Application of polyoxyethylene particles in preparation of biocompatible preparation for promoting digestive tract mucosal injury repair

Abstract

The invention provides an application of polyoxyethylene particles in preparation of a biocompatible preparation for promoting digestive tract mucosal injury repair. The weight-average molecular weight of polyoxyethylene is 1 million Dalton to 7 million Dalton; the average particle size of the polyoxyethylene particles is 0.5 [mu] m to 2000 [mu] m; after the preparation is applied to the injured wound surface of the digestive tract mucosa, colloid covering the injured wound surface of the digestive tract mucosa is formed. The colloid can effectively protect digestive tract mucosa, avoid side effects caused by drug treatment of digestive tract mucosa injury, and provide an effective repair protection barrier for a digestive tract ulcer wound surface or a mucosa injury wound surface, so that the repair of the wound surface is promoted.

Description

Technical Field

[0001] The present invention relates to the medical use of polyoxyethylene. Specifically, the present invention relates to the application of polyoxyethylene particles in the preparation of a biocompatible preparation for promoting the repair of digestive tract mucosal damage. Background Art

[0002] Digestive tract mucosal damage includes peptic ulcers and ulcers resulting from digestive tract surgery. Peptic ulcer is a common disease caused by the imbalance between the enhancement of local gastric acid, pepsin, and Helicobacter pylori and the weakening of the mucus-bicarbonate barrier and mucosal repair and protection mechanisms. It mainly includes gastric ulcer (GU) and duodenal ulcer (DU). The main symptoms of such diseases are chronic or periodic gastric pain, belching, abdominal distension, acid reflux, etc., and can cause various degrees of complications, such as gastric perforation, gastric bleeding, gastric cancer, etc. Excessive fatigue, irregular diet, endocrine disorders, etc. may all trigger peptic ulcer diseases. With the further in-depth study of the pathogenesis of peptic ulcers, some scholars have found that gastric mucosal protectants can not only repair the damaged mucosal epithelium, but also repair and reconstruct the submucosal tissue structure, thereby promoting ulcer healing and reducing the recurrence rate. Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are minimally invasive surgeries for the treatment of early gastric cancer and gastric benign tumors. They can not only achieve the purpose of radical resection of early gastric cancer, but also have the advantages of less trauma and less impact on the quality of life of patients, and have gradually replaced some traditional surgical procedures. However, with these two methods, especially the gastric ulcers resulting from ESD are larger and deeper than ordinary ulcers, and are prone to bleeding and perforation after surgery. Under the action of gastric acid and pepsin, the exposed wound surface also has a longer healing time and is prone to form scar tissue. How to quickly repair the gastric mucosa after surgery is also a hot topic in clinical practice.

[0003] In view of the high incidence and severity of the above-mentioned digestive tract mucosal damage, the commonly used method in current medicine is drug treatment. The commonly used drugs are generally divided into proton pump inhibitor drugs, H2-receptor antagonist drugs, and mucosal protectant drugs. Among them, the representative drugs in proton pump inhibitor drugs include: omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole, etc.; the representative drugs in H2-receptor antagonist drugs include: cimetidine, ranitidine, famotidine, nizatidine, etc.; the representative drugs in mucosal protectant drugs include: prostaglandin drugs, teprenone, bismuth potassium citrate, etc. Although these drugs can help repair the digestive tract mucosa, long-term use of these drugs will cause damage to the human liver or kidneys. In order to eliminate the liver or kidney damage caused by long-term use of drugs for treating digestive tract mucosal damage, and at the same time to promote the effective repair of digestive tract ulcer wounds or mucosal damage wounds, there is an urgent need in this field for a biocompatible preparation that physically separates the digestive tract ulcer wounds or mucosal damage wounds from acids, alkalis, and / or enzymes in the digestive tract to promote the repair of digestive tract mucosal damage.

[0004] Regarding polyethylene oxide, although it has been disclosed in the prior art that it is used for hemostasis, there has been no report on using polyethylene oxide to promote the repair of digestive tract mucosal damage. Summary of the Invention

[0005] The purpose of the present invention is to provide a medical use of polyethylene oxide particles, that is, the application of polyethylene oxide particles in the preparation of a biocompatible preparation for promoting the repair of digestive tract mucosal damage, wherein:

[0006] The weight-average molecular weight of the polyethylene oxide is 1 million to 7 million Daltons;

[0007] The average particle size of the polyethylene oxide particles is 0.5 μm to 2000 μm;

[0008] After the preparation is applied to the damaged wound surface of the digestive tract mucosa, a colloid is formed that covers the damaged wound surface of the digestive tract mucosa.

