Compound sodium salicylate composition for treating acute pancreatitis and preparation method thereof

Abstract

The application belongs to the technical field of medicine, and relates to a compound composition, a preparation method and application, in particular to a compound sodium salicylate composition for treating acute pancreatitis and a preparation method. The compound sodium salicylate composition comprises quercetin, diammonium glycyrrhizinate and sodium salicylate, wherein the mass ratio of quercetin, diammonium glycyrrhizinate and sodium salicylate is 1-5:5-20:50-200. When the compound sodium salicylate composition is an injection, it comprises quercetin, diammonium glycyrrhizinate, sodium salicylate, 1,2-propanediol, sodium bisulfite, dimethyl sulfoxide and 0.9% sodium chloride injection. The volume ratio of 1,2-propanediol and dimethyl sulfoxide in the injection is 14-20% and 0.25-1% respectively; and the mass / volume ratio of sodium bisulfite in the injection is 0.1-0.3%. The compound sodium salicylate composition can significantly reduce amylase, lipase, IL-6 and IL-1beta, and can be used for preparing a medicine for treating pancreatitis.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a compound composition, its preparation method, and its application, specifically to a compound sodium salicylate composition for treating acute pancreatitis and its preparation method. Background Technology

[0002] Acute pancreatitis is an inflammatory disease characterized by necrosis of the peripancreatic adipose tissue and damage to acinar cells, and is relatively common in carnivores such as dogs and cats. In recent years, the incidence of this disease has been rising globally, seriously threatening the health of both humans and animals. If not treated promptly and effectively, acute pancreatitis often leads to various complications. Clinically, it typically requires comprehensive medical treatment, including fluid resuscitation, correction of dehydration and electrolyte imbalances, regulation of acid-base balance, anti-infection, anti-shock, symptomatic supportive care, and protection of the pancreatic and gastrointestinal mucosa, as well as enhanced pain management. However, these treatment strategies cannot directly intervene in key pathological mechanisms such as abnormal activation of pancreatic enzymes, inflammatory cascade reactions, and cell necrosis, thus resulting in limited efficacy, high recurrence rates, treating symptoms but not the root cause, and high treatment costs. Therefore, there is an urgent need to develop a drug that is effective, affordable, and has a good safety profile.

[0003] Currently, clinical treatment for acute pancreatitis mainly relies on comprehensive symptomatic treatment, including fasting, fluid restriction, rehydration, analgesia, enzyme inhibition, anti-inflammation, and liver protection. There is a lack of dedicated compound preparations with definite efficacy, clear targets, and synergistic effects. Clinically, anti-inflammatory, liver-protective, or antioxidant drugs are often used alone, but single-component drugs have drawbacks such as limited target action, limited efficacy, and the potential for toxic side effects with long-term or high-dose use.

[0004] Sodium salicylate is a nonsteroidal anti-inflammatory drug (NSAID) that can inhibit prostaglandin synthesis, reduce inflammation, and relieve pain. It has a certain basis for application in the anti-inflammatory treatment of acute pancreatitis. However, when used alone, it has a weak protective effect on pancreatic cells, and high doses may cause liver and kidney burden.

[0005] Diammonium glycyrrhizate has anti-inflammatory, hepatoprotective, cell membrane-protective, and liver function-improving effects, and is often used for inflammatory diseases accompanied by liver damage. However, its direct control effect on local pancreatic inflammation when used alone is limited.

[0006] Quercetin is a natural flavonoid compound with strong antioxidant, free radical scavenging, inflammatory factor inhibition, and pancreatic acinar cell protection effects. However, its poor water solubility and low bioavailability when administered alone limit its application in injectable formulations.

[0007] In the existing technology, there are no reports of scientifically combining sodium salicylate, diammonium glycyrrhizate, and quercetin to prepare a compound composition for the treatment of acute pancreatitis.

