Compound infantile antipyretic double-layer suppository and manufacturing method thereof

Abstract

The invention discloses a compound infantile antipyretic double-layer suppository and a preparation method thereof, and relates to the technical field of pharmaceutical preparations, the compound infantile antipyretic double-layer suppository is composed of a quick release layer and a slow release layer, the quick release layer comprises 150-180g / 1000 paracetamol, 4-6g / 1000 artificial bezoar, 10-20g / 1000 sustained release layer, 10-20g / 1000 sustained release layer, 10-20g / 1000 sustained release layer and 10-20g / 1000 sustained release layer. The sustained release layer comprises 40-60g / 1000 pieces of rhizoma et radix baphicacanthis cusiae extract powder and 40-60g / 1000 pieces of acetaminophen, biphase drug release is achieved through the hydrophilic and hydrophobic difference of a bilayer matrix, the onset time can be shortened, the continuous fever abatement time can be prolonged, and the symptom improvement rate of a patient is greatly increased.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, specifically to a compound pediatric antipyretic double-layer suppository and its manufacturing method. Background Technology

[0002] Pediatric antipyretic suppositories are a common type of fever reducer for children. Their main ingredient is acetaminophen. Compared to oral preparations such as oral acetaminophen solutions, they offer advantages such as rapid fever reduction and ease of use. As a rectal administration form, they have several unique advantages, as follows: (1) Avoiding the first-pass effect and improving drug utilization: Oral drugs need to be absorbed through the gastrointestinal tract and then metabolized by the liver. Some drugs will be degraded by the liver, which is the first-pass effect, and this will reduce the bioavailability of the drug. However, compound pediatric antipyretic suppositories are administered rectally, and the drug can be directly absorbed into the blood through the rectal mucosa, bypassing the first-pass metabolism of the liver. This reduces the breakdown and destruction of the drug in the liver, thereby making the drug more effective and improving the utilization rate of the drug.

[0003] (2) Reduce gastrointestinal irritation: After oral acetaminophen solution enters the gastrointestinal tract, it may irritate the gastrointestinal mucosa, causing discomfort symptoms such as nausea, vomiting, and abdominal pain. This irritation may be more pronounced, especially for children's delicate gastrointestinal tract. Rectal administration of compound pediatric antipyretic suppositories avoids direct contact between the drug and the gastrointestinal tract, greatly reducing the risk of gastrointestinal irritation and making it more suitable for children.

[0004] (3) More convenient administration method, suitable for specific scenarios: For some children who are in a state of high fever, unconsciousness or vomiting, oral medication may be difficult to take smoothly, and the dosage may be insufficient due to vomiting, affecting the antipyretic effect. Compound pediatric antipyretic suppositories are administered rectally, which is relatively simple to operate. Even if the child is crying or unable to cooperate with oral administration, the medication can be administered more smoothly, ensuring that the medication enters the body on time and in sufficient quantity, thereby controlling the body temperature in a timely manner.

[0005] (4) Reduced dosage error risk: When administering traditional oral medications to children, the actual dosage may deviate from the prescribed dosage due to factors such as parents' inaccurate dosage control or children's lack of cooperation. However, as a solid dosage form, compound pediatric antipyretic suppositories have a precisely pre-set dosage for each suppository. During administration, as long as the correct method of use is followed, the prescribed dosage can be delivered more accurately, reducing the treatment risk caused by dosage error.

[0006] However, existing pediatric antipyretic suppositories have the following drawbacks: (1) Single drug release mode: Most commercially available pediatric antipyretic suppositories have a single-layer structure. For example, although acetaminophen suppositories can reduce fever, the onset time is as long as 40±8 minutes and the effect lasts only 3.1±0.5 hours. The medication needs to be repeated every 4 hours, which increases the pain of children taking the medication.

[0007] (2) Insufficient symptom coverage: Simple chemical suppositories (such as ibuprofen suppositories) only target fever symptoms, and the improvement rate of accompanying symptoms such as sore throat and cough is less than 70%. In contrast, single Chinese medicine suppositories (such as Shuanghuanglian suppositories) have a slow onset of action (60±10 minutes) and are difficult to control acute high fever.

[0008] (3) Poor dosage accuracy: Traditional suppositories cannot achieve dosage stratification, and children need to be manually divided when taking the medication, resulting in a dosage error rate of ±20%, which increases the risk of liver and kidney damage (such as acetaminophen overdose can cause liver toxicity).

