, placing the drug-containing immediate release layer granules on the pre-compressed tablets, compressing the tablets, and coating to obtain the sustained release tablets.

13. The method of claim 12, wherein, The pre-compression pressure in step (4) is 0.1-2 KN; the compression pressure is 5-25 KN.

14. The method of claim 12, wherein, The pre-compression pressure in step (4) is 0.1-0.5 KN; the compression pressure is 8-20 KN.

15. Use of the sustained release tablets of loxoprofen sodium as claimed in any one of claims 1-11 or prepared by the preparation method as claimed in any one of claims 12-14 in the preparation of a medicament for treating a painful disease.

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