Clofenac tablet and coating process thereof

Abstract

The invention discloses a clofenyellow tablet and a coating process thereof, and belongs to the technical field of production of the clofenyellow tablet. The preparation method comprises the following steps: sieving dihydroxyaluminium aminoacetate to obtain dihydroxyaluminium aminoacetate superfine powder, adding a cosolvent, a solubilizer and purified water, uniformly mixing to form dihydroxyaluminium aminoacetate compound mixed liquor, uniformly mixing the dihydroxyaluminium aminoacetate compound mixed liquor, a thickening agent, a filling agent and purified water to obtain coating liquid, and finally spraying the coating liquid on a lofenac-huangsensitive tablet, thereby obtaining the lofenac-huangsensitive tablet. And drying to obtain the lofenac yellow tablet. According to the invention, a film coating in a conventional process is replaced by a medicine (dihydroxyaluminum glycinate) coating, so that the moisture-proof, oxygen-isolating, wear-resistant and shading functions of the lofenac sodium tablet are enhanced, and the content of impurities B and C in diclofenac sodium is effectively reduced. Experiments show that the medicine irritation can be effectively reduced, adverse reactions such as vomiting and diarrhea can be reduced, gastrointestinal peristalsis can be better increased, the gastrointestinal motility function can be promoted, the safety of the medicine is greatly improved, and the medicine has a wide application scene.

Description

Technical Field

[0001] The present invention belongs to the technical field of the production of chlorphenamine maleate and diclofenac sodium tablets, and particularly relates to a chlorphenamine maleate and diclofenac sodium tablet and its coating process. Background Art

[0002] Chlorphenamine maleate and diclofenac sodium tablets are compound preparations composed of diclofenac sodium, artificial bezoar, and chlorphenamine maleate. They are film-coated tablets and are mainly used to treat symptoms such as headache, fever, nasal congestion, runny nose, sore throat, and excessive phlegm caused by colds.

[0003] Chlorphenamine maleate and diclofenac sodium tablets contain the non-steroidal anti-inflammatory drug diclofenac sodium. This drug exerts anti-inflammatory, analgesic, and antipyretic effects by inhibiting the activity of cyclooxygenase and reducing prostaglandin synthesis. However, due to the strong irritation of the existing film-coated tablet dosage form to the gastrointestinal tract, a small number of patients may experience tolerable symptoms such as nausea, vomiting, and stomach discomfort during use. Long-term use may also increase the risk of digestive tract ulcers or bleeding. These adverse reactions not only affect the patient's medication experience and compliance but may also have a certain impact on the patient's health status and prolong the recovery time. Therefore, exploring a new oral dosage form preparation process to effectively reduce the occurrence of adverse reactions of chlorphenamine maleate and diclofenac sodium tablets is of great significance for improving the medication safety and comfort of patients. Summary of the Invention

[0004] Aiming at the deficiencies of the prior art, the purpose of the present invention is to provide a chlorphenamine maleate and diclofenac sodium tablet and its coating process, which can reduce the occurrence of adverse reactions and enable the tablets to exert better therapeutic effects.

[0005] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0006] The first aspect of the present invention is to provide a coating process for chlorphenamine maleate and diclofenac sodium tablets, comprising the following steps:

[0007] S1: After sieving glyceryl aluminum hydroxide, glyceryl aluminum hydroxide ultrafine powder is obtained;

[0008] S2: Add glyceryl aluminum hydroxide ultrafine powder, cosolvent, solubilizer, and purified water into a container, and mix to obtain a glyceryl aluminum hydroxide complex mixed solution;

[0009] S3: Add thickener, filler, and purified water into the glyceryl aluminum hydroxide complex mixed solution, mix, and adjust the pH to obtain a coating solution;

[0010] S4: Spray the coating solution prepared in S3 onto the plain tablets, and dry to obtain chlorphenamine maleate and diclofenac sodium tablets.

[0011] The above plain tablets are chlorphenamine maleate and diclofenac sodium tablets, and each tablet contains: 15 mg of diclofenac sodium, 15 mg of artificial bezoar, and 2.5 mg of chlorphenamine maleate.