[0008] In addition, how to achieve synergistic effects of the three drugs in terms of pharmacological action, while improving anti-inflammatory, hepatoprotective and antioxidant effects, and reducing the dosage of each single drug and improving the safety and stability of the formulation, is a technical problem that urgently needs to be solved in the development of drugs for the treatment of acute pancreatitis. Summary of the Invention

[0009] To overcome the shortcomings of the prior art, the present invention provides a compound sodium salicylate composition, which can be used to treat acute pancreatitis with significant therapeutic effect.

[0010] The objective of this invention is achieved through the following technical solution: This invention provides a compound sodium salicylate composition comprising quercetin, diammonium glycyrrhizate, and sodium salicylate, wherein the mass ratio of quercetin, diammonium glycyrrhizate, and sodium salicylate is 1-5:5-20:50-200. Furthermore, the mass ratio of quercetin, diammonium glycyrrhizate, and sodium salicylate is 3-5:10-20:50, 1-5:5-20:100, or 5:5:200. Furthermore, the mass ratio of quercetin, diammonium glycyrrhizate, and sodium salicylate is 1-5:5-20:100, preferably 1-5:10-20:100, more preferably 1-5:10:100, and most preferably 1:10:100.

[0011] The compound sodium salicylate composition of the present invention can be a tablet, capsule, granule, oral liquid or injection containing quercetin, diammonium glycyrrhizate and sodium salicylate.

[0012] When the compound sodium salicylate composition is an injection solution, it contains quercetin, diammonium glycyrrhizate, sodium salicylate, 1,2-propanediol, sodium bisulfite, dimethyl sulfoxide, and 0.9% sodium chloride injection solution.

[0013] The mass-volume content (mg / mL) of quercetin, diammonium glycyrrhizate, and sodium salicylate in the injection solution is 0.1-0.5 mg / mL, 0.5-2 mg / mL, and 5-20 mg / mL, respectively; preferably 0.3-0.5 mg / mL, 1-2 mg / mL, and 5 mg / mL, or 0.1-0.5 mg / mL, 0.5-2 mg / mL, and 10 mg / mL, or 0.5 mg / mL, 0.5 mg / mL, and 20 mg / mL; more preferably 0.1-0.3 mg / mL, 1 mg / mL, and 10 mg / mL; and most preferably 0.1 mg / mL, 1 mg / mL, and 10 mg / mL.

[0014] The volume ratios of 1,2-propanediol and dimethyl sulfoxide in the injection solution are as follows: 14-20% for 1,2-propanediol and 0.25-1% for dimethyl sulfoxide; the volume ratio of sodium bisulfite in the injection solution is 0.1-0.3%.

[0015] Furthermore, the present invention provides a method for preparing compound sodium salicylate injection, comprising the following steps: (1) Take 55-60% of the total volume of the injection solution of 0.9% sodium chloride solution, add sodium bisulfite and 1,2-propanediol in sequence, and mix well; (2) Add sodium salicylate and diammonium glycyrrhizate to the solution mixed in step (1), stirring while adding until completely dissolved, and adjust the pH to 7-8 with sodium hydroxide; (3) Dissolve quercetin in dimethyl sulfoxide by stirring, and then add it to the solution in step (2); (4) Make up to volume with 0.9% sodium chloride solution, filter, and dispense to obtain the product.

[0016] Furthermore, in step (2) as described above, the pH is adjusted to 7-7.5 using sodium hydroxide.

[0017] The pH value of the compound sodium salicylate injection is 7-8, preferably 7-7.5.

[0018] This invention provides the use of a compound sodium salicylate composition in the preparation of a drug for treating pancreatitis.

[0019] Furthermore, the pancreatitis described is acute pancreatitis.

[0020] Furthermore, the drug may be a veterinary drug.

[0021] The compound sodium salicylate composition of the present invention achieves multi-target intervention for acute pancreatitis through the synergistic effect of multiple components. This compound combines the anti-inflammatory and analgesic effects of sodium salicylate, the potent anti-inflammatory and hepatoprotective effects of diammonium glycyrrhizate, and the antioxidant and cell-protective functions of quercetin, and the three exert their anti-inflammatory effects synergistically.

