Diclofenac sodium enteric-coated tablet and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a diclofenac sodium enteric-coated tablet and a preparation method thereof. The diclofenac sodium enteric-coated tablet comprises a quick release layer, a slow release layer and an enteric coating layer, the quick release layer comprises the following components in parts by weight: 20-40 parts of diclofenac sodium, 5-15 parts of a disintegrating agent, 20-50 parts of a filling agent, 1-3 parts of a lubricating agent and 1-5 parts of an adhesive; the sustained release layer comprises the following components in parts by weight: 50-80 parts of diclofenac sodium, 5-15 parts of cross-linked chitosan, 1-3 parts of a lubricant and 1-5 parts of an adhesive; the enteric coating layer is prepared from the following components in parts by weight: 20 to 45 parts of enteric material and 5 to 15 parts of N-acetylneuraminic acid derivative. The diclofenac sodium enteric-coated tablet disclosed by the invention has excellent in-vitro accumulative release rate, relatively low hygroscopicity and relatively high stability and friability.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a diclofenac sodium enteric-coated tablet and a preparation method thereof. BACKGROUND

[0002] Diclofenac sodium is a non-steroidal anti-inflammatory drug (NSAID) which exerts anti-inflammatory, analgesic and antipyretic effects by inhibiting the activity of cyclooxygenase (COX-1 / COX-2) and reducing the synthesis of prostaglandins. Since it was launched in the 1970s, it has been widely used in the treatment of inflammatory and painful diseases such as osteoarthritis, rheumatoid arthritis, acute gout, musculoskeletal pain and dysmenorrhea.

[0003] Due to the strong irritability of diclofenac sodium to gastric mucosa, it is often prepared into an enteric-coated tablet to reduce direct irritation to the stomach. This dosage form can release the drug in the intestinal tract to achieve rapid onset of action, and is particularly suitable for the treatment of acute pain. However, ordinary enteric-coated preparations often lead to a sharp increase in blood drug concentration after rapid drug release, which easily exceeds the therapeutic window and increases the risk of adverse reactions. In addition, such preparations are difficult to maintain an effective blood drug concentration for a long time, and patients need to take the drug multiple times a day, which not only leads to poor drug compliance, but also increases the treatment burden.

[0004] Therefore, it is of great clinical value to develop a more advantageous enteric-coated diclofenac sodium preparation to achieve a more stable blood drug concentration, prolong the drug action time and improve the stability of the tablet. SUMMARY

[0005] In order to overcome the shortcomings of the prior art, one of the purposes of the present application is to provide a diclofenac sodium enteric-coated tablet which has excellent in-vitro cumulative release rate and also has low hygroscopicity, high stability and friability.

[0006] The second purpose of the present application is to provide a preparation method of the diclofenac sodium enteric-coated tablet, which is simple.

[0007] One of the purposes of the present application is achieved by the following technical scheme: A diclofenac sodium enteric-coated tablet comprises a rapid-release layer, a sustained-release layer and an enteric-coated layer. The rapid-release layer comprises the following components in parts by weight: 20-40 parts of diclofenac sodium, 5-15 parts of a disintegrant, 20-50 parts of a filler, 1-3 parts of a lubricant and 1-5 parts of a binder. The sustained-release layer comprises the following components in parts by weight: 50-80 parts of diclofenac sodium, 5-15 parts of cross-linked chitosan, 1-3 parts of a lubricant and 1-5 parts of a binder. The enteric-coated layer comprises the following components in parts by weight: 20-45 parts of an enteric material and 5-15 parts of an N-acetylneuraminic acid derivative. The structural formula of the N-acetylneuraminic acid derivative is: .

[0008] Further, the preparation method of the cross-linked chitosan comprises the following steps: Under the protection of inert gas, a dimethyl sulfoxide solution of a cross-linking agent is added to a dimethyl sulfoxide solution of chitosan and stirred, and the cross-linked chitosan is obtained after purification; The structural formula of the cross-linking agent is: .

[0009] Further, the mass ratio of the chitosan and the cross-linking agent is 1: (1.6-2); the concentration of chitosan in the dimethyl sulfoxide solution of chitosan is 20-30 mg / mL; the concentration of the cross-linking agent in the dimethyl sulfoxide solution of the cross-linking agent is 0.16-0.2 g / mL; the stirring temperature is 80-85 °C, and the stirring time is 8-12 h.

[0010] Further, the preparation method of the cross-linking agent is as follows: 2-hydroxy-5-[2-(4-hydroxyphenyl) diazenyl] benzoic acid is added to N, N-dimethylformamide, anhydrous potassium carbonate and 1, 5-dibromopentane are then added, and the mixture is reacted overnight under reflux condition, and the cross-linking agent is obtained after purification.

