Capsule preparation for relieving and preventing damage of alcohol to digestive tract mucosa and application of capsule preparation

Abstract

The invention provides a capsule preparation for relieving and preventing damage of alcohol to digestive tract mucosa and application of the capsule preparation, the capsule preparation comprises a capsule shell and polyoxyethylene particles encapsulated in the capsule shell, and the capsule shell is gastric soluble and / or enteric soluble; the weight-average molecular weight of the polyoxyethylene ranges from 400,000 Daltons to 800,000 Daltons; the average particle size of the polyoxyethylene particles is 0.5 [mu] m to 2000 [mu] m; according to the capsule, after the capsule preparation is orally administrated by a mammal, the polyoxyethylene particles packaged by the capsule shell are released in the alimentary canal, and an adhesive film covering the mucosa of the alimentary canal is formed in the alimentary canal; the lasting time of the adhesive film adhered to the digestive tract mucosa corresponds to the residence time of alcohol in the digestive tract, and the adhesive film which is formed by the capsule preparation and covers the digestive tract mucosa can form a physical adhesive film on the surface of the digestive tract, so that stimulation and damage of the alcohol to the gastrointestinal tract mucosa are effectively prevented and relieved.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to a capsule preparation for alleviating and preventing alcohol damage to digestive tract mucosa and application thereof. Background Art

[0002] Drinking is part of Chinese food culture, but the harm caused by drinking is becoming increasingly serious. The absorption pathway of alcohol in the human body mainly starts from the gastrointestinal tract. Most of the ethanol enters the blood after being absorbed by the gastrointestinal tract and enters various organs of the human body through the blood circulation. There are three main types of hangover products on the market: chemical drugs, Chinese herbal preparations, and health products. Chemical drugs and Chinese herbal medicines have a good effect on hangover, but taking these two drugs will put a greater burden on the patient's kidneys. The effect of health products on hangover is relatively poor, and most of the so-called hangover drugs on the market are added with hormones, diuretics, and even illegal drugs such as stimulants. After taking them, you can feel excited and sober in a short time, which is actually an illusion.

[0003] Alcohol has direct toxic and side effects on human tissues. It can not only cause gastric mucosal damage, but also damage blood vessels under the gastric mucosa. Moreover, frequent drinking can cause high concentrations of ethanol to remain in the stomach, affecting the gastric and duodenal mucosa, causing ischemia, hypoxia and necrosis, and causing gastric mucosal erosion or ulcer formation. Drinking a large amount of alcohol at one time may cause acute stress damage to the gastric mucosa, thereby inducing complications such as erosive gastritis and hematemesis. Therefore, alcohol as a gastric mucosal damage factor is also a pathogenic factor that cannot be ignored. How to prevent and reduce alcohol damage to the gastric mucosa and research on the protective mechanism of the gastric mucosa are increasingly attracting widespread attention. Currently, commonly used gastrointestinal mucosal protective agents include prostate derivatives, bismuth agents, teprenone, sucralfate, aluminum magnesium carbonate and terpene derivatives, but the above drugs all have toxic side effects and cannot be taken for a long time. There are currently no reports on non-drug products that reduce and prevent alcohol damage to the gastrointestinal mucosa. Summary of the invention

[0004] On the one hand, one of the purposes of the present invention is to provide a capsule preparation for reducing and preventing alcohol damage to the digestive tract mucosa, comprising a capsule shell and polyoxyethylene particles encapsulated therein, wherein:

[0005] The capsule shell is gastric soluble and / or enteric soluble;

[0006] The weight average molecular weight of polyoxyethylene is 400,000 Daltons to 800,000 Daltons;

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

[0008] The capsule is configured such that, after a mammal orally administers the capsule preparation, the polyethylene oxide particles encapsulated by the capsule shell are released into the digestive tract and form a viscous film covering the digestive tract mucosa in the digestive tract, and the duration for which the viscous film adheres to the digestive tract mucosa corresponds to the residence time of alcohol in the digestive tract.