[0009] In addition, existing compound pediatric antipyretic suppositories also have the problem of easy stratification, so it is necessary to further improve the existing compound pediatric antipyretic suppositories. Summary of the Invention

[0010] The purpose of this invention is to at least solve one of the technical problems existing in the prior art, and to provide a compound pediatric antipyretic double-layer suppository and its manufacturing method.

[0011] The technical solution of the present invention is as follows: Basic prescription: 5g artificial bezoar, 50g Isatis indigotica root extract powder, 50g acetaminophen. The above three ingredients are added in small amounts to mixed fatty acid glycerides in several batches. At the same time, an appropriate amount of ethanol solution of polysorbate 80 and ethylparaben is added dropwise. After stirring evenly, the mixture is poured into a mold to make 1000 tablets. After cooling, the tablets are demolded and packaged to obtain the suppository. The weight of the suppository is 1.0g / tablet.

[0012] A compound pediatric antipyretic double-layer suppository comprises an immediate-release layer and a sustained-release layer from the inside out. The immediate-release layer contains 150-180g / 1000 suppositories of acetaminophen and 4-6g / 1000 suppositories of artificial bezoar. The sustained-release layer contains 40-60g / 1000 suppositories of Isatis indigotica extract powder and 40-60g / 1000 suppositories of acetaminophen.

[0013] This invention also discloses a method for manufacturing a compound pediatric antipyretic double-layer suppository, comprising the following steps: S1: Heat the mixed fatty acid glycerides until melted, add acetaminophen and artificial bezoar, and stir well; add polysorbate and an ethanol solution containing ethylparaben, and stir well to obtain the immediate-release matrix; S2: Heat the mixed fatty acid glycerides until melted, add Isatis indigotica root extract powder and acetaminophen, and stir until there are no particles; add polysorbate and an ethanol solution containing ethylparaben, stir, and prepare a sustained-release matrix; S3: First, pour the immediate-release matrix into the mold, cool it to form an immediate-release layer; then pour the slow-release matrix into the mold, cool it, demold it, and obtain the product.

[0014] Preferably, in step S1, the mass ratio of the mixed fatty acid glycerides, acetaminophen, artificial bezoar, polysorbate, and ethanol solution is 40-50:30:1:0.6-0.8:1.

[0015] Preferably, in step S2, the mass ratio of the mixed fatty acid glycerides, Isatis indigotica extract powder, acetaminophen, polysorbate, and ethanol solution is 50-60:10:10:0.6-0.8:1.

[0016] Preferably, in steps S1 and S2, the hydroxyphenylethyl ester is 1-2 wt% of an ethanol solution.

[0017] Preferably, in step S1, the viscosity of the immediate-release matrix is ​​400-500 cp.

[0018] Preferably, in step S2, the viscosity of the slow-release matrix is ​​600-700 cp.

[0019] Preferably, a temperature gradient infusion process is adopted, with the immediate-release matrix infusion temperature at 45-55℃ and cooling from -5℃ to 0℃ for 20-40 minutes after infusion, and the slow-release matrix infusion temperature at 40-50℃ and cooling at 20-25℃ for 1-3 hours.

[0020] The beneficial effects of this invention are: This invention provides a compound pediatric antipyretic double-layer suppository, which controls the release of fever through the immediate-release layer and the sustained-release layer in the double-layer suppository, thereby shortening the onset time, prolonging the duration of fever reduction, and greatly improving the symptom improvement rate of patients. Detailed Implementation

[0021] The embodiments of the present invention are described in detail below. These embodiments are exemplary and are only used to explain the present invention, and should not be construed as limiting the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the art or according to the product instructions. Reagents or instruments used, unless otherwise specified, are all commercially available conventional products.

[0022] 1. Design of a two-layer drug delivery system Immediate-release layer (upper surface layer): Ingredients: 150g acetaminophen (75% of total drug content), 5g artificial bezoar, supplemented with 3.5g polysorbate 80 (HLB=15.0) to promote rapid dissolution; Drug release mechanism: The hydrophilic matrix (mixed fatty acid glycerides + surfactant) rapidly disintegrates in rectal mucus, and the drug dissolution rate reaches 85% within 30 minutes, achieving "rapid control of high fever and acute illness".

[0023] Slow-release layer (base layer): Ingredients: 50g of Isatis indigotica root extract powder, 50g of acetaminophen, with 0.105g of ethylparaben forming a sustained-release matrix; Drug release mechanism: The hydrophobic matrix forms a gel network with the polysaccharide extract, releasing 75% of the drug in 6 hours, maintaining the antipyretic effect and providing sustained anti-inflammatory effects.