[0011] Further, the molar ratio of 2-hydroxy-5-[2-(4-hydroxyphenyl) diazenyl] benzoic acid, 1, 5-dibromopentane and anhydrous potassium carbonate is 5: (12-16): (12-16).

[0012] Further, the preparation method of the N-acetylneuraminic acid derivative comprises the following steps: N-acetylneuraminic acid methyl ester and 4-dimethylaminopyridine are added to anhydrous pyridine, a lauroyl chloride dichloromethane solution is added to the mixture under stirring at 0-5 °C, and the mixture is reacted at room temperature, and the N-acetylneuraminic acid derivative is obtained after purification.

[0013] Further, the molar ratio of N-acetylneuraminic acid methyl ester, 4-dimethylaminopyridine and lauroyl chloride is 2.5: (0.55-0.58): (2.5-2.8); the concentration of the lauroyl chloride dichloromethane solution is 0.5 mmol / mL; the concentration of N-acetylneuraminic acid methyl ester in anhydrous pyridine is 0.25 mmol / mL; the stirring time is 1-2 h; and the reaction time is 12-18 h.

[0014] Further, the mass ratio of diclofenac sodium in the immediate-release layer and the sustained-release layer is 1: (3-5) ; the adhesive in the immediate-release layer and the sustained-release layer is selected from one of hydroxypropyl cellulose, sodium carboxymethyl cellulose and povidone; and the lubricant in the immediate-release layer and the sustained-release layer is magnesium stearate or talc.

[0015] Further, the adhesive in the immediate-release layer and the sustained-release layer is sodium carboxymethyl cellulose; and the lubricant in the immediate-release layer and the sustained-release layer is magnesium stearate.

[0016] Further, the filler is selected from one of lactose, microcrystalline cellulose, starch and mannitol; the disintegrant is sodium croscarmellose or sodium carboxymethyl starch; and the enteric material is methacrylic acid-ethyl acrylate copolymer Eudragit® L100-55.

[0017] Further, the filler is starch; and the disintegrant is sodium carboxymethyl starch.

[0018] The second purpose of the present application is achieved by using the following technical solution: The preparation method of the diclofenac sodium enteric-coated tablet comprises the following steps: (1) according to the weight parts, the raw materials of the immediate-release layer are weighed and mixed, and the immediate-release layer granules are obtained after granulation; (2) according to the weight parts, the raw materials of the sustained-release layer are weighed and mixed, and the sustained-release layer granules are obtained after granulation; (3) the immediate-release layer granules and the sustained-release layer granules are stacked and compressed into tablets to obtain the diclofenac sodium double-layer sustained-release tablet; (4) according to the weight parts, the raw materials of the enteric-coated layer are weighed and added to an ethanol solution with a volume fraction of 70-80% to obtain an enteric-coated solution; (5) the enteric-coated solution is sprayed onto the surface of the diclofenac sodium double-layer sustained-release tablet until the weight gain is 3-5%.

[0019] Compared with the prior art, the present application has the following advantages: 1. The present application provides a diclofenac sodium enteric-coated tablet, which effectively solves the problems of short drug efficacy maintenance time, large blood drug concentration fluctuation, high drug taking frequency and local intestinal mucosa irritation in the prior art, and significantly improves the stability of the tablet.

[0020] 2. The double-release tablet core of the diclofenac sodium enteric-coated tablet provided by the present application is composed of an immediate-release layer and a sustained-release layer, and by adding cross-linked chitosan and N-acetylneuraminic acid derivatives in the sustained-release layer and the coating layer respectively, the diclofenac sodium enteric-coated tablet has excellent in-vitro cumulative release rate, and also has low hygroscopicity, high stability and high friability.

[0021] 3、The present application adds cross-linked chitosan as a release retardant of the sustained-release layer in the diclofenac sodium enteric-coated tablets, significantly improves the sustained-release effect of diclofenac sodium, and effectively prolongs the action time of diclofenac sodium in the body. Specifically, the cross-linked chitosan of the present application is obtained by reacting the hydroxyl or amino group in the chitosan molecule with a cross-linking agent containing azobenzene. By introducing covalent bonds between the chitosan molecular chains through cross-linking reaction, a stable three-dimensional network structure is formed, which can significantly improve the sustained-release effect of diclofenac sodium, effectively prolong the action time of diclofenac sodium in the body, and thus reduce the frequency of drug administration for patients. The azobenzene structure in the cross-linked chitosan has π-π stacking or hydrophobic interaction with diclofenac sodium, which not only improves the uniformity of the dispersion of diclofenac sodium, but also helps to further enhance the sustained-release effect of diclofenac sodium. In addition, the introduction of hydrophobic alkyl chains in the cross-linked chitosan molecule reduces the hydrophilicity, not only effectively prevents the occurrence of adhesion phenomenon during coating process, but also improves the overall moisture-proof performance of the tablet core.