[0009] In some embodiments of the present invention, the viscous film adheres to the digestive tract mucosa for 4 - 6 hours.

[0010] In some embodiments of the present invention, the capsule shell is gastric - soluble, and the polyethylene oxide particles encapsulated by the capsule shell form a viscous film covering the gastric mucosa.

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

[0012] In some embodiments of the present invention, the capsule preparation further comprises at least one of polysaccharide and povidone.

[0013] In some embodiments of the present invention, the capsule preparation further comprises a polysaccharide, and the mass ratio of polyethylene oxide to the polysaccharide is 9:1 to 1:1.

[0014] In some embodiments of the present invention, the capsule preparation further comprises povidone, and the mass ratio of polyethylene oxide to povidone is 9:1 to 1:1.

[0015] In some embodiments of the present invention, the capsule preparation further comprises a polysaccharide and povidone, and the mass ratio of polyethylene oxide, polysaccharide and povidone is 8:1:1.

[0016] In some embodiments of the present invention, the viscosity of the polyethylene oxide particles under the condition of a concentration of 5% wt is 3000 - 6000 mPa·s.

[0017] In some embodiments of the present invention, the polysaccharide is selected from sodium carboxymethyl starch granules and hydroxypropyl cellulose granules, and its average particle size is 0.5 μm to 2000 μm.

[0018] In some embodiments of the present invention, the capsule shell is made of gelatin.

[0019] On the other hand, another object of the present invention is to provide a pharmaceutical use of the capsule preparation according to the first aspect of the present invention, that is, to provide an application of the described biocompatible capsule preparation in the preparation of a drug for reducing and preventing alcohol - induced damage to the digestive tract mucosa.

[0020] The present invention has the following advantages over the prior art: By selecting polyoxyethylene particles with a weight average molecular weight of 400,000 to 800,000 Daltons and formulating them into gastric-soluble and / or enteric-soluble capsule preparations, after orally administering the capsule preparations, the capsule shell dissolves in the gastrointestinal tract, thereby releasing the encapsulated polyoxyethylene particles to form a viscous film covering the gastrointestinal mucosa. The duration of adhesion of this viscous film to the digestive tract mucosa is designed to correspond to the residence time of alcohol in the digestive tract, that is, the duration is not less than the alcohol residence time. Since the viscous film formed by the capsule preparation covering the gastrointestinal mucosa can form a physical adhesion film on the surface of the digestive tract, it can effectively prevent and reduce the irritation and damage of alcohol to the gastrointestinal mucosa.

[0021] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments. Description of the Drawings

[0022] Figure 1 It is a schematic diagram of the adhesion force test for evaluating the adhesion performance in the embodiment of the present invention;

[0023] Figure 2 It is a schematic diagram of the tolerance test simulating the digestive tract environment in the embodiment of the present invention;

[0024] Figure 3 It is the erosion test result of the viscous film formed by the contents of capsule preparations #1-#3 in Example 1 of the present invention;

[0025] Figure 4 It is the gastric ulcer situation of the rats in the capsule preparation #1-#3 administration group, model group and sham operation group in Example 1 of the present invention after intragastric administration of absolute ethanol;

[0026] Figure 5 It is the HE staining map of the stomach of the rats in the capsule preparation #2 administration group, model group and sham operation group in Example 1 of the present invention after intragastric administration of absolute ethanol;

[0027] Figure 6 It is the erosion test result of the viscous film formed by the contents of capsule preparations #4 and #5 in Example 2 of the present invention;

[0028] Figure 7 It is the gastric ulcer situation of the rats in the capsule preparation #4 and #5 administration group, model group and sham operation group in Example 2 of the present invention after intragastric administration of absolute ethanol;

[0029] Figure 8 It is the erosion test result of the viscous film formed by the contents of the control capsule preparation #6 of the present invention. Detailed Description of the Embodiments

[0030] The technical solution of the present invention will be further elaborated 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.