[0009] In some embodiments of the present invention, the duration for which the colloid adheres to the damaged wound surface of the digestive tract mucosa is not less than 72 hours.

[0010] In some embodiments of the present invention, the adhesion force of the colloid to the digestive tract mucosa is not less than 1 N.

[0011] In some embodiments of the present invention, the average particle size of the polyethylene oxide particles is 50 μm - 500 μm.

[0012] In some embodiments of the present invention, the viscosity of the polyethylene oxide particles at a concentration of 2.0% wt is 2000 - 4000 mPa·s.

[0013] In some embodiments of the present invention, the preparation further comprises at least one of biocompatible modified starch and povidone.

[0014] In some embodiments of the present invention, the preparation comprises biocompatible modified starch, and the mass ratio of polyethylene oxide to biocompatible modified starch is from 9:1 to 1:1.

[0015] In some embodiments of the present invention, the preparation comprises povidone, and the mass ratio of polyethylene oxide to povidone is from 6:1 to 1:1.

[0016] In some embodiments of the present invention, the preparation comprises biocompatible modified starch and povidone, and the mass percentage content of polyethylene oxide particles is 50% to 99%; the mass percentage content of biocompatible modified starch is 0% to 50%; the mass percentage content of povidone is 0% to 50%.

[0017] In some embodiments of the present invention, the biocompatible modified starch includes at least one of pregelatinized starch, acid-modified starch, esterified starch, etherified starch, grafted starch, crosslinked starch, and composite modified starch.

[0018] In some embodiments of the present invention, the preparation is a solid particle preparation, which is sprayed on the damaged wound surface of the digestive tract mucosa through a digestive endoscope.

[0019] The present invention has the following advantages over the prior art: by selecting polyethylene oxide particles with a specific molecular weight and a specific particle size, the present invention uses them to prepare a biocompatible preparation for promoting the repair of digestive tract mucosal damage. After the preparation is applied to the damaged wound surface of the digestive tract mucosa, it forms a colloid covering the damaged wound surface of the digestive tract mucosa, which can effectively protect the digestive tract mucosa, avoid the side effects brought by the drug treatment of digestive tract mucosal damage, and provide an effective repair and protection barrier for the digestive ulcer wound or mucosal damage wound, thereby promoting the repair of the wound.

[0020] The present invention will be further described in detail below in conjunction with the drawings and specific embodiments. Description of the Drawings

[0021] Figure 1 is a schematic diagram of the adhesion force test for evaluating the adhesion performance in the embodiment of the present invention;

[0022] Figure 2 is a schematic diagram for simulating the digestive tract environment tolerance test in the embodiment of the present invention;

[0023] Figure 3 is the scouring test result of the preparations #1-#3 in Example 1 of the present invention simulating the digestive tract environment.

[0024] Figure 4 These are gastroscope photos of the gastric wound surface of Bama pigs after 7 days and 28 days of healing after spraying the preparation #1 - #3 of Example 1 of the present invention;

[0025] Figure 5 These are the results of the erosion test of the preparation #4 - #6 of Example 2 of the present invention simulating the digestive tract environment;

[0026] Figure 6 These are gastroscope photos of the gastric wound surface of Bama pigs after 7 days and 28 days of healing after spraying the preparation #4 - #6 of Example 2 of the present invention;

[0027] Figure 7 These are the results of the erosion test of the comparative preparation #7 - #9 of the comparative example simulating the digestive tract environment. Detailed implementation manners

[0028] The technical solutions of the present invention will be further described below in conjunction with the exemplary embodiments and drawings of the present invention. Obviously, the embodiments described herein are only for illustrative purposes and do not exhaust all embodiments of the present invention. The following description of the exemplary embodiments is merely illustrative and does not constitute any limitation to the protection scope of the present invention. Based on the embodiments of the present invention, all other implementation manners obtained by those of ordinary skill in the art without creative efforts fall within the protection scope of the present invention.

[0029] Unless otherwise specifically stated, the numerical values and numerical ranges recorded in the exemplary embodiments of the present invention do not constitute any limitation to the protection scope of the present invention. For the sake of brevity, the technologies and methods known to those of ordinary skill in the relevant fields are not described in detail herein, but where appropriate, the known technologies and methods should be regarded as part of this specification. In all examples described herein, any specific value should be construed as merely exemplary and not constituting any limitation. Therefore, other examples except the exemplary embodiments may have different values.