[0022] 4、The present application adds N-acetylneuraminic acid derivative as a plasticizer of the coating layer in the diclofenac sodium enteric-coated tablets, significantly improves the stability of diclofenac sodium. Specifically, the N-acetylneuraminic acid derivative of the present application is prepared by reacting N-acetylneuraminic acid methyl ester with lauroyl chloride. The derivative not only ensures the plasticizing effect, but also its alkyl chain segment can be densely packed in the film to reduce the hygroscopicity; and its N-acetylneuraminic acid polar end can form hydrogen bonds with the hydroxyl groups on the surface of the tablet core, significantly enhancing the adhesion. In addition, the N-acetylneuraminic acid derivative can release N-acetylneuraminic acid groups in the intestinal environment, and the N-acetylneuraminic acid groups can inhibit the P-glycoprotein efflux function in intestinal cells, reducing the drug being pumped back to the intestinal cavity, thereby helping to improve the oral bioavailability of diclofenac sodium. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 is the infrared spectrum of the cross-linked chitosan prepared in Example 4, wherein curve a is the infrared spectrum of the cross-linked chitosan, and curve b is the infrared spectrum of chitosan. DETAILED DESCRIPTION

[0024] The present application will be further described below in conjunction with the drawings and specific embodiments. It should be noted that the following described embodiments or technical features can be combined in any manner to form new embodiments without conflict. The specific conditions in the embodiments are carried out according to the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments used, if not specifically stated, are conventional products obtained through commercial channels.

[0025] Example 1 This embodiment provides a cross-linking agent, and the preparation method is as follows: According to the amount ratio of 2-hydroxy-5-[2-(4-hydroxyphenyl) diazenyl] benzoic acid, 1,5-dibromopentane, anhydrous potassium carbonate, N,N-dimethylformamide is 5 mmol: 10 mmol: 10 mmol: 20 mL, 2-hydroxy-5-[2-(4-hydroxyphenyl) diazenyl] benzoic acid (CAS: 259151-72-9) is dissolved in N,N-dimethylformamide, anhydrous potassium carbonate and 1,5-dibromopentane are added, after reaction overnight under reflux condition, cooling to room temperature, filtering to obtain the product, washing with dichloromethane, column chromatography purification, vacuum drying to obtain the crosslinking agent (yield 65.7%), the nuclear magnetic resonance and mass spectrum results of the crosslinking agent are as follows: 1 HNMR: (C 22 H 28 O4N2Br2, 400 MHz, DMSO-d6) δ: 1.27-1.31 (m, 4H), 1.75-1.84 (m, 8H), 3.50-3.54 (m, 4H), 1.04-4.08 (m, 4H), 7.06-7.08 (d, 2H), 7.36-7.38 (d, 1H), 7.77-7.79 (d, 2H), 8.23-8.25 (d, 1H), 8.48 (s, 1H), 12.04 (s, 1H); MS (ESI) m / z = 556.04 [M].

[0026] Example 2 This example provides a crosslinking agent, the preparation method is as follows: According to the amount ratio of 2-hydroxy-5-[2-(4-hydroxyphenyl) diazenyl] benzoic acid, 1,5-dibromopentane, anhydrous potassium carbonate, N,N-dimethylformamide is 5 mmol: 10 mmol: 10 mmol: 20 mL, 2-hydroxy-5-[2-(4-hydroxyphenyl) diazenyl] benzoic acid (CAS: 259151-72-9) is dissolved in N,N-dimethylformamide, anhydrous potassium carbonate and 1,5-dibromopentane are added, after reaction overnight under reflux condition, cooling to room temperature, filtering to obtain the product, washing with dichloromethane, column chromatography purification, vacuum drying to obtain the crosslinking agent (yield 65.7%), the nuclear magnetic resonance and mass spectrum results of the crosslinking agent are as follows:

[0027] Example 3 This example provides a crosslinking agent, the preparation method is as follows: According to the dosage ratio of 2-hydroxy-5-[2-(4-hydroxyphenyl) diazenyl] benzoic acid, 1,5-dibromopentane, anhydrous potassium carbonate, N,N-dimethylformamide is 5 mmol: 16 mmol: 16 mmol: 30 mL, 2-hydroxy-5-[2-(4-hydroxyphenyl) diazenyl] benzoic acid is dissolved in N,N-dimethylformamide, anhydrous potassium carbonate and 1,5-dibromopentane are added, after reaction overnight under reflux condition, cooling to room temperature, filtering to obtain the product, washing with dichloromethane, column chromatography purification, vacuum drying to obtain the crosslinking agent (yield 63.9%), the nuclear magnetic resonance and mass spectrum results of the crosslinking agent are as follows, which are the same as those of Example 1.