[0012] It should be noted that the control of the particle size of aluminum glycinate and the pH of the coating solution are key links in the coating process. Excessive particle size not only easily causes clogging of the spray gun of the coating machine, but also leads to significant differences in the content of aluminum glycinate in each tablet of the drug, affecting the uniformity of product quality; too small particle size requirements will lead to a significant reduction in the grinding speed, which will not only greatly increase the working intensity of the operators, but also generate a large amount of dust, seriously endangering the health of the operators. At the same time, the aluminum glycinate complex has a relatively high solubility in an acidic environment. Therefore, by precisely regulating the pH value, its solubility can be effectively increased, further optimizing the performance of the coating solution.

[0013] In some embodiments, in the coating solution of chlorpheniramine maleate and diclofenac sodium tablets, each component is calculated by weight percentage, with ultrafine aluminum glycinate powder being 10 - 15%, cosolvent being 10 - 15%, solubilizer being 0.1 - 2%, thickener being 10 - 16%, filler being 1 - 3%, and the balance being pure water.

[0014] It should be noted that the dosage of ultrafine aluminum glycinate powder has an important impact on the coating process and the exertion of drug efficacy. When the dosage of aluminum glycinate is too much, the following problems will occur: First, since the amount of pure water used decreases correspondingly, the viscosity of the coating solution increases, which will directly affect the atomization effect of the spray gun and even cause the spray gun to clog severely in serious cases; second, excessive use of aluminum glycinate may cause abnormal phosphorus metabolism, resulting in phosphorus loss and an increase in urinary calcium excretion, thus increasing the risk of osteomalacia. When the dosage of aluminum glycinate is too little, adverse effects will also occur: On the one hand, the increase in the amount of pure water used will cause a change in the viscosity of the coating solution, thereby affecting the solvent evaporation rate and reducing the drying efficiency; on the other hand, insufficient dosage may not achieve the expected drug efficacy.

[0015] In some embodiments, the cosolvent is selected from at least one of gluconic acid, oxalic acid, tartaric acid, citric acid, maleic acid, carboxymethylhydroxy malonic acid, carboxymethylhydroxy succinic acid, and hydroxyethylglycine; the solubilizer is selected from at least one of Tween 20, Tween 40, Tween 60, Tween 80, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 500, and polyethylene glycol 600.

[0016] It should be noted that in the aluminum glycinate complex mixture, aluminum glycinate, as the core component, mainly plays the function of protecting the gastric mucosa; the cosolvent forms a complex with aluminum glycinate and introduces hydrophilic groups, significantly increasing its solubility; the solubilizer further enhances the dissolution performance by reducing the surface tension, thus forming a stable and uniform aluminum glycinate complex mixture.

[0017] In some embodiments, the thickener is selected from at least one of sodium carboxymethylcellulose, guar gum, gelatin, sodium carboxymethyl cellulose, gum arabic, carbomer, polyvinyl alcohol, pectin, and agar; the filler is selected from at least one of microcrystalline cellulose, pregelatinized starch, sucrose, dextrin, mannitol, and lactose.

[0018] It should be noted that the addition of a thickening agent to the coating solution can increase the viscosity of the liquid, thereby improving the adhesion and uniformity of the coating solution; the filler is used to adjust the coating weight, but attention should be paid to the dosage control. Excessive weight gain will delay the dissolution rate of the tablets, while too little weight gain will make it difficult to achieve the ideal coating effect.

[0019] In some embodiments, the dosage of the coating solution is 2-5% of the total weight of the core tablets.

[0020] In some embodiments, the mesh number of the sieving of dihydroxyaluminum aminoacetate in S1 is 180-220 meshes.

[0021] In some embodiments, the pH value of the coating solution in S3 is 4.0-5.0.

[0022] It should be noted that by controlling the pH value of the coating solution, the present invention can reduce the occurrence of the hydrolysis reaction of diclofenac sodium, thereby reducing the generation of impurities.

[0023] In some embodiments, the coating process parameters in S4 are: the tablet bed temperature is 45-55 °C, and the peristaltic pump frequency is 12-16 Hz.

[0024] In some embodiments, the pan coating method is adopted in S4.