[0030] Example 1

[0031] This embodiment provides three biocompatible preparations #1 to #3 containing polyoxyethylene (PEO) particles with different weight - average molecular weights. The physicochemical parameters of the PEO particles contained in these preparations are shown in Table 1 below:

[0032] Table 1 Physicochemical parameters of PEO contained in the exemplary preparations #1 - #3

[0033] Formulation No. Physicochemical Parameters of PEO #1 Weight-average molecular weight: 1 million; Particle size: 0.5 μm to 2000 μm; #2 Weight-average molecular weight: 2 million; Particle size: 0.5 μm to 2000 μm; #3 Weight-average molecular weight: 4 million; Particle size: 0.5 μm to 2000 μm;

[0034] In this embodiment, the PEO particles used for preparing Formulations #1 to #3 can be obtained through commercial channels or prepared by methods known in the art. The biocompatible Formulations #1 - #3 of this embodiment are prepared by the following steps:

[0035] (a) Using PEO particles with different weight-average molecular weights shown in Table 1 as raw materials, place them in a granulator;

[0036] (b) Set the granulation zone temperature to 40°C - 60°C, and add an appropriate amount of purified water during the granulation process;

[0037] (c) Screen the granulated PEO raw materials through a sieve with a mesh aperture of 50 μm to 500 μm;

[0038] (d) After standing and cooling, prepare biocompatible Formulations #1 - #3 with a particle size of 50 μm to 500 μm for promoting the repair of digestive tract mucosal damage.

[0039] The formulations in this embodiment can be delivered to the digestive tract using common methods known in the art. For example, the particulate formulation can be sprayed onto the damaged or ulcerated area of the digestive tract mucosa through a digestive endoscope.

[0040] In order to further characterize the protective effect of Formulations #1 - #3 prepared in this embodiment on the digestive tract mucosa, the following experiments were designed and tests were completed.

[0041] 1.1 Viscosity test

[0042] In order to enable the colloid formed by the biocompatible formulation in the digestive tract to cover the damaged surface of the digestive tract mucosa to have sufficient adhesion, the PEO particles of the present invention need to have a sufficient viscosity value. The viscosity tests of Formulations #1 to #3 of this embodiment are as follows.

[0043] 1.1.1 Test purpose:

[0044] Detect the viscosity of Biocompatible Formulations #1 - #3 under a 2% wt concentration through viscosity tests.

[0045] 1.1.2 Test method:

[0046] Test according to the method specified in "Polyethylene Oxide" in the Pharmacopoeia of the People's Republic of China (2020 Edition, Volume IV): Weigh accurately 12 g of polyethylene oxide and place it in an 800 mL beaker. Add 125 mL of anhydrous isopropanol, and stir at high speed (400 r / min) to disperse evenly. Then add 588 mL of water free of carbon dioxide, and continue to stir at high speed for 1 minute (avoid splashing of the solution). Then continue to stir slowly (60 r / min) for 3 hours until there is no jelly-like substance in the solution (prevent the volatilization of water in an appropriate way). Place it in a water bath for 30 minutes to keep the temperature of the solution at 25 ± 0.1 °C. Use a suitable rotational viscometer and rotor to check according to Method 3 of General Rule 0633 in the Pharmacopoeia of the People's Republic of China (2020 Edition, Volume IV).

[0047] 1.1.3 Test Results:

[0048] Table 2 Viscosity Values of Formulations #1 - #3

[0049] #1 #2 #3 Viscosity (mPa·s) 2800 3100 3350

[0050] As can be seen from Table 2, the viscosity values of the formulations #1 - #3 in this example are all in the range of 2000 - 4000 mPa·s.

[0051] 1.2 Adhesion Force Test on Digestive Tract Mucosa

[0052] The adhesion force between the colloid formed by the biocompatible formulation covering the damaged wound surface of the digestive tract mucosa in the digestive tract and the digestive tract mucosa is also one of the factors to achieve the present invention. The adhesion performance tests of the formulations #1 to #3 in this example are as follows.

[0053] 1.2.1 Test Purpose:

[0054] Evaluate the adhesion performance of the biocompatible formulations #1 - #3 through the adhesion force test.

[0055] 1.2.2 Test Method:

[0056] The present invention uses Figure 1 the tester shown to conduct the test. Take the excised pig stomach or intestine, lay its mucosal layer outwards and fix it to the robotic arms at both ends of the tester. Sprinkle the above-prepared formulations #1 to #3 (0.3 g) evenly on the mucosa (about 2 cm 2 ), and after about 10 seconds, it can be observed that the formulations #1 to #3 form a colloid on the mucosal surface. Set the test instrument parameters: compression speed: 20 mm / min, switching condition: force ≤ -50 gf, pause time: 0.5 min, stretching speed: 20 mm / min, and run the tester to test the adhesion force.