[0024] 2. Synergistic combination techniques of traditional Chinese and Western medicines (see Table 1) Table 1 Comparison of Synergistic Combinations of Traditional Chinese Medicine and Western Medicine

[0025] 3. Optimization of children's specific dosage forms Precise dosage control: Each tablet contains 200mg of acetaminophen, which exactly meets the recommended dose of 13.3mg / kg for a 3-year-old child (15kg) at one time, avoiding splitting errors; Mucosal protection design: Glyceryl esters and ethylparaben form a protective film in the sustained-release matrix. The rectal mucosal irritation test showed that the congestion score was reduced by 70% compared with commercially available suppositories (P<0.01).

[0026] The technical solution of the present invention will be further described below with reference to specific embodiments.

[0027] Example 1

[0028] S1, Steps for preparing the immediate-release layer; (1) Heat 200g of mixed fatty acid glycerides (type 38) to 50°C to melt, add 150g of acetaminophen (passed through a 100-mesh sieve) and 5g of artificial bezoar (ultra-finely pulverized to 500 mesh), and stir for 15 minutes until uniform; (2) Add 3.5g of polysorbate 80 and 5g of ethanol solution containing 0.0525g of ethylparaben, and continue stirring for 10 minutes to prepare an immediate-release matrix (viscosity 450cP).

[0029] S2, Steps for preparing the sustained-release layer (1) Heat 300g of mixed fatty acid glycerides to 45℃ to melt, add 50g of Isatis indigotica root extract powder (spray-dried powder, particle size D90 < 20μm) and 50g of acetaminophen, and stir for 20 minutes until there are no particles; (2) Add the remaining 3.5g of polysorbate 80 and 5g of ethanol solution containing 0.0525g of ethylparaben, stir until the viscosity is 680cP, and prepare a sustained-release matrix.

[0030] S3, Layered grouting process; (1) First, pour the quick-release matrix into the 3D printing mold and cool it at -5℃ for 30 minutes to form a quick-release layer (thickness 6mm). (2) The slow-release matrix is ​​then poured into the mold until it is full. After cooling at 25°C for 2 hours, each particle weighs 1.0g after demolding. DSC test shows that the melting point difference between the two matrix layers is 5°C (38°C for the immediate-release layer and 43°C for the slow-release layer).

[0031] Comparative Example 1 Commercially available acetaminophen suppositories were used. The ingredients of commercially available acetaminophen suppositories are: each suppository contains 150mg of acetaminophen as the main drug, and the excipients are mixed fatty acid glycerides and Tween-80 as comparative example 1.

[0032] The preparation method is as follows: The mixed fatty acid glycerides were heated to melt, acetaminophen was added and stirred until homogeneous; polysorbate was added and stirred until homogeneous to obtain the final product.

[0033] Comparative Example 2 The main ingredients of commercially available compound pediatric antipyretic suppositories were: 5g of artificial bezoar, 50g of Isatis indigotica root extract powder, and 50g of acetaminophen per suppository. The excipients were mixed fatty acid glycerides, polysorbate 80, and ethylparaben, which were used as comparative example 2.

[0034] The standard preparation method for commercially available suppositories is as follows: Artificial bezoar, Isatis indigotica root extract powder, and acetaminophen are added in small amounts in portions to a mixture of fatty acid glycerides (type 38) kept at around 50°C. At the same time, 7g of polysorbate 80 and 10g of ethanol solution containing 0.105g of ethylparaben are added dropwise while stirring. After the addition is complete, stirring is continued for 30 minutes. The solution is poured into molds to make 1000 suppositories. After cooling, the suppositories are demolded and packaged to obtain the final product.

[0035] Using the standard formula and preparation method (see Table 2), filling was carried out at the following different temperatures: Table 2 Temperature settings for different schemes

[0036] Comparison shows that using Scheme 3 with material handling temperature (50℃~55℃) and material cooling temperature (14℃~20℃) allows the product to be molded well. After molding, using Scheme 2 with sealing temperature (120℃~135℃) can achieve a good sealing effect.

[0037] Trial Example 1: Comparison of Clinical Efficacy (1) Antipyretic effect (n=60, children aged 3-6 years), rectal administration, one tablet at a time, twice a day. Indications: antipyretic, analgesic, soothing and detoxifying, expectorant and calming. Used for fever, palpitations, sore throat and cough with phlegm due to lung heat in children. Results are shown in Table 3.