[0028] Example 4 This example provides a crosslinked chitosan, and the preparation method is as follows: Under the protection of nitrogen, according to the mass ratio of chitosan to crosslinking agent is 1:1.8, 0.18 g / mL of the dimethyl sulfoxide solution of the crosslinking agent obtained in Example 1 is added to the dimethyl sulfoxide solution of chitosan with a concentration of 26 mg / mL, stirring at 82℃ for 10 h, then precipitating the product with acetone at 25℃, washing with acetone at 40℃, removing dimethyl sulfoxide by dialysis, and freeze-drying to obtain the crosslinked chitosan.

[0029] Example 5 This example provides a crosslinked chitosan, and the preparation method is as follows: Under the protection of nitrogen, according to the mass ratio of chitosan to crosslinking agent is 1:1.6, 0.16 g / mL of the dimethyl sulfoxide solution of the crosslinking agent obtained in Example 2 is added to the dimethyl sulfoxide solution of chitosan with a concentration of 30 mg / mL, stirring at 80℃ for 12 h, then precipitating the product with acetone at 25℃, washing with acetone at 40℃, removing dimethyl sulfoxide by dialysis, and freeze-drying to obtain the crosslinked chitosan.

[0030] Example 6 This example provides a crosslinked chitosan, and the preparation method is as follows: Under the protection of nitrogen, according to the mass ratio of chitosan to crosslinking agent is 1:2, 0.2 g / mL of the dimethyl sulfoxide solution of the crosslinking agent obtained in Example 3 is added to the dimethyl sulfoxide solution of chitosan with a concentration of 20 mg / mL, stirring at 85℃ for 8 h, then precipitating the product with acetone at 25℃, washing with acetone at 40℃, removing dimethyl sulfoxide by dialysis, and freeze-drying to obtain the crosslinked chitosan.

[0031] Example 7 This example provides a N-acetylneuraminic acid derivative, and the preparation method is as follows: The N-acetylneuraminic acid methyl ester, DMAP and lauroyl chloride were dissolved in anhydrous pyridine in a molar ratio of 2.5:0.56:2.7, so that the concentration of the N-acetylneuraminic acid methyl ester in the anhydrous pyridine was 0.25 mmol / mL; a dichloromethane solution of lauroyl chloride with a concentration of 0.5 mmol / mL was added to the above mixture at 4°C and stirred for 1.5 h, and then the temperature was raised to room temperature and reacted for 16 h; after the reaction was completed, water was added for dilution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated to dryness, and purified by column chromatography to obtain the N-acetylneuraminic acid derivative, and the nuclear magnetic and mass spectrometry results were as follows: 1 HNMR: (C 24 H 43 O 10 N, 400 MHz, DMSO-d6) δ: 0.86-0.90 (m, 3H), 1.24-1.35 (m, 16H), 1.64-1.68 (m, 2H), 1.99 (s, 3H), 2.11-2.15 (m, 1H), 2.30-2.34 (m, 2H), 2.36-2.40 (m, 1H), 3.58-3.62 (t, 2H), 3.66 (s, 3H), 4.06-4.14 (m, 3H), 4.30-4.39 (m, 4H), 4.51 (s, 1H), 5.37 (s, 1H), 8.14 (s, 1H); MS (ESI) m / z = 505.29 [M].

[0032] Example 8 The present example provides a N-acetylneuraminic acid derivative, and the preparation method is as follows: The N-acetylneuraminic acid methyl ester and DMAP were dissolved in anhydrous pyridine in a molar ratio of 2.5:0.55, so that the concentration of the N-acetylneuraminic acid methyl ester in the anhydrous pyridine was 0.25 mmol / mL; a dichloromethane solution of lauroyl chloride with a concentration of 0.5 mmol / mL was added to the above mixture at 0°C and stirred for 1 h, and then the temperature was raised to room temperature and reacted for 12 h; after the reaction was completed, water was added for dilution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, evaporated to dryness, and purified by column chromatography to obtain the N-acetylneuraminic acid derivative, and the nuclear magnetic and mass spectrometry results were the same as those of Example 7.