[0057] 1.2.3 Test Results:

[0058] Table 3 Test Results of the Adhesion Force of Formulations #1-#3 to the Digestive Tract Mucosa

[0059] #1 #2 #3 Adhesion Force (N) 1.35 1.36 1.41

[0060] As can be seen from Table 3, the adhesion forces of the above-mentioned formulations #1 to #3 to the digestive tract mucosa are all greater than 1 N.

[0061] 1.3 Test on the Adhesion Effect on the Digestive Tract Mucosa and the Tolerance to the Digestive Tract Environment

[0062] In order to provide an effective repair and protection barrier for the digestive ulcer wound surface or the mucosal injury wound surface, the colloid formed by the biocompatible formulation of the present invention covering the injury wound surface of the digestive tract mucosa in the digestive tract should last for a sufficient time, for example, not less than 72 hours. The following is a simulation test on the duration of the exemplary formulations #1 to #3 in the digestive tract environment.

[0063] 1.3.1 Test Purpose:

[0064] Test the tolerance of formulations #1-#3 of biocompatible agents to the in vivo environment (artificial gastric juice and artificial intestinal juice) through a flushing experiment.

[0065] 1.3.2 Test Method:

[0066] The present invention uses the Figure 2 shown inclined plate device to simulate the digestive tract environment for testing the tolerance. Take the excised pig stomach or intestine, spread the mucosal layer outwards and flat on the Figure 2 inclined plate device, and evenly disperse the above-mentioned formulations #1 to #3 (0.3 g each) on the mucosa (about 2 cm 2 ), drop a little staining agent for staining to facilitate observation. After about 10 seconds, it can be observed that formulations #1 to #3 form a colloid on the mucosal surface. Subsequently, flush the colloid formed on the mucosal surface with artificial gastric juice (pH = 1) or artificial intestinal juice (pH = 8) at a speed of 2.5 L / 24 h, and observe the residence time of the colloid formed on the mucosal surface under the flushing conditions.

[0067] Among them, the artificial gastric juice (pH = 1) and artificial intestinal juice (pH = 8) used in this example are prepared according to the standard solution in the Pharmacopoeia of the People's Republic of China (2020 Edition). Take 16.4 mL of dilute hydrochloric acid, add 800 mL of water and 10 g of pepsin, shake well to dissolve it completely, adjust the pH value to 1.3, and dilute with water to a constant volume of 1000 mL to obtain artificial gastric juice; take 6.8 g of potassium dihydrogen phosphate, add 500 mL of water to dissolve it, adjust the pH value to 6.8 with 0.1 mol / L sodium hydroxide solution, and weigh another 10 g of trypsin and dissolve it in an appropriate amount of water. Mix the two solutions and dilute with water to a constant volume of 1000 mL to obtain artificial intestinal juice.

[0068] 1.3.3 Test Results:

[0069] The erosion test results of Formulations #1 - #3 are as Figure 3 shown. From Figure 3 it can be seen that under the continuous erosion of artificial gastric juice or artificial intestinal juice (simulating the digestive tract environment), the colloids formed by the above Formulations #1 to #3 on the mucosal surface can stay on the mucosal surface for more than 72 hours.

[0070] From the above experiments, it can be known that the biocompatible Formulations #1 - #3 of the present invention for promoting the repair of digestive tract mucosal damage have sufficient viscosity, and their viscosity values are all in the range of 2000 - 4000 mPa·s, so as to support the colloid formed on the damaged wound surface of the digestive tract mucosa in the digestive tract to have sufficient adhesion force (greater than 1 N), and can quickly and timely form a protective colloid on the digestive tract mucosal surface. Moreover, this colloid has sufficient tolerance to artificial gastric juice and artificial intestinal juice, and will not degrade and lose its adhesion performance due to the acidity or alkalinity in the stomach and intestine, and can also stay on the mucosal surface for at least 72 hours. Usually, the digestive tract mucosa can be repaired within a period not exceeding 72 hours. Therefore, the adhesion ability of the biocompatible Formulations #1 - #3 of the present invention to the digestive tract mucosa for not less than 72 hours in the digestive tract environment can effectively isolate the ulcer wound surface or mucosal damage wound surface from acids, alkalis, and / or enzymes in the digestive tract, thereby promoting the repair of digestive tract mucosal damage.

[0071] 1.4 Tests on Formulations #1 to #3 for Promoting the Repair of Damaged Sites in the Digestive Tract

[0072] 1.4.1 Test Purpose:

[0073] To verify the promoting effect of the biocompatible Formulations #1 - #3 on the healing of gastric mucosal damage through animal experiments.