[0038] Table 3. Comparison of clinical efficacy between Example 1, Comparative Examples 1 and 2

[0039] (2) Symptom improvement rate (48h after medication), the results are shown in Table 4.

[0040] Table 4 Symptom improvement rates of Example 1, Comparative Examples 1 and 2

[0041] In summary, this application has the following advantages compared with the prior art, as shown in Table 5.

[0042] Table 5 Advantages of Example 1

[0043] Summary of advantages and reasons: Drug delivery mode: Ordinary suppositories are single-stage immediate-release or single-stage sustained-release, while this invention is a dual-layer controlled-release system combining immediate-release and sustained-release. The immediate-release layer rapidly releases the drug, quickly reaching an effective blood drug concentration; the sustained-release layer slowly and continuously releases the drug, maintaining a stable blood drug concentration, thus balancing onset and long-lasting effect. Ordinary suppositories, with their single-mode approach, cannot achieve both.

[0044] Onset time: Commercially available ordinary antipyretic suppositories take 40±8 minutes, traditional Chinese medicine antipyretic suppositories take 60±10 minutes, while this invention takes 25±5 minutes, an improvement of 37.5%. Because the immediate-release layer rapidly dissolves and releases the drug, it is quickly absorbed through the mucous membrane and enters the circulation, thus taking effect faster and quickly relieving fever.

[0045] Duration of fever reduction: Commercially available ordinary fever-reducing suppositories last 3.1±0.5 hours, traditional Chinese medicine fever-reducing suppositories last 4.0±0.6 hours, while this invention lasts 5.2±0.8 hours, representing an improvement of 67.7%. The sustained-release layer utilizes controlled-release technology (such as matrix, membrane control, etc.) to delay drug release and absorption, prolonging the duration of action and providing sustained fever reduction.

[0046] Multi-symptom improvement rate: 65% for commercially available ordinary antipyretic suppositories (fever only), 78% for traditional Chinese medicine antipyretic suppositories (focusing on cough), and 92% for this invention (fever + sore throat + cough). On the one hand, the drug combination or formulation can act on multiple targets; on the other hand, the dual-layer suppository release characteristic allows the effective drug concentration to cover multiple symptom-related pathological links, synergistically improving fever, sore throat, cough, etc.

[0047] Experimental Example 2

[0048] (1) Breakthrough in drug release kinetics DSC thermal analysis confirmed that when the above product was broken down into small pieces of approximately 5-6 mm, and 0.5-10 mg of sample was weighed, the crystallinity of the immediate-release matrix was measured to be 25% (low crystallinity promotes rapid dissolution), and the crystallinity of the slow-release layer was 65% (high crystallinity delays release). The in vitro release experiment conformed to the two-phase kinetic model. 0-1 hour: The immediate-release layer releases 80% of acetaminophen, and artificial bezoar releases 90%; 1-6 hours: The sustained-release layer continuously releases the remaining drug, with the release rate of the active ingredient (indirubin) of Isatis indigotica reaching 75%.

[0049] (2) Technological innovation Temperature gradient filling process: The liquid valve temperature is 50℃~60℃; the material temperature inside the tank is 45℃~55℃; the freezing box temperature is 20℃~30℃, 20℃~30℃, 20℃~30℃, 18℃~25℃, 16℃~25℃, 14℃~20℃; the sealing temperature is 130℃~150℃, 130℃~150℃, 135℃~155℃, 120℃~135℃. Different temperatures are used for filling.

[0050] The immediate-release layer is infused at 50°C and then rapidly cooled to -5°C for 30 minutes after infusion to form a porous immediate-release skeleton. The sustained-release layer was infused at 45°C and then slowly cooled at 25°C for 2 hours to form a dense sustained-release structure. CT scans showed that there was no drug miscibility at the interface between the two layers (cross-permeability <5%).

[0051] Improved 3D printing mold: A 12mm diameter mold specifically designed for children is used, and the thickness of the immediate-release layer is precisely controlled to 6mm (accounting for 1 / 3 of the thrombus height) to ensure accurate drug release ratio.

[0052] (3) Safety and stability advantages

[0053] Acute toxicity test: Animal selection for experiments: Rats and mice are commonly used. Generally, the animals should be healthy and have similar weights. Rats should weigh 180-220g and mice should weigh 18-22g. Half of the animals should be male and half female.

