Medicament for treating pancreatitis and preparation method thereof

Abstract

The application discloses a medicine for treating pancreatitis and a preparation method thereof, and the medicine contains astragaloside and calycosin-7-glucoside as active ingredients, and the weight ratio of the astragaloside and the calycosin-7-glucoside is 1-2:4-7. The astragaloside and the calycosin-7-glucoside are extracted from traditional Chinese medicine components through a large number of tests, and the combination of the two in a certain proportion has a good effect on treating acute pancreatitis, has no toxic side effect and is low in cost.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a drug for treating pancreatitis and its preparation method. Background Technology

[0002] Pancreatitis is a disease caused by the autodigestion of the pancreas by trypsin. The pancreas may exhibit edema, congestion, hemorrhage, or necrosis. Clinical symptoms include abdominal pain, bloating, nausea, vomiting, and fever. Laboratory tests show elevated levels of amylase in blood and urine. Under normal circumstances, pancreatic juice contains inactive pro-pancreatic zymogens in its glandular tissue. Pancreatic juice continuously flows from the pancreatic duct through the sphincter of Oddi into the duodenum. Due to the presence of bile in the duodenum and the secretion of enterokinase by the duodenal mucosa, the pro-pancreatic zymogens are converted into highly active digestive enzymes. If the outflow is obstructed, pancreatitis can occur.

[0003] When the sphincter of Oddi spasms or the pressure within the bile duct increases, such as due to obstruction by gallstones or tumors, bile can reflux into the pancreatic duct and enter the pancreatic tissue. At this time, the lecithin contained in the bile is broken down into lysophosphatase A in the pancreatic juice, which can have a toxic effect on the pancreas. Alternatively, during biliary tract infections, bacteria can release kinases that activate pancreatic enzymes, which can also become active substances that can damage and dissolve pancreatic tissue. These substances convert pro-zymase in the pancreatic juice into trypsin, an enzyme with strong digestive activity that can penetrate into the pancreatic tissue and cause autodigestion, potentially leading to pancreatitis.

[0004] Commonly used treatments for pancreatitis in clinical practice include the administration of antispasmodic and analgesic drugs, drugs that inhibit pancreatic exocrine secretion and pancreatic enzymes, and antibiotics. Severe cases often require surgical treatment. However, the clinical efficacy of these treatments is not satisfactory, and patient compliance is poor, failing to meet the needs of clinical medication.

[0005] Chinese patent CN112156087B discloses a medicament for treating pancreatitis, the medicament comprising 5-((4-chlorophenyl)(cyano)methyl)-2-(methanesulfonamide)-N-(3,4,5-trichlorophenyl)benzamide or a pharmaceutically acceptable salt thereof and optionally comprising one or more pharmaceutically acceptable carriers.

[0006] Chinese patent CN111358780B discloses the application of mangiferin in the preparation of drugs for the prevention and treatment of severe acute pancreatitis, as well as tablets, pills, and injectable emulsions. Mangiferin reduces the expression of pro-inflammatory factors by inhibiting the NF-κB signaling pathway and increasing IκBα levels, thereby playing a role in the prevention and treatment of severe acute pancreatitis.

[0007] Although there are literature reports on the use of both traditional Chinese medicine and Western medicine to treat pancreatitis, how to further explore the active ingredients in traditional Chinese medicine to improve the therapeutic effect on pancreatitis remains a technical problem that needs to be solved by those skilled in the art. Summary of the Invention

[0008] For the reasons stated above, this invention aims to provide a drug for treating pancreatitis and a method for preparing the same. Specifically, to achieve the objective of this invention, the following technical solution is proposed:

[0009] One aspect of this invention relates to a medicament for treating pancreatitis, the medicament containing gentianin and verbascoside as active ingredients.

[0010] In a preferred embodiment of the present invention, the drug may or may not contain other active ingredients.

[0011] In a preferred embodiment of the present invention, the weight ratio of the gentianin and the verbascoside isoflavone is 1-2:4-7; preferably 1:4-6; particularly preferably 1:5.

[0012] In a preferred embodiment of the present invention, the drug is one of the following: injection, subcutaneous implant, tablet, powder, granule, capsule, oral liquid, and sustained-release agent.

[0013] In a preferred embodiment of the invention, the drug further contains pharmaceutically acceptable excipients.

[0014] In a preferred embodiment of the invention, the pharmaceutically acceptable excipients include mannitol, maltodextrin, sucralose, and microcrystalline cellulose.

[0015] In a preferred embodiment of the present invention, the drug is made from 1-2 parts by weight of gentianoside, 4-7 parts by weight of verbascoside, 25-35 parts by weight of mannitol, 8-12 parts by weight of maltodextrin, 0.3-0.7 parts by weight of sucralose and 12-18 parts by weight of microcrystalline cellulose.