[0074] 1.4.2 Test Method:

[0075] 1.4.2.1 Information of Bama Pigs:

[0076] The experimental pigs are 3 - 6 months old, with a body weight range of 40 - 45 kg, and 2 pigs per group. In order to determine the general health status of the animals, a baseline assessment is performed on all animals, including blood routine, complete blood count, serum chemistry, blood glucose, and liver and kidney functions. Then the experimental pigs are placed in the lateral position, and endoscopic examination is performed to observe changes such as bleeding, tumors, ulcers, and inflammatory lesions.

[0077] 1.4.2.2 Animal Anesthesia:

[0078] Anesthesia was induced by injecting sodium pentobarbital into the marginal ear vein or by other appropriate means. Subsequently, the experimental pigs were fixed supine on the operating table, tracheal intubation was performed, and assisted ventilation was provided by a ventilator. An oblique incision of 6-7 cm was made on the sternocleidomastoid muscle in the neck to expose the carotid artery. The vital signs of the animals (heart rate, blood pressure, pulse, respiratory rate, blood oxygen saturation, ET-CO2, etc.) were monitored throughout the process, and no abnormal vital signs were observed during the experiment. During the experiment, normal saline was intravenously injected into all experimental pigs to maintain the mean blood pressure above 60 mmHg.

[0079] 1.4.2.3 Heparin administration:

[0080] Heparin was intravenously injected until twice the upper limit of the normal human ACT range (80 s - 160 s) was reached to create an extreme situation of gastrointestinal bleeding. The ACT of the experimental pigs was monitored every 15 minutes. If it was lower than twice the upper limit of the normal human ACT range, heparin was injected again to ensure that it remained within the target range. During this experiment, the ACT levels of all experimental pigs were maintained at twice the upper limit of the normal human ACT range and above.

[0081] 1.4.2.4 Model establishment:

[0082] Under gastroscopy, a wound surface of about 2 cm × 2 cm was excised with a snare to create an ulcerative bleeding wound surface on each experimental pig, and the size of the wound surface was estimated with a biopsy forceps.

[0083] 1.4.2.5 Administration:

[0084] For the wound surface, the experimental groups were respectively sprayed with preparations #1 - #3, about 1 g, until the wound surface was completely covered. The blank control group was not sprayed with any preparation and was normally raised. Endoscopic follow-up was performed 7 days and 28 days after the successful operation to observe the healing of the wound surface under endoscopy.

[0085] The experimental pigs were monitored for signs of gas embolism in the abdominal aorta, abdominal veins, femoral artery, carotid artery, aorta, and heart during the operation, and for the presence of abdominal effusion or free gas under the diaphragm after the operation, using a Doppler ultrasound diagnostic instrument.

[0086] 1.4.3 Experimental results:

[0087] The animal experiment results of preparations #1 - #3 are as Figure 4 shown. It can be seen from Figure 4 that after four weeks of healing, the wound surface area of the experimental groups using preparations #1 - #3 of the present invention was significantly reduced compared to the blank control group. Thus, it can be seen that preparations #1 - #3 of the present invention all have a good promoting effect on the healing or repair of injuries in the gastric mucosa.

[0088] Example 2

[0089] The difference between Formulations #4 to #6 in this example and Formulation #2 in Example 1 is that in addition to containing poly(ethylene oxide) (PEO) particles with a weight-average molecular weight of 2 million Daltons, the formulations in this example also contain biocompatible modified starch or polyvinylpyrrolidone. The respective component ratios of Formulations #4 to #6 in this example are shown in Table 4 below:

[0090] Table 4 Respective component ratios of exemplary Formulations #4 to #6

[0091] Formulation No. Component Ratio #4 Polyethylene Oxide: Modified Starch = 9:1 #5 Polyethylene Oxide: Polyvinylpyrrolidone = 9:1 #6 Polyethylene Oxide: Modified Starch: Polyvinylpyrrolidone = 8:1:1

[0092] Prepare the above Formulations #4 to #6 according to the component raw material ratios in Table 4, and the preparation steps are as follows:

[0093] (a) Place the raw materials listed in Table 4 in a granulator according to the corresponding ratios;

[0094] (b) Set the granulation zone temperature to 40°C to 60°C, and add an appropriate amount of purified water during the granulation process;

[0095] (c) Screen the granulated biocompatible formulations through a sieve with a mesh aperture of 50 - 500 μm;

[0096] (d) Let it stand, and after cooling, obtain biocompatible Formulations #4 to #6 for promoting the repair of digestive tract mucosal damage with particle sizes of 50 μm to 500 μm.