[0054] Route of administration: Depending on the method of use, suppositories are usually administered rectally or vaginally. Suppositories are formulated into suitable dosage forms (such as suspensions, emulsions, etc.) for easy administration.

[0055] Dosage design: Preliminary tests can be conducted to determine the approximate toxicity range before formal testing. If using the Horn method, 4-5 dose groups should be set up, with the dose ratio between adjacent groups generally being 1.5-2.0 times. The lowest dose group should not cause animal mortality, while the highest dose group should cause mortality in most animals.

[0056] Observation indicators: Animals were observed for 14 consecutive days after administration. Their physical appearance (e.g., coat color, behavior, mental state), signs of poisoning (e.g., convulsions, diarrhea, difficulty breathing), and mortality were observed daily, and the time of death was recorded. At the end of the experiment, surviving animals were grossly dissected to observe for any obvious lesions in vital organs (e.g., heart, liver, spleen, lungs, kidneys).

[0057] Results: After rectal administration of 20 times the clinical dose (acetaminophen 4000 mg / kg) to rats, there were no deaths within 7 days, and there were no significant differences in liver and kidney function indicators (ALT, AST) compared with the control group (P>0.05).

[0058] Long-term toxicity testing:

[0059] Animal selection for experiments: In addition to rats and mice, beagle dogs and other animals may also be used. The number of animals should meet statistical requirements, generally no less than 20 rats per group and no less than 6 dogs per group, with half males and half females.

[0060] Route of administration and duration of administration: Consistent with acute toxicity studies, administration is performed rectally or vaginally. The duration of administration is determined based on the clinically anticipated duration of use of the suppository. If short-term use is anticipated (not exceeding 2 weeks), the administration period may be 4-6 weeks; if long-term use is anticipated, the administration period may be 3-6 months or even longer.

[0061] Dosage design: Generally, three dosage groups are set up: low, medium, and high. The high-dose group should induce a certain toxic reaction in animals, but not lead to death or serious irreversible damage; the low-dose group should not induce obvious toxic reactions in animals; and the medium-dose group is in between. A blank control group (administered with the corresponding excipients) is also set up.

[0062] The observation indicators are as follows:

[0063] General observation: Observe the animal's diet, weight, behavior and activities every day, and record the weight and food intake once a week.

[0064] Hematological parameters: During the experiment, animal blood was collected periodically to test blood routine (such as red blood cell count, white blood cell count, hemoglobin, etc.) and blood biochemical parameters (such as alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, creatinine, etc.).

[0065] Organ coefficients and pathological examination: At the end of the experiment, the animals were euthanized, and the organ coefficients (organ weight / body weight × 100%) of important organs such as heart, liver, spleen, lungs, and kidneys were calculated. Histopathological examination was performed to observe for any lesions.

[0066] Results: After rectal administration of 20 times the clinical dose (acetaminophen 4000 mg / kg) to rats, there were no deaths within 6 weeks, and there were no significant differences in liver and kidney function indicators (ALT, AST) compared with the control group (P>0.05).

[0067] Skin irritation test:

[0068] Animal selection for testing: Rabbits are commonly used, generally requiring a weight of 2-3 kg and good health without skin diseases. Guinea pigs, etc., can also be used.

[0069] Test methods: divided into irritation tests on intact skin and broken skin.

[0070] Intact Skin Test: Hair was removed from both sides of the spine on the animal's back, covering an area of ​​approximately 3-5 cm². An appropriate amount of suppository contents was evenly applied to the hair-removed area, covered with two layers of gauze (2.5 cm × 2.5 cm) and one layer of cellophane, and then secured with non-irritating adhesive tape. The other hair-removed area served as a blank control, with the corresponding excipient applied. The skin at the application site was observed for irritation reactions such as erythema and edema at 4 h, 24 h, 48 h, and 72 h after application, and scored according to standards.

[0071] Broken skin test: After removing hair from the back of the animal, create a slight break in the skin using sandpaper or other methods (preferably without bleeding). Then, apply the suppository contents and set up a control group as in the intact skin test. Observe the skin irritation reaction at different time points and score it.

[0072] Results: Based on the skin irritation response score, there was no significant irritation, and the condition was good for children with symptoms.

[0073] The results of the fusion timeframe analysis are shown in Table 6.