[0016] Another aspect of the present invention relates to a method for preparing the above-mentioned drug, the method comprising the following steps:

[0017] Step 1: Take the gentian root glycoside, verbascoside, mannitol, maltodextrin, sucralose and microcrystalline cellulose, mix and stir evenly to obtain a mixture;

[0018] Step 2: The ethanol-water solution in the mixture is wet-granulated using a wet granulator to obtain wet granules;

[0019] Step 3: Dry the wet granules using a hot air circulating oven to obtain dry granules;

[0020] Step 4: Place the dry granules into a granulator for granulation;

[0021] Step 5: Compress the granulated dry granules using a tableting machine to obtain tablets.

[0022] Another aspect of the present invention relates to the use of the above-mentioned drug in the preparation of a medicament for treating pancreatitis; preferably, the pancreatitis is acute pancreatitis.

[0023] Beneficial effects

[0024] Through extensive experiments, this invention extracts gentianin and verbascoside from traditional Chinese medicine ingredients. When combined in a certain proportion, the two have a good therapeutic effect on acute pancreatitis, with no toxic side effects and low cost. Detailed Implementation

[0025] To further understand the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0026] Unless otherwise specified, all reagents involved in the embodiments of this invention are commercially available products and can be purchased through commercial channels.

[0027] Example 1: Preparation of tablets

[0028] Step 1: Take 1 part by weight of gentian glycoside, 5 parts by weight of verbascoside, 30 parts by weight of mannitol, 10 parts by weight of maltodextrin, 0.5 parts by weight of sucralose and 15 parts by weight of microcrystalline cellulose, mix and stir evenly to obtain a mixture;

[0029] Step 2: Add a 60% ethanol solution to the mixture and perform wet granulation using a wet granulation machine to obtain wet granules;

[0030] Step 3: Dry the wet granules in a hot air circulating oven at 65°C to obtain dry granules;

[0031] Step 4: Place the dry granules into a granulator for granulation;

[0032] Step 5: Compress the granulated dry granules using a tableting machine to obtain tablets.

[0033] Example 2

[0034] Same as in Example 1, except that the amount of gentianin is 1.5 parts by weight.

[0035] Example 3

[0036] Same as in Example 1, except that the amount of gentianin is 1.8 parts by weight.

[0037] Example 4

[0038] Same as in Example 1, except that the amount of verbascoside is 6 parts by weight.

[0039] Comparative Example 1

[0040] Similar to Example 1, except that the amount of gentianin is 3 parts by weight, and verbascoside is not added.

[0041] Comparative Example 2

[0042] Same as in Example 1, except that the amount of verbena isoflavone glycoside is 6 parts by weight, and no gentianoside is added.

[0043] Example 5: Pharmacodynamic study of the drug of the present invention

[0044] 1. Experimental objective:

[0045] The purpose of this experiment is to investigate whether the solid dispersions prepared according to Examples 1-4 and Comparative Examples 1-2 of the present invention have the desired alleviating effect on acute pancreatitis.

[0046] 2. Laboratory animals:

[0047] Male Wistar rats weighing 240g ± 10g were used in this experiment and purchased from the Animal Center of the First Hospital of Qiqihar City.

[0048] 3. Experimental Procedure:

[0049] 1. Establishment of a rat model of acute pancreatitis:

[0050] Eighty Wistar rats were randomly divided into eight groups: one blank control group, one model group, two positive control groups, and four treatment groups, with ten rats in each group. Except for the blank control group, the other groups were modeled using the method described in "Initiation of Severe Acute Pancreatitis Model by Retrograde Injection of Sodium Taurine via Intestinal Wall Puncture into the Pancreatobiliary Duct," Zhang Mingjun et al., Journal of Shanghai Jiaotong University (Medical Edition), 2006(5):488-490. The rat model of severe acute pancreatitis (SAP) was established by injecting 5% sodium taurine (dose: 30 μg / kg body weight) into the pancreatobiliary duct via intestinal wall puncture. The blank control group was injected with the same amount of 0.9% saline using the same method.

[0051] 2. Dosing regimen:

[0052] Drug administration to each experimental group was administered 1 hour before modeling, 3 hours after modeling, and 9 hours after modeling, respectively. The administration regimen is shown below:

[0053] Blank control group: Distilled water of the same volume as the drug treatment group was administered by gavage.

[0054] Model group: Same as blank control group.

[0055] Positive control group: The solid dispersions prepared in Comparative Examples 1 and 2 (dispersed in an appropriate amount of distilled water) were administered by gavage at a dose of 5 mg / kg body weight, whereby the dose was calculated based on the amount of the active ingredient, gentianin or verbascoside.

[0056] Treatment group: The solid dispersions prepared in Examples 1-4 (dispersed in an appropriate amount of distilled water) were administered by gavage at a dose of 5 mg / kg body weight. The dose is calculated based on the total amount of the active ingredients mangosteenin and verbascoside.