[0033] Example 9 The present example provides a N-acetylneuraminic acid derivative, and the preparation method is as follows: The N-acetylneuraminic acid methyl ester, DMAP is dissolved in anhydrous pyridine according to the molar ratio of N-acetylneuraminic acid methyl ester, DMAP, lauroyl chloride is 2.5:0.58:2.8, so that the concentration of N-acetylneuraminic acid methyl ester in anhydrous pyridine is 0.25 mmol / mL; at 5°C, add the lauroyl chloride solution in dichloromethane with a concentration of 0.5 mmol / mL to the above mixture and stir for 2 h, then raise the temperature to room temperature and react for 18 h, after the reaction is completed, dilute with water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous magnesium sulfate, filter, evaporate to dryness, and purify by column chromatography to obtain the N-acetylneuraminic acid derivative, and the nuclear magnetic resonance and mass spectrometry results are the same as those of Example 7.

[0034] Example 10 The present example provides a diclofenac sodium enteric-coated tablet, which comprises a fast-release layer, a slow-release layer, and an enteric-coated layer, and the mass ratio of diclofenac sodium in the fast-release layer and the slow-release layer is 1:4.

[0035] The fast-release layer comprises the following components in parts by weight: 25 parts of diclofenac sodium, 10 parts of sodium carboxymethyl starch, 30 parts of starch, 2 parts of magnesium stearate, and 4 parts of sodium carboxymethyl cellulose; The slow-release layer comprises the following components in parts by weight: 60 parts of diclofenac sodium, 11 parts of the cross-linked chitosan of Example 4, 2 parts of magnesium stearate, and 4 parts of sodium carboxymethyl cellulose; The enteric-coated layer comprises the following components in parts by weight: 30 parts of methacrylic acid-ethyl acrylate copolymer Eudragit® L100-55, and 10 parts of the N-acetylneuraminic acid derivative of Example 7.

[0036] The present example also provides a preparation method of the above-mentioned diclofenac sodium enteric-coated tablet, which comprises the following steps: (1) According to the weight parts, weigh and mix the raw materials of the fast-release layer, and then sieve the mixture through a 30-mesh sieve to obtain fast-release layer granules; (2) According to the weight parts, weigh and mix the raw materials of the slow-release layer, and then sieve the mixture through a 30-mesh sieve to obtain slow-release layer granules; (3) According to the mass ratio of diclofenac sodium in the fast-release layer and the slow-release layer, first add the slow-release layer granules to the tablet press, then add the fast-release layer granules, and then press the tablet to obtain a diclofenac sodium double-layer slow-release tablet; (4) According to the weight parts, weigh the raw materials of the enteric-coated layer and add them to an ethanol solution with a volume fraction of 75% to obtain an enteric-coating solution; (5) Place the diclofenac sodium double-layer slow-release tablet in a coating machine, set the rotation speed of the coating kettle to 10 rpm, the air inlet temperature to 55°C, the air inlet speed to 1000 rpm, and the atomization pressure to no less than 0.2 MPa, and then spray the enteric-coating solution until the weight gain is 4%.

[0037] Example 11 The present example provides a diclofenac sodium enteric-coated tablet, which comprises a fast-release layer, a slow-release layer and an enteric-coating layer, and the mass ratio of diclofenac sodium in the fast-release layer and the slow-release layer is 1:3.

[0038] The fast-release layer comprises the following components in parts by weight: diclofenac sodium 20 parts, sodium carboxymethyl starch 5 parts, starch 20 parts, magnesium stearate 1 part, sodium carboxymethyl cellulose 1 part; The slow-release layer comprises the following components in parts by weight: diclofenac sodium 50 parts, cross-linked chitosan of Example 5 5 parts, magnesium stearate 1 part, sodium carboxymethyl cellulose 1 part; The enteric-coating layer comprises the following components in parts by weight: methacrylic acid-ethyl acrylate copolymer Eudragit® L100-55 20 parts, N-acetylneuraminic acid derivative of Example 8 5 parts.

[0039] The present example also provides a preparation method of the above-mentioned diclofenac sodium enteric-coated tablet, which comprises the following steps: (1) The raw materials of the fast-release layer are weighed according to the weight parts and mixed, and then granulated with a 30-mesh sieve to obtain fast-release layer granules; (2) The raw materials of the slow-release layer are weighed according to the weight parts and mixed, and then granulated with a 30-mesh sieve to obtain slow-release layer granules; (3) The slow-release layer granules are added to the tablet press first, and then the fast-release layer granules are added according to the mass ratio of diclofenac sodium in the fast-release layer and the slow-release layer, and then the tablet is pressed to obtain a diclofenac sodium double-layer slow-release tablet; (4) The raw materials of the enteric-coating layer are weighed according to the weight parts and added to an ethanol solution with a volume fraction of 70% to obtain an enteric-coating solution; (5) The diclofenac sodium double-layer slow-release tablet is placed in a coating machine, the coating pan rotation speed is set to 10 rpm, the air inlet temperature is set to 55°C, the air inlet speed is set to 1000 rpm, the atomizing pressure is not less than 0.2 MPa, and the enteric-coating solution is sprayed until the weight gain is 3%.