[0031] Unless otherwise specifically stated, the numerical values and numerical ranges recited 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 in appropriate cases, the known technologies and methods should be regarded as a part of this specification. In all examples recited herein, any specific value should be construed as merely exemplary and not constituting any limitation. Therefore, other examples other than the exemplary embodiments may have different values.

[0032] Example 1

[0033] This embodiment provides three capsule preparations #1 to #3 involving poly(ethylene oxide) (PEO) particles with different weight average molecular weights, and these capsule preparations contain PEO particles having the physicochemical properties listed in Table 1 below.

[0034] Table 1 Physicochemical parameters of PEO contained in exemplary capsule preparations #1 to #3

[0035]

[0036] The capsule shells of the capsule preparations in this embodiment are gastric-soluble and / or enteric-soluble, made of gelatin, and can be obtained from commercial channels. They can dissolve within 1 hour after being administered into the digestive tract, thereby releasing the PEO particles loaded in the capsule shells. The capsule preparations of this embodiment are prepared by the following steps:

[0037] (a) Place PEO particles with different weight average molecular weights as raw materials into a granulator.

[0038] (b) Add an appropriate amount of purified water to the raw materials placed in the granulator in step (a).

[0039] (c) Granulate and screen at 40°C to 60°C, and fill the PEO particles with a particle size of 50 μm to 500 μm into the capsule shells.

[0040] To evaluate the technical effects of the capsule preparations #1 to #3 in this embodiment, the viscosity of the PEO particles used in each capsule preparation, the adhesion force of the viscous film formed on the digestive tract mucosa to the digestive tract mucosa, the adhesion effect on the digestive tract mucosa, and the tolerance to the digestive tract environment were tested respectively as follows.

[0041] 1.1 Viscosity test

[0042] In order to enable the viscous film formed by the capsule preparation on the digestive tract mucosa to have sufficient adhesion force, the PEO particles of the present invention need to have a sufficient viscosity value. The viscosity tests of the PEO particles in the capsule preparations #1 to #3 in this embodiment are as follows.

[0043] 1.1.1 Test purpose:

[0044] Test the viscosity of the raw material PEO particles of the capsule preparations #1 to #3 under the condition of 5% wt concentration.

[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 30 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 570 mL of water without carbon dioxide, continue to stir at high speed for 1 minute (splashing of the solution should be avoided), continue to stir slowly (60 r / min) for 3 hours until there is no gel in the solution (prevent the volatilization 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 according to law using a suitable rotational viscometer and rotor (Method 3 of General Rule 0633 in the Pharmacopoeia of the People's Republic of China).

[0047] 1.1.3 Test results:

[0048] The viscosity values of the raw material PEO particles used in the #1 - #3 capsule preparations under the condition of 5% wt concentration are shown in Table 2 below. It can be seen from Table 2 that the viscosity values of the raw material PEO particles used in the #1 - #3 preparations are all in the range of 3000 - 6000 mPa·s.

[0049] Table 2 Viscosity values of the raw material PEO particles used in the #1 - #3 capsule preparations

[0050] #1 #2 #3 Viscosity (mPa·s) 3500 4200 5500

[0051] 1.2 Adhesion force test on the digestive tract mucosa

[0052] There should be a certain adhesion force between the viscous film covering the digestive tract mucosa formed by the capsule preparation in the digestive tract and the digestive tract mucosa. For example, the adhesion force measured according to the method of this embodiment is not less than 0.7 N. The adhesion forces of the capsule preparations #1 to #3 of this embodiment are tested below.

[0053] 1.2.1 Test purpose:

[0054] Evaluate the adhesion performance of capsule preparations #1 to #3 through the adhesion force test.

[0055] 1.2.2 Test method:

[0056] Use the tester as Figure 1 shown. Take the excised pig stomach or intestine, lay its mucosal layer outward and fix it to the robotic arms at both ends of the adhesion force tester. Scatter the content particles (0.3 g) of the above-prepared capsule preparations #1 to #3 evenly on the mucosa (about 2 cm 2 ), and then after about 10 seconds, it can be observed that a colloid (i.e., a viscous film) is formed 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 test the adhesion force.