[0057] 3. Methods for evaluating drug efficacy:

[0058] Twenty-four hours after modeling, rats were anesthetized by intraperitoneal injection of 2% sodium pentobarbital at a dose of 50 mg / kg. Blood was collected via the abdominal aorta and left at room temperature for 1 hour. The blood was then centrifuged at 4,000 rpm for 10 minutes in a low-temperature centrifuge. The supernatant was collected, and the serum amylase and lipase levels were measured.

[0059] 4. Experimental Results and Discussion:

[0060] The specific experimental results are shown in Table 1.

[0061] Table 1. Serum amylase and lipase levels in rats of each experimental group 24 hours after modeling.

[0062] Group Number Dosage (mg / kg) Amylase (U / L) Lipase (U / L) Blank control group 10 - 2684±297 42.5±20.7 Model group 10 - 6012±412 239.8±54.9 Example 1 Group 10 10 2945±352* 67.5±18.7* Example 2 group 10 10 3158±340* 82.3±22.4* Example 3 Group 10 10 3211±332* 84.9±25.3* Example 4 group 10 10 3102±349* 71.6±24.1* Comparative Example 1 10 10 5249±408* 134.2±31.5* Comparative Example 2 10 10 4937±429* 164.7±33.7*

[0063] Note: Results are expressed as mean ± standard deviation; * indicates comparison with the negative control group: P<0.05.

[0064] Analysis of experimental results: Elevated amylase levels are most commonly seen in acute pancreatitis and are one of the important diagnostic indicators of acute pancreatitis. The greater the increase in amylase activity, the greater the likelihood of acute pancreatitis. Additionally, lipase, mainly derived from the pancreas, is one of the digestive enzymes secreted by the pancreas. Elevated lipase levels are also associated with acute pancreatitis and are one of the indicators reflecting the severity of the condition. The experimental results in Table 1 show that, compared with the blank control group, the model group rats showed significantly increased serum amylase and lipase levels 24 hours after modeling, suggesting that the rat model of severe acute pancreatitis was successfully established by retrograde injection of sodium taurine into the pancreatobiliary duct via intestinal wall puncture.

[0065] The experimental results in Table 1 also show that the tablets of Examples 1-4 and Comparative Examples 1-2 can significantly reduce the serum amylase and lipase levels in rats 24 hours after modeling, which is statistically significant. In comparison, Examples 1-4 can more significantly reduce the serum amylase and lipase levels in rats 24 hours after modeling, which is statistically significant compared to Comparative Examples 1-2. This demonstrates that the present invention, by simultaneously administering gentianin and verbascoside within a certain ratio range, can significantly improve pancreatitis, and that gentianin and verbascoside within a certain ratio range have a synergistic effect in improving pancreatitis. It should be particularly noted that the tablet of Example 1 of the present invention has the most significant efficacy, and the ratio of gentianin and verbascoside described therein constitutes the most preferred technical solution of the present invention.

[0066] The preferred embodiments of the present invention have been described above, but are not intended to limit the invention. Those skilled in the art can make modifications and variations to the embodiments disclosed herein without departing from the scope and spirit of the invention.

Claims

1. A medicament for treating pancreatitis, the medicament comprising as active ingredients formononetin and calycosin with a weight ratio of 1:

5.

2. The medicament according to claim 1, which contains or does not contain other active ingredients.

3. The medicament according to claim 1 or 2, which is one of an injection, a subcutaneous implant, a tablet, a powder, a granule, a capsule, an oral solution, and a sustained-release preparation.

4. The medicament according to claim 1 or 2, which further contains a pharmaceutically acceptable excipient.

5. A medicament for treating pancreatitis, the medicament being prepared from 1 part by weight of formononetin, 5 parts by weight of calycosin, 30 parts by weight of mannitol, 10 parts by weight of maltodextrin, 0.5 part by weight of sucralose, and 15 parts by weight of microcrystalline cellulose.

6. A method for preparing the medicament according to claim 5, the method comprising the following steps: Step 1: mixing and stirring the formononetin, the calycosin, the mannitol, the maltodextrin, the sucralose, and the microcrystalline cellulose to obtain a mixture; Step 2: adding an aqueous ethanol solution to the mixture and using a wet granulator to perform wet granulation to obtain wet granules; Step 3: drying the wet granules using a hot air circulation oven to obtain dry granules; Step 4: placing the dry granules into a granulator to perform granulation; and Step 5: using a tablet press to compress the granules to obtain tablets.

7. Use of the medicament according to any one of claims 1 to 5 in the preparation of a medicament for treating pancreatitis.

8. The use according to claim 7, wherein the pancreatitis is acute pancreatitis. ​ ​ ​ ​ ​