[0040] Example 12 The present example provides a diclofenac sodium enteric-coated tablet, which comprises a fast-release layer, a slow-release layer and an enteric-coating layer, and the mass ratio of diclofenac sodium in the fast-release layer and the slow-release layer is 1:5.

[0041] The fast-release layer comprises the following components in parts by weight: diclofenac sodium 40 parts, sodium carboxymethyl starch 15 parts, starch 50 parts, magnesium stearate 3 parts, sodium carboxymethyl cellulose 5 parts; The slow-release layer comprises the following components in parts by weight: diclofenac sodium 80 parts, cross-linked chitosan of Example 6 15 parts, magnesium stearate 3 parts, sodium carboxymethyl cellulose 5 parts; The enteric coating layer comprises the following components in parts by weight: methacrylic acid-ethyl acrylate copolymer Eudragit® L100-55 45 parts, the N-acetylneuraminic acid derivative of Example 9 15 parts.

[0042] The present embodiment also provides a preparation method of the above-mentioned diclofenac sodium enteric-coated tablet, comprising the following steps: (1) according to the weight parts, the raw materials of the immediate-release layer are weighed and mixed, and then granulated with a 30-mesh sieve to obtain immediate-release layer granules; (2) according to the weight parts, the raw materials of the sustained-release layer are weighed and mixed, and then granulated with a 30-mesh sieve to obtain sustained-release layer granules; (3) according to the mass ratio of diclofenac sodium in the immediate-release layer and the sustained-release layer, the sustained-release layer granules are first added to the tablet press, and then the immediate-release layer granules are added, and after tabletting, diclofenac sodium double-layer sustained-release tablets are obtained; (4) according to the weight parts, the raw materials of the enteric coating layer are weighed and added to an ethanol solution with a volume fraction of 80% to obtain an enteric coating solution; (5) the diclofenac sodium double-layer sustained-release tablets are placed in a coating machine, the rotation speed of the coating kettle is set to 10 rpm, the air inlet temperature is 55°C, the air inlet speed is 1000 rpm, the atomizing pressure is not less than 0.2 MPa, and the enteric coating solution is sprayed until the weight gain is 3-5%.

[0043] Comparative Example 1 The difference between this comparative example and Example 10 is that chitosan is used instead of the cross-linked chitosan of Example 4 in the sustained-release layer.

[0044] Comparative Example 2 The difference between this comparative example and Example 10 is that the N-acetylneuraminic acid derivative is omitted from the enteric coating layer.

[0045] Experimental Example 1 The cross-linked chitosan prepared in Example 4 is subjected to infrared spectroscopy (FT-IR) analysis, and the results are shown in Figure 1 .

[0046] Figure 1 is the infrared spectrum of the cross-linked chitosan prepared in Example 4, wherein curve a is the infrared spectrum of the cross-linked chitosan, and curve b is the infrared spectrum of chitosan. Compared with chitosan, the cross-linked chitosan has characteristic absorption peaks of benzene ring skeleton and -N=N- bond at 1503 and 1458 cm -1 , indicating that the cross-linked chitosan is successfully prepared.

[0047] Experimental Example 2 The friability, stability and hygroscopicity of the diclofenac sodium enteric-coated tablets obtained in Examples 10-12 and Comparative Examples 1-2 are detected, as follows: (1) Friability: 50 tablets of the diclofenac sodium enteric-coated tablets obtained in Examples 10-12 and Comparative Examples 1-2 were taken respectively, and the friability test was performed according to the friability test method for tablets (general test 0923) in the Chinese Pharmacopoeia 2020 edition, using a friability tester, and the average value was taken, and the specific data are shown in Table 1 below.