[0022] Furthermore, when the compound sodium salicylate composition is administered intravenously, the drug can rapidly enter the systemic bloodstream, resulting in a quick onset of action, making it suitable for clinical application. Simultaneously, the combined use of multiple components helps reduce the dosage requirements of each individual drug, decreases the risk of side effects, and improves medication safety.

[0023] Therefore, compound sodium salicylate injection provides a new and effective treatment option for acute pancreatitis, possessing significant clinical translational value and broad application prospects. Furthermore, it has high safety and can be used as a veterinary drug. Attached Figure Description

[0025] Figure 1 The results of histopathological examination of mouse pancreas tissue in Example 7 (100×).

[0026] A: Healthy group B: Model group C: Ulinastatin group D: Low-dose group E: Medium-dose group F: High-dose group

[0027] Figure 2 The results of the pathological morphological examination of rat pancreatic tissue in Example 8 (100×).

[0028] A: Healthy group B: Model group C: Ulinastatin group D: Compound sodium salicylate group Detailed Implementation

[0030] Example 1: Screening of drug composition content in compound sodium salicylate injection Add 6 mL of 0.9% NaCl solution to the container, add 20% (2 mL) of 1,2-propanediol (by volume of injection solution) and mix well. Add 0.1% (0.01 mg) of sodium bisulfite (by mass of injection solution) and dissolve. Add sodium salicylate and diammonium glycyrrhizate while stirring until completely dissolved and adjust the pH to 7.0. Then add 1% (0.1 mL) of dimethyl sulfoxide (DMSO) solution (containing quercetin) (by volume of injection solution) and stir until completely dissolved. Then add 0.9% NaCl solution to bring the total volume to 10 mL. Finally, filter the solution using a 0.22 μm microporous membrane for sterilization.

[0031] A three-factor, three-level orthogonal experimental design was used to investigate sodium salicylate (A: 50, 100, 200 mg), diammonium glycyrrhizate (B: 5, 10, 20 mg), and quercetin (C: 1, 3, 5 mg). The compatibility schemes are shown in Table 1.

[0032]

[0033] This invention selected 110 male Kunming mice and randomly divided them into 11 groups of 10 mice each: a healthy group, a model group, and 9 paired groups (1-9). Mice were intraperitoneally injected with 20% L-arginine 4 g / kg three times, with each injection 1 hour apart, to establish a mouse model of acute pancreatitis. 24 hours after modeling, the mice in the compound sodium salicylate group received a tail vein injection of 1 mL / kg of compound sodium salicylate injection. The healthy group mice received an intraperitoneal injection of the same volume of physiological saline. Administered the medication every 6 hours for a total of 4 times. 72 hours after modeling, all mice were sacrificed, and blood and pancreatic tissue were collected from each group to measure serum lipase (LPS), amylase (AMS), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). The results are shown in Table 2.

[0034]

[0035] The results showed that when the mass ratio of quercetin, diammonium glycyrrhizate, and sodium salicylate was 1:5:5:20:50:200, the levels of amylase, lipase, IL-6, and IL-1β in each group decreased to varying degrees. The decreases were more significant when the ratio was 3:5:10:20:50, 1:5:5:20:100, or 5:5:200; even more significant when the ratio was 1:5:5:20:100; and the most significant decrease was observed when the ratio was 1:10:100. Therefore, this invention uses a mass ratio of quercetin, diammonium glycyrrhizate, and sodium salicylate of 1:10:100 as the main active ingredient for subsequent research.