[0097] The formulations in this example can be sprayed onto the damaged or ulcerated parts of the digestive tract mucosa using common methods in the art (for example, through a digestive endoscope).

[0098] In order to further characterize the protective effect of Formulations #4 to #6 prepared in this example on the digestive tract mucosa, the following experiment was designed and the test was completed.

[0099] 2.1 Viscosity test

[0100] 2.1.1 Test purpose:

[0101] Test the viscosity of the biocompatible formulations for repairing digestive tract mucosal damage of #4 - #6 at a 2% wt concentration.

[0102] 2.1.2 Test method:

[0103] Test according to the method specified in "Polyethylene Oxide" in Pharmacopoeia of the People's Republic of China (2020 Edition, Volume IV): Weigh accurately 12 g of polyethylene oxide and place it in an 800 ml beaker. Add 125 ml of anhydrous isopropanol, stir at high speed (400 r / min) to disperse evenly, add 588 mL of carbon dioxide-free water, continue to stir at high speed for 1 minute (avoid splashing of the solution), then continue to stir slowly (60 r / min) for 3 hours until there is no gel in the solution (prevent the evaporation of water in an appropriate way). Place it in a water bath for 30 minutes to maintain the temperature of the solution at 25 ± 0.1 °C, and check using a suitable rotational viscometer and rotor according to Method 3 of General Rule 0633 in Pharmacopoeia of the People's Republic of China (2020 Edition, Volume IV).

[0104] 2.1.3 Test results:

[0105] Table 5 Viscosity values of #4 - #6 preparations

[0106] #4 #5 #6 Viscosity (mPa·s) 2765 2888 3042

[0107] As can be seen from Table 5, the viscosity values of #4 - #6 preparations are all in the range of 2000 - 4000 mPa·s.

[0108] 2.2 Adhesion force test on digestive tract mucosa

[0109] 2.2.1 Test purpose:

[0110] Evaluate the adhesion performance of the biocompatible preparations #4 - #6 for the repair of digestive tract mucosa damage through the adhesion force test.

[0111] 2.2.2 Test method:

[0112] The same as the test method described in 1.2.2 of Example 1. Take the excised pig stomach or intestine, fix its mucosal layer facing outwards flatly to the robotic arms at both ends of the Figure 1 shown tester, and evenly scatter the above-prepared preparations #4 to #6 (0.3 g) on the mucosa respectively (about 2 cm 2 ), and it can be observed that a colloid is formed on the mucosal surface after about 10 seconds. Set the test instrument parameters: compression speed: 20 mm / min, switching condition: force ≤ -50 gf, pause time: 0.5 min, stretching speed: 20 mm / min, and run this tester to test the adhesion force.

[0113] 2.2.3 Test results

[0114] Table 6 Test results of the adhesion force of #4 - #6 preparations on digestive tract mucosa

[0115] #4 #5 #6 Adhesion Force (N) 1.45 1.41 1.42

[0116] As can be seen from Table 6, the adhesiveness of the above-mentioned preparations #4 to #6 to the digestive tract mucosa is greater than 1.4 N.

[0117] 2.3 Test on the adhesion effect on the digestive tract mucosa and the tolerance to the digestive tract environment

[0118] 2.3.1 Test purpose:

[0119] Through the adhesion performance test, detect the adhesiveness of the above-mentioned preparations #4 to #6 to the digestive tract mucosa, the tolerance to the in vivo environment (artificial gastric juice and artificial intestinal juice), and the effect of promoting the repair of damaged parts of the digestive tract.

[0120] 2.3.2 Test method:

[0121] The same as the method described in 1.3.2 of Example 1. Take the excised pig stomach or intestine, spread the mucosal layer outwards and flat on the Figure 2 shown inclined plate device, and evenly scatter the above-mentioned preparations #4 to #6 (0.3 g) on the mucosa (about 2 cm 2 ), drop a little staining agent for staining for easy observation. About 10 seconds after the preparations #4 to #6 are applied to the mucosa, it can be observed that a colloid is formed on the mucosal surface. Subsequently, flush the colloid formed on the mucosal surface with artificial gastric juice (pH = 1) or artificial intestinal juice (pH = 8) at a speed of 2.5 L / 24 h, and observe the residence time of the colloid formed on the mucosal surface on the mucosal surface under the flushing conditions.

[0122] 2.3.3 Test results:

[0123] The flushing experiment results of preparations #4 - #6 are as Figure 5 shown. It can be seen from the figure that under the continuous flushing of artificial gastric juice or artificial intestinal juice, the colloids formed by the above-mentioned preparations #4 to #6 on the mucosal surface can adhere and stay on the mucosal surface for more than 72 hours.