[0048] (2) Stability, hygroscopicity: The diclofenac sodium enteric-coated tablets obtained in Examples 10-12 and Comparative Examples 1-2 were packaged according to the market, and placed in a temperature of 40±2℃ and a relative humidity of 75%±5% for 180 days of testing, and samples were taken at the 30th day, 60th day, 90th day and 180th day of the test, and the content of diclofenac sodium was detected according to the requirements of the Chinese Pharmacopoeia 2020 edition “9001 Raw Materials and Preparation Stability Test Guidelines” using high performance liquid chromatography, and the specific data are shown in Table 2 below; in addition, the hygroscopicity of diclofenac sodium was detected at the 10th day and 30th day of the test, and the specific data are shown in Table 3 below.

[0049] Table 1 Table 2 Table 3 As shown in Table 1, the diclofenac sodium enteric-coated tablets obtained in Examples 10-12 of the present application have no cracking, cracking and crushing, meeting the requirements of tablets, and can reduce the waste caused by crushing of the medicine. The diclofenac sodium enteric-coated tablets obtained in Comparative Examples 1-2 are prone to cracking, cracking and crushing.

[0050] As shown in Table 2, the diclofenac sodium enteric-coated tablets obtained in Examples 10-12 of the present application exhibit high stability, and the content of diclofenac sodium remains basically unchanged in the accelerated test.

[0051] As shown in Table 3, the diclofenac sodium enteric-coated tablets obtained in Examples 10-12 of the present application have low hygroscopicity.

[0052] Compared with Example 10, the brittle degree of the diclofenac sodium enteric-coated tablets obtained by using chitosan instead of cross-linked chitosan in Comparative Example 1 and by omitting the N-acetylneuraminic acid derivative in Comparative Example 2 is low, the stability is poor, and the hygroscopicity is relatively high. Further analysis shows that the introduction of the hydrophobic alkyl chain in the cross-linked chitosan molecule reduces the hydrophilicity, which not only effectively prevents the adhesion phenomenon in the coating process, but also improves the overall moisture-proof performance of the tablet core. The N-acetylneuraminic acid derivative acts as a plasticizer for the coating layer, and while ensuring the plasticizing effect, the alkyl chain segment can be densely packed in the film, reducing the hygroscopicity, and the polar end can form hydrogen bonds with the hydroxyl groups on the surface of the tablet core, significantly enhancing the adhesion. The cross-linked chitosan and the N-acetylneuraminic acid derivative synergize to effectively prevent the coating film from cracking, peeling or moisture failure during storage and transportation, and comprehensively improve the physical stability and moisture-proof performance of the tablets.

[0053] Experimental Example 3 The release rates of the diclofenac sodium enteric-coated tablets obtained in Examples 10-12 and Comparative Examples 1-2 were detected, as follows. According to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition Part IV General Chapter 0931 Second Method), the pH = 7.4 phosphate buffer was used as the dissolution medium, the rotation speed was 100 r / min, and the operation was carried out according to the method. At 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 12 h, 8 mL of sample was taken (while the same temperature of dissolution medium was supplemented), filtered, and the filtrate was taken as the test solution. The phosphate buffer was used as the reference liquid, the absorbance was measured at a wavelength of 276 nm by ultraviolet spectrophotometry, the cumulative release rate of diclofenac sodium was calculated, and the specific data are shown in Table 4 below.

[0054] Table 4 As can be seen from Table 4, the diclofenac sodium enteric-coated tablets obtained in Example 10 have excellent in-vitro release rate, and the release rate is ≥95% at 12 h. Compared with Example 10, the diclofenac sodium enteric-coated tablets obtained by using chitosan instead of cross-linked chitosan in Comparative Example 1 release faster in the intestinal tract. Further analysis shows that the cross-linked chitosan obtained by reacting the hydroxyl or amino groups in the chitosan molecule with the cross-linking agent containing azobenzene is used as the release retardant of the release layer. By introducing covalent bonds between the chitosan molecular chains through cross-linking reaction, a stable three-dimensional network structure is formed, which can significantly improve the sustained release effect of diclofenac sodium, effectively prolong the action time of the drug in the body, and thus reduce the frequency of drug administration for patients. The azobenzene structure in the cross-linked chitosan has π-π stacking or hydrophobic interaction with diclofenac sodium, which not only improves the dispersion uniformity of diclofenac sodium, but also helps to further enhance the sustained release effect of diclofenac sodium.

[0055] The above embodiments are only the preferred embodiments of the present application, and cannot be used to limit the protection scope of the present application, and any non-essential changes and replacements made by those skilled in the art on the basis of the present application shall fall within the protection scope of the present application.