[0036] Example 2: Concentration screening of cosolvents dimethyl sulfoxide and 1,2-propanediol Add 72 mL of 0.9% NaCl solution to a container, then add 1200 mg of sodium salicylate and 120 mg of diammonium glycyrrhizate while stirring until completely dissolved and adjust the pH to 7.0. Prepare 12 parallel injections, each 6 mL. Dissolve 12 mg of quercetin in dimethyl sulfoxide solution for later use. Add different concentrations of dimethyl sulfoxide (0.25%, 0.5%, 1%) and 1,2-propanediol (14%, 16%, 18%, 20%) to the 12 injections, respectively, and then bring the volume up to 10 mL. Filter the solution sterilely using a 0.22 μm microporous membrane and seal.

[0037] The clarity and stability of the solution were used as evaluation indicators to select appropriate concentrations. The results are shown in Table 3. The results indicate that when the concentration of dimethyl sulfoxide is 0.25-1% and the concentration of 1,2-propanediol is 14-20%, the prepared injection solutions are all clear solutions. In particular, when the concentration of dimethyl sulfoxide is 1% and the concentration of 1,2-propanediol is 20%, the injection solution is not only clear but also has good stability.

[0038]

[0039] Example 3: Screening of the mass-volume concentration of the antioxidant sodium bisulfite Add 60 mL of 0.9% NaCl solution to a container, add 20 mL of 1,2-propanediol and mix well. Add sodium bisulfite of different mass-volume concentrations (0, 0.1%, 0.2%, 0.3%), then add 1000 mg of sodium salicylate and 100 mg of diammonium glycyrrhizate, stirring continuously until completely dissolved and the pH adjusted to 7.68, 7.41, 7.25, and 7.16 for each concentration. Then add 1 mL of dimethyl sulfoxide solution containing 10 mg of quercetin, stirring until completely dissolved. Next, add 0.9% NaCl solution to a final volume of 100 mL, mix well, and finally filter sterilely through a 0.22 μm microporous membrane. Seal and place in a 60 ℃ oven for observation. The properties of the injection solution are used as the evaluation index to screen for suitable concentrations. The results are shown in Table 4.

[0040] The results show that the injection solution without added antioxidants changed color after high temperature. However, when sodium bisulfite was added at a concentration of 0.1-0.3% (w / v), the color did not change after high temperature, and the pH value did not change significantly. Therefore, the injection solution is stable at this concentration. Considering the amount of excipients, this invention preferably uses 0.1% sodium bisulfite as an antioxidant.

[0041]

[0042] Example 4: Preparation of Compound Sodium Salicylate Injection Add 6 mL of 0.9% sodium chloride solution to a container, add 2 mL of 1,2-propanediol, and after it is fully dissolved, add 0.01 mg of sodium bisulfite and stir until completely dissolved. Then add 100 mg of sodium salicylate and 10 mg of diammonium glycyrrhizate while stirring until completely dissolved and adjust the pH to 7.0. Next, add 0.1 mL of dimethyl sulfoxide solution, which contains 1 mg of quercetin, and stir until completely dissolved. Make up the volume to 10 mL with isotonic 0.9% sodium chloride solution. Finally, filter through a 0.22 μm microporous membrane to obtain the final product.

[0043] Example 5: Quality Inspection of Compound Sodium Salicylate Injection Formulation The appearance, solution color, clarity, pH value, and pyrogen levels were checked according to the "Veterinary Pharmacopoeia of the People's Republic of China (2020 Edition)". Appearance and solution color were observed visually; clarity of the injection solution was observed using a clarity meter; pH value of the injection solution was measured using a pH meter; pyrogen check: Three experimental rabbits were used, and their body temperature was measured. The injection solution was slowly injected into the marginal ear vein of the rabbits. This step needed to be completed within 15 minutes, and body temperature was measured every 30 minutes for a total of 6 times.

[0044] The injection solution is a pale yellow, clear liquid with no visible foreign matter, meeting the requirements for injections. pH testing showed that the pH values ​​of the three batches of samples 2025102401, 2025102402, and 2025102403 were 7.44, 7.42, and 7.38, respectively, which are within the pH range of 4-9 for injection solutions.