[0025] The second aspect of the present invention lies in providing a chlorpheniramine maleate and diclofenac sodium tablets prepared by the above coating process.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] 1. The present invention replaces the conventional film coating with a drug (dihydroxyaluminum aminoacetate) coating. Dihydroxyaluminum aminoacetate in the drug coating can reduce gastric acid and the activity of pepsin, which can relieve the discomfort symptoms in the upper abdomen, thereby reducing the irritation of the drug and the occurrence of adverse reactions. The drug coating can not only reduce the discomfort symptoms in the upper abdomen, but also significantly enhance the moisture-proof, oxygen-barrier, wear-resistant performance and light-shielding function of the tablets, greatly improving the safety of the drug.

[0028] 2. The dihydroxyaluminum aminoacetate coating solution provided by the present invention has certain water solubility, which is beneficial to the release of the active substance and enables the tablets to play a better therapeutic effect.

[0029] 3. The coating process provided by the present invention can ensure the uniform concentration distribution of dihydroxyaluminum aminoacetate in the tablets, thereby ensuring the accurate dosage and reliable drug efficacy every time the drug is used.

[0030] 4. Impurities B and C are the products of the oxidative disproportionation degradation of diclofenac sodium under the influence of factors such as moisture, oxygen, and light. Due to their high toxicity, they need to be detected and controlled with emphasis. The impurity content levels in the products prepared without taking special measures are relatively high. However, the coating process adopted in the present invention effectively controls the generation of impurities B and C in diclofenac sodium through a quadruple protection mechanism, namely light shielding, moisture proofing, oxygen barrier, and precise pH regulation, providing a reliable guarantee for the safe and effective use of the drug. Description of the Drawings

[0031] Figure 1 It is a degradation mechanism diagram of impurities B and C.

[0032] Figure 2 It is a positioning diagram of each impurity peak.

[0033] Figure 3 It is a graph of the body weight changes of each group of mice. Compared with the control group, ** P < 0.01, * P < 0.05.

[0034] Figure 4 It is a graph of the daily food intake changes of each group of mice. Compared with the control group, ** P < 0.01, * P < 0.05. Detailed Description of the Embodiments

[0035] The present invention will be further described in detail below with reference to the drawings. The embodiments described by referring to the drawings are exemplary and are intended to explain the present invention, rather than being construed as a limitation to the present invention.

[0036] Example 1 Coating Process 1 of Chlorpheniramine Maleate and Diclofenac Sodium Tablets

[0037] A kind of chlorpheniramine maleate and diclofenac sodium tablet is prepared by the following coating process:

[0038] S1: After passing aluminum glycinate through a 200-mesh sieve, extremely fine powder of aluminum glycinate is obtained;

[0039] S2: Add 12% of the extremely fine powder of aluminum glycinate and 12% of tartaric acid into a container and mix to obtain an aluminum glycinate complex. Then continue to add 1% of Tween 80 and an appropriate amount (30%) of purified water, and mix ultrasonically for 5 min to obtain an aluminum glycinate complex mixed solution;

[0040] S3: Continuously add 10% of sodium carboxyethyl cellulose, 3% of microcrystalline cellulose, 0.2% of guar gum and the remaining purified water into the container containing the aluminum glycinate complex mixed solution. After stirring with a magnetic stirrer for 10 min, adjust the pH to 4.0 - 4.5, and filter with double-layer gauze to obtain a coating solution;

[0041] S4: Place the plain tablets into a coating pan. Using the rolling coating method, adjust the tablet bed temperature to 50°C and the peristaltic pump frequency to 14 Hz. Spray the coating solution prepared in S3 into the pan using a sprayer. The amount of the coating solution used is 4% of the total weight of the plain tablets. After the spraying of the coating solution is completed and drying is carried out, the diclofenac sodium, artificial cow-bezoar and chlorpheniramine maleate tablets are obtained. Each plain tablet contains 15 mg of diclofenac sodium, 15 mg of artificial cow-bezoar and 2.5 mg of chlorpheniramine maleate.

[0042] Example 2 Coating Process of Diclofenac Sodium, Artificial Cow-bezoar and Chlorpheniramine Maleate Tablets 2

[0043] The preparation steps are the same as those in Example 1, with the only difference being that, by weight percentage, the extremely fine powder of dihydroxyaluminum aminoacetate is 10%, oxalic acid is 10%, Tween 80 is 0.5%, sodium carboxymethylcellulose is 13%, microcrystalline cellulose is 1%, and guar gum is 0.1%; in S3, the pH is adjusted to 4.0 - 4.5; in S4, the amount of the coating solution used is 2% of the total weight of the plain tablets.