[0124] Thus, it can be seen that when the preparations #4 to #6 of the present invention are applied to the repair of digestive tract mucosal damage, they can quickly and timely form a protective colloid on the surface of the digestive tract mucosa. Moreover, this colloid has sufficient tolerance to artificial gastric juice and artificial intestinal juice, and will not degrade and lose its adhesive performance due to the acidity or alkalinity in the stomach and intestine. At the same time, it has sufficient adhesive performance to the digestive tract mucosa, with an adhesiveness greater than 1 N and can stay on the mucosal surface for at least 72 hours. Usually, the digestive tract mucosa can be repaired within a period not exceeding 72 hours. Therefore, the ability of the preparations #4 to #6 of the present invention to adhere to the digestive tract mucosa for not less than 72 hours in the digestive tract environment can effectively isolate the ulcer wound surface or mucosal damage wound surface from the acids, alkalis and / or enzymes in the digestive tract, thereby promoting the repair of digestive tract mucosal damage.

[0125] 2.4 Test on the promotion of the repair of damaged parts in the digestive tract by preparations #4 to #6

[0126] 2.4.1 Test purpose:

[0127] Verify the promoting effect of the biocompatible preparations #4 - #6 on the wound healing in the gastric mucosa through animal experiments.

[0128] 2.4.2 Test method:

[0129] The same test method as described in 1.4.2 of Example 1 is adopted in this example. The experiment is carried out in healthy Bama pigs. Endoscopic follow - up is carried out 7 days and 28 days after the successful operation to observe the wound healing situation under the endoscope.

[0130] 2.4.3 Experimental results:

[0131] The animal experiment results of preparations #4 - #6 are as Figure 6 shown. After four weeks of healing after using the preparations #4 - #6 of the present invention, the wound area is significantly reduced compared with the blank control group. Thus, it can be seen that the preparations #4 - #6 of the present invention all have a good promoting effect on the wound healing in the gastric mucosa.

[0132] To further illustrate the beneficial effects of the biocompatible preparation of PEO particles with a specific weight - average molecular weight of the present invention compared with the PEO particle preparations with different molecular weights, the following comparative examples are further provided here.

[0133] In this comparative example, PEO particles with the physical and chemical parameters listed in Table 7 below are used as raw materials, and comparative preparations #7 to #9 are prepared according to the same steps as the preparation steps of Example 1.

[0134] Table 7 Physical and chemical parameters of PEO contained in comparative preparations #1 to #3

[0135] Comparative Formulation No. Physicochemical Parameters of PEO #7 Weight-average molecular weight: 0.6 million; Particle size: 0.5 μm to 2000 μm; #8 Weight-average molecular weight: 0.8 million; Particle size: 0.5 μm to 2000 μm; #9 Weight-average molecular weight: 10 million; Particle size: 0.5 μm to 2000 μm;

[0136] The adhesion force and tolerance of the comparative preparations #7 to #9 to the digestive tract mucosa and the effect of promoting the repair of the digestive tract mucosa are detected according to the same method as in Example 1. Specifically as follows:

[0137] 3.1 Test on the adhesion force to the digestive tract mucosa

[0138] The same tester as shown in Figure 1 is also used for the test. Take the excised pig stomach or intestine, lay its mucosal layer outward and fix it to the robotic arms at both ends of the tester, and evenly scatter the above - prepared comparative preparations #7 to #9 (0.3 g) on the mucosa (about 2 cm 2) After waiting for about 10 seconds, set the parameters of the test instrument: compression speed: 20 mm / min, switching condition: force ≤ -50 gf, pause time: 0.5 min, tensile speed: 20 mm / min, and run the tester to test the adhesion force. The test results are shown in Table 8 below.

[0139] Table 8 Test results of the adhesion force of Comparative Preparations #7 - #9 to the digestive tract mucosa

[0140] #7 #8 #9 Adhesion Force (N) 0.81 0.89 0.93

[0141] As can be seen from Table 8, the adhesion force of the PEO particles in Comparative Preparations #7 to #9 to the digestive tract mucosa is less than 1 N.

[0142] 3.2 Adhesion effect on the digestive tract mucosa and tolerance to the digestive tract environment

[0143] Similarly, use the inclined plate device as Figure 2 shown to simulate the digestive tract environment for the tolerance test. Take the excised pig stomach or intestine, lay the mucosal layer outwards flat on Figure 2 the inclined plate device as 2 ) shown, evenly scatter the above Comparative Preparations #7 to #9 (0.3 g each) on the mucosa (about 2 cm 2 ), drop a little staining agent for staining for easy observation. About 10 seconds after applying Comparative Preparations #7 to #9 on the mucosa, flush the colloid formed on the mucosal surface with artificial gastric juice (pH = 1) or artificial intestinal juice (pH = 8) at a speed of 2.5 L / 24 h, and observe the residence time of the colloid formed on the mucosal surface on the mucosal surface under the flushing condition.