[0074] Table 6. Fusion Time Limit

[0075] Conclusion: This study, conducted according to the melting time limit method of the General Rules of Part IV of the 2020 edition of the Chinese Pharmacopoeia, meets the requirements of the general rules for suppositories.

[0076] Accelerated stability test:

[0077] The artificial bezoar was placed at 40℃ / 75% RH for 6 months. The results of the test on the decrease in bilirubin and acetaminophen content or the accelerated degradation rate were observed. The results are shown in Table 7.

[0078] Table 7 Acceleration Stability

[0079] Accelerated testing results show that the acetaminophen content in the suppositories of this invention is <5%, and the degradation rate of artificial bezoar content is <3%, which meets expectations.

[0080] In summary, this invention pioneers a dual-layer suppository technology for pediatric fever reduction: through rapid-release and sustained-release dual-phase drug delivery, it fills the gap in domestic suppository technology for "rapid fever reduction + continuous symptom control," reducing the frequency of medication by 50% compared to traditional suppositories. Innovative layered combination of traditional Chinese and Western medicine: Artificial bezoar and acetaminophen work synergistically to reduce fever in the immediate-release layer, while Isatis indigotica root provides sustained anti-inflammatory effects in the sustained-release layer, forming a dual-target treatment model that addresses both the symptoms and the root cause; Standardization of process parameters: Establish quantitative standards for key process parameters such as double-layer plug injection temperature and cooling time (e.g., quick-release layer cooling temperature -5℃±1℃) to achieve stable control in industrial production.

[0081] The embodiments described above are merely preferred embodiments of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various other corresponding changes and modifications based on the technical solutions and concepts described above, and all such changes and modifications should fall within the protection scope of the claims of the present invention.

Claims

1. A compound pediatric antipyretic double-layer suppository, characterized in that, It includes a sustained-release layer and an immediate-release layer from the inside out. The immediate-release layer contains 150-180g / 1000 tablets of acetaminophen and 4-6g / 1000 tablets of artificial bezoar. The sustained-release layer contains 40-60g / 1000 tablets of Isatis indigotica extract powder and 40-60g / 1000 tablets of acetaminophen. The suppository weight is 1.0g / tablet.

2. A method for manufacturing a compound pediatric antipyretic double-layer suppository, characterized in that, Includes the following steps: S1: Heat the mixed fatty acid glycerides until melted, add acetaminophen and artificial bezoar, and stir well; add polysorbate and an ethanol solution containing ethylparaben, and stir well to obtain the immediate-release matrix; S2: Heat the mixed fatty acid glycerides until melted, add Isatis indigotica root extract powder and acetaminophen, and stir until there are no particles; add polysorbate and an ethanol solution containing ethylparaben, stir, and prepare a sustained-release matrix; S3: First, pour the immediate-release matrix into the mold, cool it to form an immediate-release layer; then pour the slow-release matrix into the mold, cool it, demold it, and obtain the product.

3. The method for manufacturing a compound pediatric antipyretic double-layer suppository according to claim 2, characterized in that, In step S1, the mass ratio of the mixed fatty acid glycerides, acetaminophen, artificial bezoar, polysorbate and ethanol solution is 40-50:30:1:0.6-0.8:

1.

4. The method for manufacturing a compound pediatric antipyretic double-layer suppository according to claim 2, characterized in that, In step S2, the mass ratio of the mixed fatty acid glycerides, Isatis indigotica extract powder, acetaminophen, polysorbate, and ethanol solution is 50-60:10:10:0.6-0.8:

1.

5. The method for manufacturing a compound pediatric antipyretic double-layer suppository according to claim 2, characterized in that, In steps S1 and S2, the hydroxyphenylethyl ester is 1-2 wt% of an ethanol solution.

6. The method for manufacturing a compound pediatric antipyretic double-layer suppository according to claim 2, characterized in that, In step S1, the viscosity of the immediate-release matrix is ​​400-500 cp.

7. The method for manufacturing a compound pediatric antipyretic double-layer suppository according to claim 2, characterized in that, In step S2, the viscosity of the slow-release matrix is ​​600-700 cp.

8. A method for manufacturing a compound pediatric antipyretic double-layer suppository according to claim 2, characterized in that, The temperature gradient infusion process is adopted. The infusion temperature of the immediate-release matrix is ​​45-55℃, and it is cooled from -5℃ to 0℃ for 20-40 minutes after infusion. The infusion temperature of the slow-release matrix is ​​40-50℃, and it is cooled from 20-25℃ for 1-3 hours.

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