[0044] Example 3 Coating Process of Diclofenac Sodium, Artificial Cow-bezoar and Chlorpheniramine Maleate Tablets 3

[0045] The preparation steps are the same as those in Example 1, with the only difference being that, by weight percentage, the extremely fine powder of dihydroxyaluminum aminoacetate is 15%, citric acid is 15%, polyethylene glycol 400 is 1%, sodium carboxymethylcellulose is 15%, microcrystalline cellulose is 2%, and guar gum is 0.5%; in S3, the pH is adjusted to 4.0 - 4.5; in S4, the amount of the coating solution used is 5% of the total weight of the plain tablets.

[0046] Example 4 Coating Process of Diclofenac Sodium, Artificial Cow-bezoar and Chlorpheniramine Maleate Tablets 4

[0047] The preparation steps are the same as those in Example 1, with the only difference being that, by weight percentage, the extremely fine powder of dihydroxyaluminum aminoacetate is 12%, maleic acid is 15%, polyethylene glycol 600 is 0.5%, sodium carboxymethylcellulose is 10%, pregelatinized starch is 3%, and arabic gum is 0.2%; in S3, the pH is adjusted to 4.5 - 5.0; in S4, the amount of the coating solution used is 4% of the total weight of the plain tablets.

[0048] Example 5 Coating Process of Diclofenac Sodium, Artificial Cow-bezoar and Chlorpheniramine Maleate Tablets 5

[0049] The preparation steps are the same as those in Example 1, with the only difference being that, by weight percentage, the extremely fine powder of dihydroxyaluminum aminoacetate is 12%, tartaric acid is 10%, polyethylene glycol 200 is 2%, sodium carboxymethylcellulose is 10%, lactose is 3%, and pectin is 0.2%; in S3, the pH is adjusted to 4.5 - 5.0; in S4, the amount of the coating solution used is 4% of the total weight of the plain tablets.

[0050] Example 6 Detection Test for Content of Dihydroxyaluminum Aminoacetate

[0051] Take an appropriate amount of this product (equivalent to about 31 mg of aluminum glycinate), weigh accurately, place it in a conical flask, add 2 ml of 7 mol / L hydrochloric acid solution, shake well, add 10 ml of water, heat in a water bath to dissolve aluminum oxide, cool, add 150 ml of water, accurately add 25 ml of disodium edetate titrant (0.05 mol / L), add 2 drops of methyl red indicator solution, gradually add 1 mol / L sodium hydroxide solution dropwise until the solution turns yellow, heat in a water bath for 30 minutes, cool, add 3 g of hexamethylenetetramine and 1 ml of xylenol orange indicator solution, gradually add 1 mol / L hydrochloric acid solution dropwise until the solution turns yellow, titrate with zinc titrant (0.05 mol / L) until the solution changes from yellow to red, and correct the titration result with a blank test. Each 1 ml of disodium edetate titrant (0.05 mol / L) is equivalent to 6.753 mg of C2H6AlNO4.

[0052] The test results of the aluminum glycinate content in the chlorphenamine maleate and diclofenac sodium tablets prepared in Example 1 are shown in Table 1 below.

[0053] Table 1 Aluminum glycinate content

[0054]

[0055] As can be seen from Table 1, the film coating process provided in this Example 1 can ensure uniform concentration distribution of aluminum glycinate in the tablets, indicating that this technical solution can ensure accurate drug dosage and reliable drug efficacy every time.

[0056] Coating process of conventional chlorphenamine maleate and diclofenac sodium tablets in the comparative example

[0057] The coating process of conventional chlorphenamine maleate and diclofenac sodium tablets includes the following steps:

[0058] S1: Prepare the coating solution (5% hydroxypropyl methylcellulose solution): Weigh a quantitative amount of hydroxypropyl methylcellulose, add a quantitative amount of purified water in a container with stirring, slowly add hydroxypropyl methylcellulose under stirring, continue to stir for 45 minutes after all are added, and pass through a 40-mesh sieve to obtain the coating solution;

[0059] S2: Put the plain tablets into the coating drum, start the main machine to make the coating drum rotate, and turn on the hot air to preheat the plain tablets. When the tablet bed temperature reaches 50 °C, turn on the peristaltic pump, the peristaltic pump frequency is 14 Hz, start spraying the coating solution, and cool with cold air after spraying is completed to obtain chlorphenamine maleate and diclofenac sodium tablets. Among them, each plain tablet contains 15 mg of diclofenac sodium, 15 mg of artificial bezoar, and 2.5 mg of chlorphenamine maleate.