[0045] The results of the pyrogen test are shown in Table 5. The sum of the body temperature rise of the three rabbits was 0.7 ℃, which is lower than the critical value of 1.4 ℃. Therefore, the pyrogen test results of the injection solution are in accordance with the regulations of the Veterinary Pharmacopoeia.

[0046]

[0047] Example 6 Safety Evaluation of Compound Sodium Salicylate Injection Preparation of high-concentration compound sodium salicylate injection: Add 4 mL of 0.9% NaCl solution to a container, add 40% 1,2-propanediol, and after it is fully dissolved, add 0.4% sodium bisulfite and stir until completely dissolved. Then add 400 mg of sodium salicylate and 40 mg of diammonium glycyrrhizate while stirring until completely dissolved and adjust the pH to 7.0. Next, add 4% dimethyl sulfoxide solution, which contains 4 mg of quercetin, and stir until completely dissolved. Make up the volume to 10 mL with 0.9% NaCl solution. Finally, filter through a 0.22 μm microporous membrane and fill into a container.

[0048] I. Safety Pharmacology Tests Forty SPF Kunming mice were randomly divided into four groups: a blank control group, a 1x dose group, a 2x dose group, and a 4x dose group, with ten mice in each group (half male and half female). All mice were administered the medication via tail vein injection. The blank control group received physiological saline, while the dose groups received high-concentration sodium salicylate injection at different doses. Specific dosages and administration methods are shown in Table 6. The mice were closely monitored for their condition within 4 hours before and after administration, and from day 1 to 7, and various indicators were measured and mortality was recorded.

[0049]

[0050] The results of weight changes are shown in Table 7.

[0051]

[0052] As shown in Table 7, there was no significant difference in mouse weight before and after administration. Within 4 hours after administration, the behavior of mice in the 1-fold and 2-fold dose groups did not change abnormally, while the mice in the 4-fold dose group showed obvious adverse reactions, including muscle spasms, and some mice became lethargic and lay still after being abnormally excited, showing obvious stress response. All mice returned to normal the day after administration.

[0053] The results of the cardiovascular and respiratory system effects are shown in Tables 8 and 9.

[0054]

[0055]

[0056] As shown in Table 8, compared with the blank control group, there was no significant difference in the 1-fold dose group, while the heart rate of mice in the 2-fold dose group was significantly reduced. P <0.05, the heart rate of mice in the 4-fold dose group was significantly reduced ( P <0.01), and all returned to normal after the seventh day of administration.

[0057] As shown in Table 9, compared with the blank control group, there was no significant difference in the 1-fold dose group, while the respiratory rate of mice in the 2-fold and 4-fold dose groups was significantly increased. P <0.01), and all returned to normal after the seventh day of administration.

[0058] In summary, excessive use of compound sodium salicylate injection may cause some adverse reactions, but it is safe to use compound sodium salicylate injection at the normal dosage.

[0059] II. Acute Toxicity Test Sixty SPF Kunming mice were randomly divided into six groups: a blank control group, and groups 1, 2, 3, 4, and 5, with ten mice in each group (half male and half female). All mice were administered the medication via tail vein injection. The blank control group received physiological saline; groups 1-5 received high-concentration sodium salicylate injection at different doses (specific dosages and methods are shown in Table 10). Toxicity and mortality were closely monitored in each group within 4 hours before and after administration, and from day 1 to 7. Mortality rates were calculated based on mortality, and the median lethal dose (LD50) was calculated using the Bliss method.

[0060]

[0061] The mice exhibited abnormal excitement, restlessness or lethargy, muscle spasms, and in some cases, lethargy and immobility. Some mice recovered to normal within about 3 days after administration, while the remaining severely poisoned mice died within 7 days. The specific mortality data for each group is shown in Table 11. It can be seen that the mortality rate of mice in each group increases with increasing dosage.

