Dichlorphenamide and its use in the treatment of hyperkalemic periodic paralysis

Abstract

The application 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-coated 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 lubricant and 1-5 parts of a binder; the slow-release layer comprises the following components in parts by weight: 50-80 parts of diclofenac sodium, 5-15 parts of crosslinked chitosan, 1-3 parts of a lubricant and 1-5 parts of a binder; and the enteric-coated layer comprises the following components in parts by weight: 20-45 parts of an enteric material and 5-15 parts of N-acetylneuraminic acid derivative. The diclofenac sodium enteric-coated tablet has excellent in-vitro cumulative release degree, and has low hygroscopicity, high stability and high friability.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, and particularly relates to a diclofenac sodium enteric-coated tablet and its preparation method. Background Technology

[0002] Diclofenac sodium is a nonsteroidal anti-inflammatory drug (NSAID) that exerts its anti-inflammatory, analgesic, and antipyretic effects by inhibiting the activity of cyclooxygenases (COX-1 / COX-2) and reducing prostaglandin synthesis. Since its introduction in the 1970s, it has been widely used to treat inflammatory and pain-related diseases such as osteoarthritis, rheumatoid arthritis, acute gout, musculoskeletal pain, and dysmenorrhea.

[0003] Because diclofenac sodium is highly irritating to the gastric mucosa, it is often formulated into enteric-coated tablets in clinical practice to reduce direct irritation to the stomach. This dosage form allows the drug to be released in the intestines, achieving rapid onset of action, and is particularly suitable for the treatment of acute pain. However, after the rapid release of the drug, conventional enteric-coated preparations often lead to a sharp increase in blood drug concentration, easily exceeding the therapeutic window and increasing the risk of adverse reactions. In addition, these preparations are difficult to maintain effective blood drug concentrations for extended periods, requiring patients to take the medication multiple times a day, resulting in poor medication adherence and increased treatment burden.

[0004] Therefore, developing a more advantageous diclofenac sodium enteric-coated formulation to achieve more stable blood drug concentrations, prolong the duration of drug action, and improve tablet stability has significant clinical value. Summary of the Invention

[0005] In order to overcome the shortcomings of the prior art, one of the objectives of the present invention is to provide a diclofenac sodium enteric-coated tablet with excellent in vitro cumulative release, as well as low hygroscopicity and high stability and brittleness.

[0006] The second objective of this invention is to provide a simple method for preparing diclofenac sodium enteric-coated tablets.

[0007] One of the objectives of this invention is achieved through the following technical solution:

[0008] A diclofenac sodium enteric-coated tablet includes an immediate-release layer, a sustained-release layer, and an enteric coating layer;

[0009] By weight, the immediate-release layer comprises the following components: 20-40 parts of diclofenac sodium, 5-15 parts of disintegrant, 20-50 parts of filler, 1-3 parts of lubricant, and 1-5 parts of binder.

[0010] The sustained-release layer comprises the following components by weight: 50-80 parts of diclofenac sodium, 5-15 parts of cross-linked chitosan, 1-3 parts of lubricant, and 1-5 parts of binder.

[0011] The enteric coating layer comprises the following components in parts by weight: 20-45 parts of an enteric material, 5-15 parts of an N-acetylneuraminic acid derivative;

[0012] The N-acetylneuraminic acid derivative has the following structural formula:

[0013] .

[0014] Further, the preparation method of the cross-linked chitosan comprises the following steps:

[0015] 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;

[0016] The cross-linking agent has the following structural formula:

[0017] .

[0018] Further, 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 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.

[0019] Further, the preparation method of the cross-linking agent is as follows:

[0020] 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 under reflux conditions overnight, and the cross-linking agent is obtained after purification.

[0021] 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).

[0022] Further, the preparation method of the N-acetylneuraminic acid derivative comprises the following steps:

[0023] N-acetylneuraminic acid methyl ester and 4-dimethylaminopyridine are added to anhydrous pyridine, a lauroyl chloride dichloromethane solution is added under 0-5 °C and stirred, and then the mixture is reacted at room temperature, and the N-acetylneuraminic acid derivative is obtained after purification after the reaction is completed.