[0057] 1.2.3 Test results:

[0058] The adhesion forces of the viscous films formed by capsule preparations #1 - #3 on the digestive tract mucosa are shown in Table 3 below.

[0059] Table 3 Test results of the adhesion forces of the viscous films formed by capsule preparations #1 to #3 on the digestive tract mucosa

[0060] #1 #2 #3 Adhesion force (N) 0.80 0.81 0.89

[0061] 1.3 Adhesion effect on the digestive tract mucosa and tolerance test to the digestive tract environment

[0062] To effectively prevent and reduce the irritation and damage of alcohol to the gastrointestinal mucosa, the viscous film covering the digestive tract mucosa formed by the capsule preparation of the present invention should last for a sufficient time, for example, not less than the retention time of alcohol in the digestive tract. The following is a simulation test on the duration of the viscous film formed by the exemplary capsule preparations #1 to #3 in the digestive tract environment.

[0063] 1.3.1 Test purpose:

[0064] Detect the adhesion force of the viscous film formed by the above capsule preparations #1 to #3, the tolerance to the in vivo environment (artificial gastric juice and artificial intestinal juice), and the protective effect on the gastrointestinal mucosa through the adhesion performance test. 1.3.2 Test method:

[0065] The tolerance was tested by simulating the digestive tract environment using the inclined plate device as Figure 2 shown. Ex vivo porcine stomach or intestine was taken and the mucosal layer was laid out facing outwards onto the Figure 2 inclined plate device as shown. 0.3 g of the content particles of each of the above capsule preparations #1 to #3 were evenly scattered on the mucosa (about 2 cm 2 ), and a little staining agent was dropped for staining to facilitate observation. After about 10 seconds, a viscous film was observed to form on the mucosal surface. Subsequently, the viscous film formed on the mucosal surface was flushed with artificial gastric juice (pH = 1) or artificial intestinal juice (pH = 8) at a rate of 2.5 L / 24 h, and the residence time of the viscous film formed on the mucosal surface under the flushing conditions was observed.

[0066] The artificial gastric juice (pH = 1) and artificial intestinal juice (pH = 8) used in the experiment were prepared according to the standard solution in the Pharmacopoeia of the People's Republic of China (2020 Edition). 16.4 mL of dilute hydrochloric acid was taken, 800 mL of water and 10 g of pepsin were added, shaken well to dissolve completely, the pH value was adjusted to 1.3, and diluted with water to a volume of 1000 mL to obtain artificial gastric juice; 6.8 g of potassium dihydrogen phosphate was taken, dissolved in 500 mL of water, the pH value was adjusted to 6.8 with 0.1 mol / L sodium hydroxide solution, and another 10 g of trypsin was weighed and dissolved in an appropriate amount of water. After mixing the two solutions, the volume was fixed to 1000 mL with water to obtain artificial intestinal juice.

[0067] 1.3.3 Test results:

[0068] The flushing test results of capsule preparations #1 - #3 are as Figure 3 shown. According to Figure 3 , after oral administration of the capsule preparation of the present invention to the digestive tract, the PEO particles in the capsule shell are released, and they can quickly and timely form a viscous protective film on the surface of the digestive tract mucosa. This viscous protective film has sufficient tolerance to artificial gastric juice and artificial intestinal juice, and stays on the mucosal surface for up to 4 - 6 hours, which is sufficient to exert a protective effect on the digestive tract mucosa.

[0069] 1.4 Protective effect of the capsule on ulcers

[0070] 1.4.1 Test purpose:

[0071] To explore the preventive and protective effects of the gastric - soluble capsule on gastric ulcers in rats

[0072] 1.4.2 Test method:

[0073] Fifty rats were randomly divided into 5 groups, namely the sham - operation group, the model group, and 3 dosing groups (administered capsule preparations #1, #2, #3 respectively), with 10 rats in each group. The rats weighed 300 - 350 g and were 10 weeks old.