[0062]

[0063] Based on the mortality rates of mice in each group, the median lethal dose (LD50) was calculated using the Bliss method. The results are shown in Table 12. The regression equation was calculated to be y = -9.781 + 12.972lg(D). 50 =13.7860 mL / kg, LD 50 The 95% confidence interval is 10.7190–15.7600 mL / kg, LD5 = 10.2950 mL / kg, LD 95 =18.4600 mL / kg.

[0064]

[0065] According to the "Guidelines for Acute Toxicity Testing of Veterinary Chemical Drugs," substances with a concentration of 51-500 mg / kg are classified as moderately toxic, and those with a concentration of 501-5000 mg / kg are classified as low-toxic. In this experiment, the intravenous LD50 of compound sodium salicylate injection in mice was determined. 50 The concentration of 13.7860 mL / kg (551.4400 mg / kg for sodium salicylate, 55.1440 mg / kg for diammonium glycyrrhizate, and 5.5144 mg / kg for quercetin) is considered relatively safe.

[0066] Example 7: Evaluation of the therapeutic effect of compound sodium salicylate injection on mice with acute pancreatitis Sixty mice were randomly divided into six groups: a healthy group, a model group, a ulinastatin group, and high-, medium-, and low-dose compound sodium salicylate groups, with ten mice in each group. Mice in the model group, ulinastatin group, and compound sodium salicylate group received intraperitoneal injections of 20% L-arginine 4 g / kg three times, with 1-hour intervals between each injection. The healthy group received an equal volume of physiological saline intraperitoneally each time. Administration began 24 hours after model establishment. The compound sodium salicylate group received a tail vein injection of 1 mL / kg of compound sodium salicylate injection (Example 4), with sodium salicylate and diammonium glycyrrhizate concentrations of 10 mg / mL and 1 mg / mL, respectively. Quercetin concentrations were 0.5 mg / mL, 0.3 mg / mL, and 0.1 mg / mL for the high-, medium-, and low-dose groups, respectively. The ulinastatin group received ulinastatin 5 × 10⁻⁶ mg / kg. 4U / kg was administered every 6 hours for a total of 4 times. 72 hours after modeling, all mice were sacrificed, and blood and pancreatic tissue were collected from each group for the determination of serum lipase (LPS), amylase serum (AMS), interleukin-6 (IL-6), interleukin-1β (IL-1β), superoxide dismutase (SOD), and malondialdehyde (MDA), as well as hematoxylin-eosin (HE) staining of pancreatic tissue.

[0067] (1) Results of the detection of serum amylase and lipase activities in mice with acute pancreatitis by compound sodium salicylate injection As shown in Table 13, compared with the healthy group, the serum lipase and amylase activities of mice in the model group were significantly increased ( P <0.01 indicates that the mouse AP model was successfully established. Compared with the AP model group, ulinastatin and low-dose compound sodium salicylate significantly reduced serum lipase activity in mice ( P <0.01. The medium and low doses of compound sodium salicylate significantly reduced serum amylase activity in mice ( P <0.01). Different doses of compound sodium salicylate can reduce the activity of serum lipase or amylase in AP mice, with the low dose of compound sodium salicylate showing the best effect.

[0068]

[0069] (2) Results of detection of serum inflammatory factor content in mice with acute pancreatitis by compound sodium salicylate injection As shown in Table 14, compared with the healthy group, the serum IL-6 and IL-1β levels in the model group mice were significantly increased ( P The value <0.01 indicates that the mouse AP model was successfully established. Compared with the AP model group, the ulinastatin group showed a highly significant decrease in IL-6 and IL-1β levels ( ). P <0.01, the low-dose compound sodium salicylate group showed a highly significant decrease in IL-6 and IL-1β levels ( P The result was <0.01, indicating that both ulinastatin and different doses of compound sodium salicylate could significantly improve the inflammatory response in AP mice.

[0070]

[0071] (3) Results of detection of serum MDA and SOD levels in mice with acute pancreatitis by compound sodium salicylate injection As shown in Table 15, compared with the healthy group, the serum MDA content of mice in the model group was significantly increased and the SOD activity was significantly decreased. P The value <0.01 indicates that the mouse AP model was successfully established. Compared with the AP model group, the serum MDA content of mice in different doses of compound sodium salicylate groups was significantly decreased ( P <0.01), SOD activity increased significantly ( P <0.01), and it exhibits a dose-dependent effect.