[0024] Further, the molar ratio of the N-acetylneuraminic acid methyl ester, 4-dimethylaminopyridine, lauroyl chloride is 2.5: (0.55-0.58): (2.5-2.8); the concentration of the dichloromethane solution of the lauroyl chloride is 0.5 mmol / mL; the concentration of the 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.

[0025] Further, the mass ratio of the diclofenac sodium in the immediate-release layer and the sustained-release layer is 1: (3-5); the binder 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.

[0026] Further, the binder 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.

[0027] 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.

[0028] Further, the filler is starch; and the disintegrant is sodium carboxymethyl starch.

[0029] The second purpose of the present application is achieved by using the following technical solution:

[0030] The preparation method of the diclofenac sodium enteric-coated tablet described above comprises the following steps:

[0031] (1) The raw materials of the immediate-release layer are weighed according to the weight parts and mixed, and the immediate-release layer granules are obtained after granulation;

[0032] (2) The raw materials of the sustained-release layer are weighed according to the weight parts and mixed, and the sustained-release layer granules are obtained after granulation;

[0033] (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;

[0034] (4) The raw materials of the enteric-coated layer are weighed according to the weight parts and added to an ethanol solution with a volume fraction of 70-80% to obtain an enteric-coated solution;

[0035] (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%.

[0036] Compared with the prior art, the present application has the following beneficial effects:

[0037] 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 frequency of medication and local intestinal mucosa irritation in the prior art, while significantly improving the stability of the tablet.

[0038] 2. The diclofenac sodium enteric-coated tablet provided by the present application comprises a double-release tablet core composed of a rapid-release layer and a slow-release layer, and by adding cross-linked chitosan and N-acetylneuraminic acid derivatives in the slow-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 and high stability and friability.

[0039] 3. The present application adds cross-linked chitosan as a release retardant in the slow-release layer of the diclofenac sodium enteric-coated tablet, which significantly improves the slow-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 slow-release effect of diclofenac sodium and effectively prolong the action time of diclofenac sodium in the body, thereby reducing 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 slow-release effect of diclofenac sodium. In addition, the introduction of hydrophobic alkyl chains in the cross-linked chitosan molecule reduces the hydrophilicity, which not only effectively prevents the occurrence of adhesion during the coating process, but also improves the overall moisture-proof performance of the tablet core.

[0040] 4. The present application adds N-acetylneuraminic acid derivative as a plasticizer in the coating layer of the diclofenac sodium enteric-coated tablet, which 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. This derivative not only ensures the plasticizing effect, but also its alkyl chain segment can be densely packed in the film, reducing the hygroscopicity; while 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, which can inhibit the P-glycoprotein efflux function in intestinal cells, reducing the pumping of drugs back to the intestinal cavity, thereby helping to improve the oral bioavailability of diclofenac sodium. BRIEF DESCRIPTION OF DRAWINGS

[0041] 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

[0042] The 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 with each other to form new embodiments without conflict. The specific conditions not mentioned in the embodiments are carried out according to the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments used are conventional products obtained through commercial channels, unless otherwise specified.

[0043] Example 1

[0044] This embodiment provides a crosslinking agent, and the preparation method is as follows:

[0045]

[0046] According to the use 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, and after overnight reaction under reflux condition, it is cooled to room temperature, filtered, washed with dichloromethane, and column chromatography is used for purification, and after vacuum drying, the crosslinking agent (yield 65.7%) is obtained. The nuclear magnetic resonance and mass spectrum results of the crosslinking agent are as follows:

[0047] 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].

[0048] Example 2

[0049] This embodiment provides a crosslinking agent, and the preparation method is as follows:

[0050] 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 5mmol: 12mmol: 12mmol: 15mL, 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 64.2%), the nuclear magnetic resonance and mass spectrum results of the crosslinking agent are as follows, which are the same as Example 1.