[0060] Impurity content detection test

[0061] To further prove that the present invention can reduce the contents of diclofenac sodium impurities B and C in chlorpheniramine maleate and diclofenac sodium tablets, the impurities in chlorpheniramine maleate and diclofenac sodium tablets prepared by the coating process of the present invention (Example 1) and the conventional production process (Comparative Example) were determined. The impurities include diclofenac sodium impurity B: CAS No. 22121-58-0; diclofenac sodium impurity C: CAS No. 27204-57-5. From Figure 1 It can be seen that the degradation of diclofenac sodium is affected by oxidation, hydrolysis and photolysis, generating diclofenac sodium impurity B and diclofenac sodium impurity C. Under oxygen or light conditions, diclofenac sodium is prone to oxidation reaction to generate oxidation products (such as impurities B and C). Oxidative degradation usually involves free radical reactions, resulting in changes in molecular structure; in acidic or alkaline environments, diclofenac sodium is prone to hydrolysis reaction, causing the ester bond or amide bond in the molecule to break and generating hydrolysis products; under light (especially ultraviolet light) conditions, diclofenac sodium is prone to photolysis reaction, causing the molecular bond to break or rearrange and generating photolysis products. Therefore, light shielding, moisture proof, oxygen barrier and precise pH regulation can reduce the occurrence of degradation reactions and further reduce the generation of impurities.

[0062] Take the prepared chlorpheniramine maleate and diclofenac sodium tablets, remove the film coating / drug coating, grind them finely, dissolve them in methanol and dilute to make a solution containing 1 mg per 1 ml as the test solution.

[0063] Take 5 mg of diethyl phthalate, place it in a 200 mL volumetric flask, accurately add 1 ml of the test solution, dissolve it in methanol and dilute to the scale, shake well, and use it as the control solution.

[0064] The test was carried out with reference to the high performance liquid chromatography method (General Rule 0512). The octadecylsilane chemically bonded silica gel was used as the filler; methanol-4% glacial acetic acid solution (65:35) was used as the mobile phase; the detection wavelength was 254 nm. Take an appropriate amount of diclofenac sodium reference substance, make a solution containing about 1 mg per 1 ml with water, expose this solution to ultraviolet light (254 nm) for irradiation for 15 minutes, take 20 μl and inject it into the liquid chromatograph, record the chromatogram, and an impurity peak appears at about 0.8 times the relative retention time of the main peak. The resolution between the two should be greater than 6.0. Accurately measure 20 μl of the test solution and the control solution respectively, inject them into the liquid chromatograph, and record the chromatogram until 2 times the retention time of the main peak.

[0065] Limit requirements: If there are impurity peaks in the chromatogram of the test solution, except for the peak of diethyl phthalate and the chromatographic peaks before it, the impurity peak (impurity B) at the relative retention time of 1.2 - 1.3 of the diclofenac peak, the peak area multiplied by 0.5 shall not be greater than the peak area of the diclofenac peak in the control solution (0.5%); the impurity peak (impurity C) at the relative retention time of 0.7 - 0.8 of the diclofenac peak, its peak area shall not be greater than the peak area of the diclofenac peak in the control solution (0.5%); the peak area of other individual impurity peaks shall not be greater than the peak area of the diclofenac peak in the control solution (0.5%), and the sum of the peak areas of each impurity peak (impurity B is calculated according to the corrected peak area) shall not be greater than 2 times the peak area of the diclofenac peak in the control solution (1.0%). Figure 2 It is the positioning map of each impurity peak.