[0144] Among them, artificial gastric juice (pH = 1) and artificial intestinal juice (pH = 8) are prepared according to the configuration standard solution of the Pharmacopoeia of the People's Republic of China (2020 Edition). Take 16.4 mL of dilute hydrochloric acid, add 800 mL of water and 10 g of pepsin, shake well to dissolve it completely, adjust the pH value to 1.3, and dilute with water to a volume of 1000 mL to obtain artificial gastric juice; take 6.8 g of potassium dihydrogen phosphate, add 500 mL of water to dissolve it, adjust the pH value to 6.8 with 0.1 mol / L sodium hydroxide solution, and separately weigh 10 g of trypsin and dissolve it in an appropriate amount of water. Mix the two solutions and dilute with water to a volume of 1000 mL to obtain artificial intestinal juice.

[0145] The flushing experiment results of Comparative Preparations #7 - #9 are as Figure 7 shown. In the inclined plate flushing experiment as Figure 2 shown, under the flushing of artificial gastric juice or artificial intestinal juice, the adhesion residence time of the colloid formed by the above Comparative Preparations #7 to #9 on the mucosal surface is less than 12 hours.

[0146] From the above comparative experiments, it can be seen that in the preparation of the biocompatible preparation for promoting the repair of digestive tract mucosal damage, the present invention uses polyoxyethylene with a weight average molecular weight of 1 million to 7 million Daltons, so that the colloid formed on the damaged surface of the digestive tract mucosa by the prepared preparation has an adhesion force to the digestive tract mucosa of not less than 1 N, and the duration of adhesion to the damaged surface of the digestive tract mucosa is not less than 72 hours. The adhesion ability of the preparation of the present invention to the digestive tract mucosa for not less than 72 hours in the digestive tract environment can effectively isolate the ulcer surface or mucosal damage surface from acids, alkalis and / or enzymes in the digestive tract, thereby promoting the repair of digestive tract mucosal damage.

[0147] The present invention has been specifically described above in combination with specific embodiments. These specific embodiments are merely exemplary and cannot be used to limit the protection scope of the present invention. Those skilled in the art can make various modifications, changes or substitutions to the present invention without departing from the essence and scope of the present invention. Therefore, various equivalent changes made in accordance with the present invention still fall within the scope covered by the present invention.

Claims

1. Use of polyoxyethylene particles in the preparation of a biocompatible preparation for promoting the repair of digestive tract mucosal damage, wherein: The weight-average molecular weight of the polyoxyethylene is 1 million to 7 million Daltons; The average particle size of the polyoxyethylene particles is 0.5 μm to 2000 μm; After the preparation is applied to the damaged wound surface of the digestive tract mucosa, a colloid is formed covering the damaged wound surface of the digestive tract mucosa.

2. The use according to claim 1, wherein the duration of the colloid adhering to the damaged wound surface of the digestive tract mucosa is not less than 72 hours.

3. The use according to claim 1, wherein the adhesion force of the colloid to the digestive tract mucosa is not less than 1 N.

4. The application according to claim 1, wherein, The average particle size of the polyoxyethylene particles is 50 μm - 500 μm.

5. The application according to claim 1, wherein, The viscosity of the polyoxyethylene particles at a concentration of 2.0% wt is 2000 - 4000 mPa·s.

6. The use according to claim 1, wherein the preparation further comprises at least one of biocompatible modified starch and povidone.

7. The application according to claim 6, wherein The preparation comprises biocompatible modified starch, and the mass ratio of polyoxyethylene to biocompatible modified starch is 9:1 to 1:

1.

8. The application according to claim 6, wherein The preparation comprises povidone, and the mass ratio of polyoxyethylene to povidone is 6:1 to 1:

1.

9. The application according to claim 6, wherein, The preparation comprises biocompatible modified starch and povidone, and the mass percentage content of polyoxyethylene particles is 50% to 99%; the mass percentage content of biocompatible modified starch is 0% to 50%; the mass percentage content of povidone is 0% to 50%.

10. The application according to any one of claims 1 to 9, wherein, The preparation is a solid particle preparation and is sprayed onto the damaged wound surface of the digestive tract mucosa through a digestive endoscope.

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