[0051] Example 3

[0052] This example provides a crosslinking agent, and the preparation method is as follows:

[0053] 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 5mmol: 12mmol: 12mmol: 15mL, 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 64.2%), the nuclear magnetic resonance and mass spectrum results of the crosslinking agent are as follows, which are the same as Example 1.

[0054] Example 4

[0055] This example provides a crosslinked chitosan, and the preparation method is as follows:

[0056] According to the mass ratio of chitosan to crosslinking agent is 1:1.8, the concentration of chitosan dimethyl sulfoxide solution is 26mg / mL, the concentration of crosslinking agent dimethyl sulfoxide solution obtained in Example 1 is 0.18g / mL, under nitrogen protection, stirring at 82℃ for 10h, then precipitating the product with 25℃ acetone, washing with 40℃ acetone, removing dimethyl sulfoxide by dialysis, and freeze-drying to obtain the crosslinked chitosan.

[0057] Example 5

[0058] This example provides a crosslinked chitosan, and the preparation method is as follows:

[0059] Under nitrogen protection, according to the mass ratio of chitosan and crosslinking agent being 1:1.6, a dimethyl sulfoxide solution of the crosslinking agent obtained in Example 2 with a concentration of 0.16 g / mL was added into a dimethyl sulfoxide solution of chitosan with a concentration of 30 mg / mL, and stirred at 80°C for 12 h, then the product was precipitated with acetone at 25°C, washed with acetone at 40°C, and the dimethyl sulfoxide was removed by dialysis, and the crosslinked chitosan was obtained after freeze-drying.

[0060] Example 6

[0061] The present example provides a crosslinked chitosan, and the preparation method is as follows:

[0062] Under nitrogen protection, according to the mass ratio of chitosan and crosslinking agent being 1:2, a dimethyl sulfoxide solution of the crosslinking agent obtained in Example 3 with a concentration of 0.2 g / mL was added into a dimethyl sulfoxide solution of chitosan with a concentration of 20 mg / mL, and stirred at 85°C for 8 h, then the product was precipitated with acetone at 25°C, washed with acetone at 40°C, and the dimethyl sulfoxide was removed by dialysis, and the crosslinked chitosan was obtained after freeze-drying.

[0063] Example 7

[0064] The present example provides a N-acetylneuraminic acid derivative, and the preparation method is as follows:

[0065]

[0066] According to the molar ratio of N-acetylneuraminic acid methyl ester, DMAP, and lauroyl chloride being 2.5:0.56:2.7, N-acetylneuraminic acid methyl ester and 4-dimethylaminopyridine (DMAP) were dissolved in anhydrous pyridine, so that the concentration of N-acetylneuraminic acid methyl ester in anhydrous pyridine was 0.25 mmol / mL; a dichloromethane solution of lauroyl chloride with a concentration of 0.5 mmol / mL was added into the above mixture at 4°C and stirred for 1.5 h, 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, and purified by column chromatography to obtain the N-acetylneuraminic acid derivative, and the nuclear magnetic resonance and mass spectrum results are as follows:

[0067] 1 HNMR: (CDCI3), δ (ppm): 7.48 (s, 2H), 6.48 (d, 2H), 6.32 (d, 2H), 4.62 (d, 2H), 4.48 (d, 2H), 4.32 (m, 2H), 4.22 (m, 2H), 3.98 (m, 2H), 3.82 (m, 2H), 3.74 (m, 2H), 3.68 (m, 2H), 3.62 (m, 2H), 3.52 (m, 2H), 3.42 (m, 2H), 3.32 (m, 2H), 2.32 (s, 6H), 2.28 (s, 3H), 2.22 (s, 3H), 2.18 (s, 3H), 2.12 (s, 3H), 2.06 (s, 3H), 1.95 (m, 2H), 1.74 (m, 2H), 1.68 (m, 2H), 1.62 (m, 2H), 1.52 (m, 2H), 1.42 (m, 2H), 1.32 (m, 2H), 1.22 (m, 2H). 24 H 43 O 10N, 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].