Claims

1. A diclofenac sodium enteric coated tablet, characterized in that, The enteric coated tablet comprises a quick-release layer, a sustained-release layer and an enteric coating layer. The quick-release layer comprises the following components in parts by weight: 20-40 parts of sodium diclofenac, 5-15 parts of disintegrant, 20-50 parts of filler, 1-3 parts of lubricant and 1-5 parts of binder. The sustained-release layer comprises the following components in parts by weight: 50-80 parts of sodium diclofenac, 5-15 parts of cross-linked chitosan, 1-3 parts of lubricant and 1-5 parts of binder. The enteric coating layer comprises the following components in parts by weight: 20-45 parts of enteric material and 5-15 parts of N-acetylneuraminic acid derivative. The N-acetylneuraminic acid derivative has the following structural formula: ； The preparation method of the cross-linked chitosan comprises the following steps: Under the protection of inert gas, a dimethyl sulfoxide solution of cross-linking agent is added to a dimethyl sulfoxide solution of chitosan and stirred, and the cross-linked chitosan is obtained after purification. The cross-linking agent has the following structural formula: 。 2. The diclofenac sodium enteric coated tablet according to claim 1, wherein The mass ratio of the chitosan to the cross-linking agent is 1: (1.6-2); the concentration of chitosan in the dimethyl sulfoxide solution of chitosan is 20-30 mg / mL; the concentration of cross-linking agent in the dimethyl sulfoxide solution of cross-linking agent is 0.16-0.2 g / mL; the stirring temperature is 80-85 ℃, and the stirring time is 8-12 h.

3. The diclofenac sodium enteric coated tablet according to claim 2, wherein The preparation method of the cross-linking agent is as follows: 2-hydroxy-5-[2-(4-hydroxyphenyl) diazenyl] benzoic acid is added to N, N-dimethylformamide, anhydrous potassium carbonate and 1, 5-dibromopentane are added, and the mixture is reacted overnight under reflux condition, and the cross-linking agent is obtained after purification.

4. The diclofenac sodium enteric-coated tablet according to claim 3, which is characterized by, The molar ratio of 2-hydroxy-5-[2-(4-hydroxyphenyl) diazenyl] benzoic acid, 1, 5-dibromopentane and anhydrous potassium carbonate is 5: (12-16): (12-16).

5. The diclofenac sodium enteric coated tablet according to claim 1, wherein The preparation method of the N-acetylneuraminic acid derivative comprises the following steps: N-acetylneuraminic acid methyl ester and 4-dimethylaminopyridine are added to anhydrous pyridine, a lauroyl chloride dichloromethane solution is added under 0-5 ℃ and stirred, then the mixture is reacted at room temperature, and the N-acetylneuraminic acid derivative is obtained after purification.

6. The diclofenac sodium enteric coated tablet according to claim 5, wherein The molar ratio of N-acetylneuraminic acid methyl ester, 4-dimethylaminopyridine and lauroyl chloride is 2.5: (0.55-0.58): (2.5-2.8); the concentration of lauroyl chloride dichloromethane solution is 0.5 mmol / mL; the concentration of N-acetylneuraminic acid methyl ester in anhydrous pyridine is 0.25 mmol / mL; the stirring time is 1-2 h; and the reaction time is 12-18 h.

7. The diclofenac sodium enteric coated tablet according to claim 1, wherein The mass ratio of sodium diclofenac in the quick-release layer and the sustained-release layer is 1: (3-5); the binder in the quick-release layer and the sustained-release layer is selected from one of hydroxypropyl cellulose, sodium carboxymethyl cellulose and povidone; and the lubricant in the quick-release layer and the sustained-release layer is magnesium stearate or talc.

8. The diclofenac sodium enteric coated tablet according to claim 1, wherein The filler is selected from one of lactose, microcrystalline cellulose, starch and mannitol; the disintegrant is cross-linked sodium carboxymethyl cellulose or sodium carboxymethyl starch; and the enteric material is methacrylic acid-ethyl acrylate copolymer Eudragit® L100-55.

9. A process for the preparation of the diclofenac sodium enteric coated tablet according to any one of claims 1 to 8, characterized in that, The method comprises the following steps: (1) according to the weight parts, the raw materials of the immediate-release layer are weighed and mixed, and the immediate-release layer granules are obtained after granulation; (2) according to the weight parts, the raw materials of the sustained-release layer are weighed and mixed, and the sustained-release layer granules are obtained after granulation; (3) the immediate-release layer granules and the sustained-release layer granules are stacked and compressed into tablets to obtain the diclofenac sodium double-layer sustained-release tablets; (4) according to the weight parts, the raw materials of the enteric coating layer are weighed and added into an ethanol solution with a volume fraction of 70-80% to obtain an enteric coating solution; (5) the enteric coating solution is sprayed onto the surface of the diclofenac sodium double-layer sustained-release tablets until the weight increases by 3-5%.

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