[0066] The detection results of the contents of impurities B and C in diclofenac sodium in the chlorpheniramine maleate tablets prepared in Example 1 and the comparative example are shown in Table 2 below. An accelerated experiment was carried out at a temperature of 40 ± 2 °C and a relative humidity of 75 ± 5%:

[0067] Table 2 Contents of impurities B and C in diclofenac sodium

[0068]

[0069]

[0070] It can be seen from Table 2 that the contents of impurities B and C in diclofenac sodium in the chlorpheniramine maleate tablets prepared in Example 1 of this example are much less than those in the comparative example. After 6 months of acceleration, the impurity content in the comparative example is 0.99%, while that in Example 1 is only 0.76%, indicating that this technical solution can effectively reduce the impurity content in chlorpheniramine maleate tablets. Effects of chlorpheniramine maleate tablets with different coating processes on the gastrointestinal tract of mice

[0071] I. Research methods

[0072] 1. Experimental materials

[0073] Chlorpheniramine maleate tablets prepared in Example 1; chlorpheniramine maleate tablets prepared in the comparative example.

[0074] 2. Grouping of experimental animals and administration methods

[0075] SPF - level Kunming mice at 5 weeks of age and weighing 20 - 25 g, with an equal number of males and females, 20 mice in each group, were randomly divided into a normal control group, a comparative example group (0.9 mg diclofenac sodium / kg / day), a low - dose group of Example 1 (0.45 mg diclofenac sodium / kg / day, equivalent to 0.5 times the adult clinical dose), a medium - dose group of Example 1 (0.9 mg diclofenac sodium / kg / day, equivalent to the adult clinical dose), and a high - dose group of Example 1 (1.8 mg diclofenac sodium / kg / day, equivalent to 2 times the adult clinical dose). Among them, 10 mice in each group were used for the determination of gastric emptying ability. Mice in the comparative example group and the low, medium, and high - dose groups of Example 1 were intragastrically administered the corresponding doses of the drug, and mice in the control group were intragastrically administered pure water. During the experiment, the body weight and daily food intake of the mice were measured every day, and the mental state, behavior, vomiting, diarrhea, and death of the mice in each group were observed.

[0076] 3. Mouse feces examination

[0077] After one week of intragastric administration, the feces of each mouse were examined on the 8th day of the experiment. The scoring criteria for mouse feces are as follows: 0 points, small amount of feces, hard, dry, and firm; 1 point, small amount of feces, hard, wet, and sticky; 2 points, large amount of feces, soft, and very sticky; 3 points, large amount of feces, soft, and loose; 4 points, large amount, loose stools.

[0078] 4. Determination of organ index

[0079] After the intragastric administration was completed, the mice were sacrificed by cervical dislocation on the 8th day of the experiment, and the animals in each group were dissected for systematic anatomical observation. After the anatomical observation, the fat and connective tissues surrounding the heart, liver, spleen, lungs, and kidneys were quickly removed, and the blood clots in the organs were washed away with physiological saline. The surface moisture of the organs was blotted dry with filter paper, and their weights were weighed on a ten - thousandth balance, and the organ coefficients of each organ were calculated. Organ coefficient = 100% × organ weight / animal body weight.

[0080] 5. Determination of gastric emptying ability

[0081] Before the last administration, the mice in each group were fasted for 12 h. After 30 min of intragastric administration, each mouse was intragastrically administered 0.1 mL of ink. After 20 min, the mice were sacrificed by cervical dislocation. The abdominal cavity was quickly opened, the cardiac and pyloric ends of the stomach were ligated, and the whole stomach was excised at the ligation site. The whole stomach was wiped dry and weighed. The stomach body was cut open along the greater curvature of the stomach, the gastric contents were washed away, and it was wiped dry and weighed net. The small intestine was taken out, the total length of the small intestine and the distance from the pylorus to the advancement of the blue - black ink were measured. The gastric emptying rate and small intestine propulsion rate and their change rates were calculated.

[0082] Gastric emptying rate (%) = (total gastric weight - net gastric weight) / intragastric administration mass × 100%;

[0083] Small intestine propulsion rate (%) = distance from the pylorus to the front end of the blue - black ink / total length of the small intestine × 100%;

[0084] Gastric emptying / small intestine propulsion change rate (%) = (Average gastric emptying rate or small intestine propulsion rate of the experimental group - Average gastric emptying rate or small intestine propulsion rate of the control group) / Average gastric emptying rate or small intestine propulsion rate of the control group × 100%.