[0068] Example 8

[0069] This example provides a N-acetylneuraminic acid derivative, the preparation method is as follows:

[0070] According to the molar ratio of N-acetylneuraminic acid methyl ester, DMAP, lauroyl chloride is 2.5:0.55:2.5, N-acetylneuraminic acid methyl ester and DMAP are dissolved in anhydrous pyridine, so that the concentration of N-acetylneuraminic acid methyl ester in anhydrous pyridine is 0.25 mmol / mL; at 0°C, add lauroyl chloride solution in dichloromethane with a concentration of 0.5 mmol / mL to the above mixture and stir for 1 h, then raise the temperature to room temperature and react for 12 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 spectrum results are the same as those of Example 7.

[0071] Example 9

[0072] This example provides a N-acetylneuraminic acid derivative, the preparation method is as follows:

[0073] According to the molar ratio of N-acetylneuraminic acid methyl ester, DMAP, lauroyl chloride is 2.5:0.58:2.8, N-acetylneuraminic acid methyl ester and DMAP are dissolved in anhydrous pyridine, so that the concentration of N-acetylneuraminic acid methyl ester in anhydrous pyridine is 0.25 mmol / mL; at 5°C, add 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 spectrum results are the same as those of Example 7.

[0074] Example 10

[0075] The embodiment provides a diclofenac sodium enteric-coated tablet, which comprises a quick-release layer, a slow-release layer and an enteric-coated layer, and the mass ratio of diclofenac sodium in the quick-release layer and the slow-release layer is 1:4.

[0076] The quick-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.

[0077] The slow-release layer comprises the following components in parts by weight: 60 parts of diclofenac sodium, 11 parts of the cross-linked chitosan in the embodiment 4, 2 parts of magnesium stearate and 4 parts of sodium carboxymethyl cellulose.

[0078] The enteric-coated layer comprises the following components in parts by weight: 30 parts of methacrylic acid-ethyl acrylate copolymer L100-55, 10 parts of the N-acetylneuraminic acid derivative in the embodiment 7.

[0079] The embodiment further provides a preparation method of the diclofenac sodium enteric-coated tablet.

[0080] (1) the quick-release layer is prepared by weighing and mixing the raw materials in the quick-release layer according to the weight parts, and then granulating the mixture with a 30-mesh sieve;

[0081] (2) the slow-release layer is prepared by weighing and mixing the raw materials in the slow-release layer according to the weight parts, and then granulating the mixture with a 30-mesh sieve;

[0082] (3) the slow-release layer granules are first added into a tablet press, then the quick-release layer granules are added, and then the diclofenac sodium double-layer slow-release tablet is obtained by tabletting according to the mass ratio of diclofenac sodium in the quick-release layer and the slow-release layer;

[0083] (4) the raw materials in the enteric-coated layer are weighed according to the weight parts and added into an ethanol solution with a volume fraction of 75%, so as to obtain an enteric-coated solution;

[0084] (5) the diclofenac sodium double-layer slow-release tablet is placed in a coating machine, the rotation speed of the coating kettle is set to 10 rpm, the air inlet temperature is 55 DEG C, the air inlet speed is 1000 rpm, the atomization pressure is not less than 0.2 MPa, and the enteric-coated solution is sprayed until the weight gain is 4%;

[0085] Embodiment 11

[0086] The embodiment provides a diclofenac sodium enteric-coated tablet, which comprises a quick-release layer, a slow-release layer and an enteric-coated layer, and the mass ratio of diclofenac sodium in the quick-release layer and the slow-release layer is 1:3.

[0087] The quick-release layer comprises the following components in parts by weight: 20 parts of diclofenac sodium, 5 parts of sodium carboxymethyl starch, 20 parts of starch, 1 part of magnesium stearate and 1 part of sodium carboxymethyl cellulose.

[0088] 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.

[0089] 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.