[0072]

[0073] (4) Pathological morphological examination results of compound sodium salicylate injection on pancreatic tissue of mice with acute pancreatitis The results of pancreatic histopathological morphological examination are as follows: Figure 1 As shown, the pancreatic tissue of healthy mice had normal morphology and no pathological changes (Figure A). In the model group, the pancreatic tissue showed disintegration, inflammatory cell infiltration, and diffuse necrosis of pancreatic cells (Figure B). Compared with the model group, the pancreatic pathological damage in the ulinastatin group (Figure C) and the compound sodium salicylate group was improved. Although low-dose (Figure D) still showed pathological phenomena such as inflammatory cell infiltration and pancreatic acinar necrosis, it was still an improvement compared to the model group. The pancreas of mice in the medium- and high-dose compound sodium salicylate groups was significantly improved, especially the pancreas of mice in the high-dose compound sodium salicylate group, which basically returned to a healthy state (Figures E and F).

[0074] Example 8: Evaluation of the therapeutic effect of compound sodium salicylate injection on rats with acute pancreatitis Sixteen rats were randomly divided into four groups: a healthy group, a model group, a ulinastatin group, and a compound sodium salicylate group, with six rats in each group. An acute pancreatitis model was established by intraperitoneal injection of 100 µg / kg of linastatin, administered five times consecutively with a 1-hour interval between each injection. The compound sodium salicylate group received a tail vein injection of compound sodium salicylate injection (Example 4), with a dosage of 1 mL / kg per rat. The ulinastatin group received a tail vein injection of 5 × 10⁵ ulinastatin. 4 U / kg, administered once every 6 hours, for a total of 2 doses. Thirteen hours after modeling, all rats were sacrificed and blood and pancreatic tissue were collected from each group for the determination of serum lipase, amylase, and hematoxylin-eosin (HE) staining of pancreatic tissue.

[0075] (1) Results of the detection of serum amylase and lipase activities in rats with acute pancreatitis by compound sodium salicylate As shown in Table 16, compared with the healthy group, the serum lipase and amylase activities of rats in the model group were significantly increased ( P<0.01 indicates that the rat AP model was successfully established. Compared with the AP model group, the serum amylase and lipase activities in the ulinastatin group and the compound sodium salicylate group were significantly higher ( P <0.01) decreased, and the compound sodium salicylate group was better than the ulinastatin group in reducing serum amylase and lipase activities in AP rats.

[0076]

[0077] (2) Pathological morphological examination results of compound sodium salicylate injection on pancreatic tissue of rats with acute pancreatitis The results of pancreatic histopathological morphological examination are as follows: Figure 2 As shown in Figure A, the pancreatic tissue of healthy rats was morphologically normal and structurally intact, with no inflammatory cell infiltration. The pancreatic tissue morphology of the model group rats (Figure B) showed obvious necrosis, edema, local congestion, and mononuclear cell infiltration. In the ulinastatin group (Figure C) and the compound sodium salicylate group (Figure D), the pancreatic tissue of the rats still showed a small amount of edema, necrosis, and inflammatory cell infiltration, but compared with the model group, the degree of pathological damage to the rat pancreatic tissue was significantly reduced.