[0085] 6. Determination of serum gastrointestinal factor levels

[0086] After the gavage was completed, the mice were anesthetized on the 8th day of the experiment, and blood was collected by eye socket puncture. The blood was allowed to stand at room temperature for 30 min, centrifuged at 3000 rpm for 10 min to obtain serum, and the levels of motilin (MOT), gastrin (GAS), and ghrelin in the serum of the mice were detected according to the instructions of the enzyme-linked immunosorbent assay (ELISA) kit.

[0087] 7. Data analysis

[0088] All data were analyzed and processed using GraphPad Prism 10 software. The data were expressed as mean ± standard deviation (mean ± SD). ANOVA variance analysis was used for comparison of differences between groups, and P < 0.05 was considered statistically significant.

[0089] II. Research results

[0090] 1. General status of mice in each group

[0091] The body weights of the mice in each group were as Figure 3 shown. It can be seen from Figure 3 that compared with the control group, the body weights of the mice in the comparative example group began to decrease from the 5th day of drug administration, and showed a significant difference on the 7th day (P < 0.05). There was no significant difference in the body weights of the mice in the low, medium, and high dose groups of Example 1 (P > 0.05).

[0092] The daily food intakes of the mice in each group were as Figure 4 shown. It can be seen from Figure 4 that compared with the control group, the daily food intakes of the mice in the comparative example group began to decrease from the 3rd day of drug administration, and showed a significant difference on the 5th day (P < 0.05). There was no significant difference in the daily food intakes of the mice in the low, medium, and high dose groups of Example 1 (P > 0.05).

[0093] From the 5th day of drug administration, some mice in the comparative example group showed vomiting, and their anuses were stained with feces. There were no vomiting or diarrhea situations in the mice in the low, medium, and high dose groups of Example 1. During the experiment, no deaths occurred in the mice in each group.

[0094] The above results suggest that the chlorpheniramine maleate and diclofenac sodium tablets prepared in the comparative example are more likely to cause gastrointestinal adverse reactions such as vomiting and diarrhea than those in Example 1, resulting in decreased appetite and reduced body weight of the mice.

[0095] 2. Fecal scores of mice in each group

[0096] The fecal score results showed (see Table 3) that compared with the control group, the fecal score of the comparative example group was significantly reduced (P < 0.05), and there were no significant changes in the fecal scores of the low, medium, and high-dose groups of Example 1 (P > 0.05). This indicates that the chlorpheniramine maleate tablets prepared in the comparative example are more likely to cause diarrhea in mice than those of Example 1.

[0097] Table 3 Fecal score results of mice in each group

[0098]

[0099] 3. Organ indices of mice in each group

[0100] On the 8th day after administration, the mice in each group were dissected for systematic anatomical observation. It was found that the animal body surface was intact, there was no secretion in the physiological cavity, and the main organs including the esophagus, trachea, thymus, adrenal gland, pancreas, stomach, intestine (duodenum, jejunum, ileum, colon, rectum), heart, lungs, liver, kidneys, spleen, brain, etc. were in normal anatomical positions, with normal color, luster, uniform texture, and no abnormal enlargement or shrinkage. After anatomical observation, five main internal organs, namely the heart, lungs, liver, kidneys, and spleen, were selected for weighing, and the organ coefficients were calculated. The results are shown in Table 4. As can be seen from Table 4, compared with the control group mice, there were no significant differences in the organ coefficients of the heart, lungs, liver, kidneys, and spleen of the comparative example group and the low, medium, and high-dose groups of Example 1 (P > 0.05). This indicates that the chlorpheniramine maleate tablets prepared in Example 1 and the comparative example do not affect the organ coefficients of mice.

[0101] Table 4 Organ indices of mice in each group

[0102]

[0103] Note: Compared with the control group, *P < 0.05, **P < 0.01.

[0104] 4. Gastric emptying ability of mice in each group

[0105] The measurement results of the gastric emptying ability of mice in each group are shown in Table 5. As can be seen from Table 5, compared with the control group, the gastric emptying rate of the comparative example group mice decreased significantly (P < 0.05), and there were no significant changes in the gastric emptying rates of the low, medium, and high-dose groups of Example 1 mice (P > 0.05); compared with the control group, there were no significant changes in the small intestine propulsion rates of the comparative example group and the low, medium, and high-dose groups of Example 1 mice (P > 0.05). This indicates that the chlorpheniramine maleate tablets prepared in Example 1 can achieve better gastric emptying and reduce gastric discomfort such as gastric distension than those of the comparative example.