[0090] The present example also provides a preparation method of the above-mentioned diclofenac sodium enteric-coated tablet, comprising the following steps:

[0091] (1) The raw materials of the immediate-release layer are weighed and mixed according to the weight parts, and then granulated with a 30-mesh sieve to obtain immediate-release layer granules;

[0092] (2) The raw materials of the sustained-release layer are weighed and mixed according to the weight parts, and then granulated with a 30-mesh sieve to obtain sustained-release layer granules;

[0093] (3) The sustained-release layer granules are first added to the tablet press, and then the immediate-release layer granules are added according to the mass ratio of diclofenac sodium in the immediate-release layer and the sustained-release layer. After tabletting, diclofenac sodium double-layer sustained-release tablets are obtained;

[0094] (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;

[0095] (5) The diclofenac sodium double-layer sustained-release tablets are placed in a coating machine, the coating pan rotation speed 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%.

[0096] Example 12

[0097] The present example provides a diclofenac sodium enteric-coated tablet, comprising an immediate-release layer, a sustained-release layer, and an enteric coating layer. The mass ratio of diclofenac sodium in the immediate-release layer and the sustained-release layer is 1:5.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] The present embodiment also provides a preparation method of the above-mentioned diclofenac sodium enteric-coated tablet, comprising the following steps:

[0102] (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;

[0103] (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;

[0104] (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;

[0105] (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;

[0106] (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%.

[0107] Comparative Example 1

[0108] 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.

[0109] Comparative Example 2

[0110] The difference between this comparative example and Example 10 is that the N-acetylneuraminic acid derivative is omitted from the enteric coating layer.

[0111] Experimental Example 1

[0112] The cross-linked chitosan prepared in Example 4 is subjected to infrared spectroscopy (FT-IR) analysis, and the results are shown in Figure 1 .

[0113] 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 absorption peaks at 1503 and 1458 cm -1The characteristic absorption peaks of benzene ring skeleton and -N=N- bond appeared, indicating that the crosslinked chitosan was successfully prepared.

[0114] Experimental Example 2

[0115] The friability, stability and hygroscopicity of the diclofenac sodium enteric-coated tablets obtained in Examples 10-12 and Comparative Examples 1-2 were detected, as follows:

[0116] (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 was tested by using a friability tester according to the friability test method (general test 0923) in the Chinese Pharmacopoeia 2020 edition, and the average value was taken, and the specific data are shown in Table 1 below.

[0117] (2) Stability and hygroscopicity: the diclofenac sodium enteric-coated tablets obtained in Examples 10-12 and Comparative Examples 1-2 were packaged according to the market, and were placed at a temperature of 40±2℃ and a relative humidity of 75%±5% for 180 days, 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 by high performance liquid chromatography according to the requirements of the Chinese Pharmacopoeia 2020 edition “9001 raw materials and preparations stability test guidelines”, and the specific data are shown in Table 2 below; in addition, the hygroscopicity of the diclofenac sodium was detected at the 10th day and 30th day of the test, and the specific data are shown in Table 3 below.

[0118] Table 1

[0119]

[0120] Table 2

[0121]

[0122] Table 3

[0123]

[0124] As shown in Table 1, the diclofenac sodium enteric-coated tablets obtained in Examples 10-12 of the present application had no fracture, cracking and crushing, met the requirements of tablets, and could reduce the waste caused by crushing of the drug. The diclofenac sodium enteric-coated tablets obtained in Comparative Examples 1-2 were prone to fracture, cracking and crushing.

[0125] As shown in Table 2, the diclofenac sodium enteric-coated tablets obtained in Examples 10-12 of the present application showed high stability, and the content of diclofenac sodium remained basically unchanged in the accelerated test.

[0126] As shown in Table 3, the diclofenac sodium enteric-coated tablets obtained in Examples 10-12 of the present application had low hygroscopicity.

[0127] 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.

[0128] Experimental Example 3

[0129] The release rates of the diclofenac sodium enteric-coated tablets obtained in Examples 10-12 and Comparative Examples 1-2 were detected, as follows:

[0130] According to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 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. 8 mL of sample was taken at 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 12 h (while supplementing the same temperature dissolution medium), filtered, and the filtrate was used 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.

[0131] Table 4

[0132]

[0133] As shown in 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 uniformity of the dispersion of diclofenac sodium, but also helps to further enhance the sustained release effect of diclofenac sodium.