[0078] In summary, this invention provides a novel compound sodium salicylate composition, which, when administered as an injection, exhibits significant therapeutic effects on acute pancreatitis. Through quality control and safety studies of this injection, this invention confirms that its quality is controllable, stable, and reliable, with good preliminary safety. Animal pharmacodynamic experiments further demonstrate that this compound preparation has a significant therapeutic effect on acute pancreatitis. Through optimized screening, when the concentrations of quercetin, diammonium glycyrrhizate, and sodium salicylate in the compound sodium salicylate composition are 0.3-0.5 mg / mL, 1-2 mg / mL, 5 mg / mL, or 0.1-0.5 mg / mL, 0.5-2 mg / mL, 10 mg / mL, or 0.5 mg / mL, 0.5 mg / mL, 20 mg / mL in the injection, significant therapeutic effects are observed. The optimal therapeutic effect is achieved when the concentrations of the three components are 0.1-0.3 mg / mL, 1 mg / mL, and 10 mg / mL, respectively. It is evident that the compound sodium salicylate composition of the present invention has good efficacy in treating acute pancreatitis, possesses clinical application potential, and has good safety, and can be used to prepare veterinary drugs for the treatment of acute pancreatitis in animals.

Claims

1. A compound sodium salicylate composition, characterized in that, The compound sodium salicylate composition comprises quercetin, diammonium glycyrrhizate, and sodium salicylate, wherein the mass ratio of quercetin, diammonium glycyrrhizate, and sodium salicylate is 1-5:5-20:50-200, preferably 3-5:10-20:50, 1-5:5-20:100, or 5:5:

200.

2. The compound sodium salicylate composition according to claim 1, characterized in that, The mass ratio of quercetin, diammonium glycyrrhizate, and sodium salicylate is 1-5:5-20:100, preferably 1-5:10-20:100, more preferably 1-3:10:100, and most preferably 1:10:

100.

3. The compound sodium salicylate composition according to claim 1 or 2, characterized in that, The composition is a tablet, capsule, granule, oral liquid or injection containing quercetin, diammonium glycyrrhizate and sodium salicylate.

4. The compound sodium salicylate composition according to claim 3, characterized in that, The injection solution contains quercetin, diammonium glycyrrhizate, sodium salicylate, 1,2-propanediol, sodium bisulfite, dimethyl sulfoxide, and 0.9% sodium chloride injection.

5. The compound sodium salicylate composition according to claim 3, characterized in that, The volume ratios of 1,2-propanediol and dimethyl sulfoxide in the injection solution are as follows: 14-20% for 1,2-propanediol and 0.25-1% for dimethyl sulfoxide; the volume ratio of sodium bisulfite in the injection solution is 0.1-0.3%.

6. The compound sodium salicylate composition according to any one of claims 3-5, characterized in that, The mass-volume contents of quercetin, diammonium glycyrrhizate, and sodium salicylate in the injection solution are 0.1-0.5 mg / mL, 0.5-2 mg / mL, and 5-20 mg / mL, respectively; preferably 0.3-0.5 mg / mL, 1-2 mg / mL, and 5 mg / mL, or 0.1-0.5 mg / mL, 0.5-2 mg / mL, and 10 mg / mL, or 0.5 mg / mL, 0.5 mg / mL, and 20 mg / mL; more preferably 0.1-0.3 mg / mL, 1 mg / mL, and 10 mg / mL; and most preferably 0.1 mg / mL, 1 mg / mL, and 10 mg / mL.

7. A method for preparing the compound sodium salicylate composition according to any one of claims 3-6, characterized in that, Includes the following steps: (1) Take 55-60% of the total volume of the injection solution of 0.9% sodium chloride solution, add sodium bisulfite and 1,2-propanediol in sequence, and mix well; (2) Add sodium salicylate and diammonium glycyrrhizate to the solution mixed in step (1), stirring while adding until completely dissolved, and adjust the pH to 7-8 with sodium hydroxide; (3) Dissolve quercetin in dimethyl sulfoxide by stirring, and then add it to the solution in step (2); (4) Make up to volume with 0.9% sodium chloride solution, filter, and dispense to obtain the product.

8. Use of the compound sodium salicylate composition according to any one of claims 1-6 in the preparation of a medicament for treating pancreatitis.

9. The application according to claim 8, characterized in that, The pancreatitis mentioned is acute pancreatitis.

10. The application according to claim 8 or 9, wherein the drug is a veterinary drug.

Images