[0106] Table 5 Gastric emptying ability of mice in each group

[0107]

[0108] Note: Compared with the control group, *P < 0.05, **P < 0.01.

[0109] 5. Serum gastrointestinal factor levels in each group of mice

[0110] The results of serum gastrointestinal factor levels in each group of mice are shown in Table 6. As can be seen from Table 6, compared with the control group, the levels of serum MOT, GAS, and Ghrelin in the comparative example mice were significantly decreased (P < 0.01), while there were no significant differences in the levels of serum MOT, GAS, and Ghrelin in the low- and medium-dose groups of Example 1 mice (P > 0.05). This indicates that the chlorpheniramine maleate tablets prepared in Example 1 can better increase gastrointestinal motility, promote gastrointestinal motor function and appetite in mice than the comparative example.

[0111] Table 6 Serum gastrointestinal factor levels in each group of mice

[0112]

[0113] Note: Compared with the control group, *P < 0.05, **P < 0.01.

[0114] III. Research conclusions

[0115] In summary, compared with the chlorpheniramine maleate tablets prepared by the conventional process, the chlorpheniramine maleate tablets prepared in the present invention can effectively reduce drug irritation, reduce the occurrence of gastrointestinal adverse reactions such as vomiting and diarrhea, better increase gastrointestinal motility, promote gastrointestinal motor function, stimulate appetite, and have no toxicological significance changes in various organs and tissues.

[0116] The above are only some embodiments of the present invention. For those of ordinary skill in the art, without departing from the inventive concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention.

Claims

1. A coating process for chlorfenapyr tablets, characterized in that: The following steps are involved: S1: Aluminum glycolate is sieved to obtain extremely fine aluminum glycolate powder; S2: adding aluminum glycolate ultrafine powder, cosolvent, solubilizer and purified water into a container, and mixing to obtain an aluminum glycolate complex mixed solution; S3: adding a thickener, a filler and purified water to the aluminum glycolate complex, mixing, and adjusting the pH to obtain a coating solution; S4: Spray the coating solution prepared in S3 onto the plain tablets, and obtain the chlorfenapyr tablets after drying.

2. The coating process according to claim 1, characterized in that: The components in the coating solution for chlorfenapyr tablets are calculated by weight percentage, including 10-15% aluminum glycolate ultrafine powder, 10-15% cosolvent, 0.1-2% solubilizer, 10-16% thickener, 1-3% filler, and the balance is purified water.

3. The coating process according to claim 2, characterized in that: The cosolvent is selected from at least one of gluconic acid, oxalic acid, tartaric acid, citric acid, maleic acid, carboxymethyl hydroxymalonic acid, carboxymethyl hydroxysuccinic acid, and hydroxyethylaminoacetic acid; the solubilizer is selected from at least one of Tween 20, Tween 40, Tween 60, Tween 80, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 500, and polyethylene glycol 600.

4. The coating process according to claim 3, characterized in that: The thickener is selected from at least one of sodium carboxyethyl cellulose, guar gum, gelatin, sodium carboxymethyl cellulose, gum arabic, carbomer, polyvinyl alcohol, pectin, and agar; the filler is selected from at least one of microcrystalline cellulose, pregelatinized starch, sucrose, dextrin, mannitol, and lactose.

5. The coating process according to claim 1, characterized in that: The amount of the coating liquid is 2-5% of the total weight of the plain tablet.

6. The coating process according to claim 1, characterized in that: In the S1, the aluminum glycolate is screened with a mesh size of 180-220 meshes.

7. The coating process according to claim 1, characterized in that: In S3, the pH of the coating solution is 4.0-5.

0.

8. The coating process according to claim 1, characterized in that: In S4, the coating process parameters are: tablet bed temperature 45-55°C, peristaltic pump frequency 12-16 Hz.

9. The coating process according to claim 1, characterized in that: The S4 adopts the rolling coating method.

10. A chlorfenapyr tablet prepared by the coating process according to any one of claims 1 to 9.

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