[0134] The above embodiments are only the preferred embodiments of the present application, and cannot be used to limit the scope of protection of the present application. Any non-essential changes and substitutions made by those skilled in the art based on the present application shall fall within the scope of protection of the present application.

Claims

1. A diclofenac sodium enteric-coated tablet, characterized in that, It includes an immediate-release layer, a sustained-release layer, and an enteric coating layer; By weight, the immediate-release layer comprises the following components: 20-40 parts of diclofenac sodium, 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 by weight: 50-80 parts of diclofenac sodium, 5-15 parts of cross-linked chitosan, 1-3 parts of lubricant, and 1-5 parts of binder. By weight, the enteric coating layer comprises the following components: 20-45 parts of enteric material and 5-15 parts of N-acetylneuraminic acid derivative; The structural formula of the N-acetylneuraminic acid derivative is: ； The method for preparing the cross-linked chitosan includes the following steps: Under inert gas protection, a cross-linking agent solution of dimethyl sulfoxide was added to a dimethyl sulfoxide solution of chitosan and stirred. After purification, the cross-linked chitosan was obtained. The structural formula of the crosslinking agent is: 。 2. The diclofenac sodium enteric-coated tablets according to claim 1, characterized in that, The mass ratio of chitosan to crosslinking agent is 1:(1.6-2); the concentration of chitosan in the dimethyl sulfoxide solution is 20-30 mg / mL; the concentration of crosslinking agent in the dimethyl sulfoxide solution 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 tablets according to claim 2, characterized in that, The crosslinking agent is prepared as follows: 2-hydroxy-5-[2-(4-hydroxyphenyl)diazepine]benzoic acid was added to N,N-dimethylformamide, followed by the addition of anhydrous potassium carbonate and 1,5-dibromopentane. The mixture was reacted overnight under reflux and purified to obtain the crosslinking agent.

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

5. The diclofenac sodium enteric-coated tablets according to claim 1, characterized in that, The preparation method of the N-acetylneuraminic acid derivative includes the following steps: N-acetylneuraminic acid methyl ester and 4-dimethylaminopyridine were added to anhydrous pyridine, and a dichloromethane solution of lauroyl chloride was added at 0-5°C with stirring. The mixture was then reacted at room temperature. After the reaction was completed, the mixture was purified to obtain the N-acetylneuraminic acid derivative.

6. The diclofenac sodium enteric-coated tablets according to claim 5, characterized in that, 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 solution in dichloromethane 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 tablets according to claim 1, characterized in that, The mass ratio of diclofenac sodium in the immediate-release layer and the sustained-release layer is 1:(3-5); the binder in the immediate-release layer and the sustained-release layer is selected from one of hydroxypropyl cellulose, sodium carboxymethyl cellulose, and povidone; the lubricant in the immediate-release layer and the sustained-release layer is magnesium stearate or talc.

8. The diclofenac sodium enteric-coated tablets according to claim 1, characterized in that, The filler is selected from one of lactose, microcrystalline cellulose, starch, and mannitol; the disintegrant is croscarmellose sodium or carboxymethyl starch sodium; and the enteric material is Eudragit® L100-55, a copolymer of methacrylate and ethyl acrylate.

9. A method for preparing diclofenac sodium enteric-coated tablets according to any one of claims 1-8, characterized in that, Includes the following steps: (1) Weigh each raw material of the immediate release layer according to the stated weight parts and mix them. After granulation, the immediate release layer particles are obtained. (2) Weigh each raw material of the sustained-release layer according to the stated weight parts and mix them. After granulation, the sustained-release layer particles are obtained. (3) The immediate-release layer particles and the sustained-release layer particles are stacked and then compressed into tablets to obtain diclofenac sodium bilayer sustained-release tablets; (4) Weigh each raw material of the enteric coating layer according to the stated weight parts and add it to an ethanol solution with a volume fraction of 70-80% to obtain the enteric coating solution; (5) Spray the enteric coating solution onto the surface of the diclofenac sodium bilayer sustained-release tablet until the weight gain is 3-5%.

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