[0074] (1) Administration group: The capsules were administered by oral ingestion.

[0075] Use straight forceps to hold the capsule preparation and place it at the throat of the rats in the administration group, and then use a gavage needle to flush water to take the capsule preparation. One rat was orally administered 1 capsule preparation (drug loading 10 mg) at a time, and 4 capsule preparations were continuously administered. Modeling was carried out 2 hours after administration.

[0076] (2) Methods for gastric ulcer modeling and specimen collection

[0077] The rats in the model group and the administration group were gavaged with absolute ethanol (15 mL / kg), and the rats in the sham operation group were gavaged with an equal amount of normal saline. After 2 hours, the rats were dissected, the stomachs were taken out, washed with normal saline, dried with filter paper, and the mucus, blood clots, etc. on the surface of the gastric mucosa were removed. After washing the residual contents, they were fixed and spread out on a white bottom plate for photographing and recording, and the damage of the gastric mucosa was observed macroscopically.

[0078] (3) Evaluation of gastric ulcer

[0079] Figure 4 The gastric ulcer conditions of the rats in each group visible to the naked eye are shown. Scoring was carried out according to the degree of ulcer, divided into four grades: none (0 points), mild (1 point), moderate (2 points), and severe (3 points). The gastric ulcer photos of the rats in each group are as Figure 4 shown, and the ulcer scoring results are shown in Table 4:

[0080] Table 4 Gastric ulcer scores of rats in each group

[0081] #1 #2 #3 Model group Sham operation group Ulcer score 1.9 1.8 1.4 2.7 0

[0082] From Figure 4 and Table 4, it can be seen that the gastric mucosa of the sham operation group was intact and smooth, without congestion, edema, ulceration, etc.; compared with the sham operation group, the model group showed mucosal damage, bleeding, and ulceration of the gastric tissue, indicating successful modeling; compared with the model group, the mucosal damage, ulceration, and bleeding in each administration group were significantly improved.

[0083] (4) Pathological analysis

[0084] HE staining was used to observe the pathological conditions of the rats in each group. Among them, the HE staining pictures of the sham operation group, the model group, and the administration group (taking the group administered with capsule preparation #2 as an example) are respectively as Figure 5 . From Figure 5 it can be seen that the gastric mucosa of the sham operation group was intact and smooth, without abnormal pathological morphology such as congestion, edema, and ulceration, and the glandular arrangement was neat, without shedding and defects; compared with the sham operation group, the model group showed damage to the tissue mucosal layer and very serious interstitial bleeding, indicating successful modeling. Compared with the model group, the capsule preparation could significantly improve the mucosal tissue damage, with less shedding of the epithelial layer and alleviation of the interstitial bleeding situation.

[0085] Example 2

[0086] Compared with Example 1, the capsule preparations #4 and #5 provided in this example not only contain PEO particles but also polysaccharides.

[0087] The capsule preparation #4 encapsulates PEO and sodium carboxymethyl starch (CMS) particles with a mass ratio of 9:1. Among them, the weight-average molecular weight of PEO is 600,000, and the particle size is 0.5 μm to 2000 μm; the particle size of CMS particles is 0.5 μm to 2000 μm.

[0088] The capsule #5 encapsulates PEO particles and hydroxypropyl cellulose (HPC) particles with a mass ratio of 9:1. Among them, the weight-average molecular weight of PEO particles is 600,000, and the particle size is 0.5 μm to 2000 μm; the particle size of HPC particles is 0.5 μm to 2000 μm.

[0089] The above capsule preparations #4 and #5 are prepared by the following steps:

[0090] (a) Place PEO and CMS or HPC as raw materials in a granulator according to the above mass ratio.

[0091] (b) Add an appropriate amount of purified water to the raw materials placed in the granulator in step (a).

[0092] (c) Granulate and screen at 40 °C to 60 °C, and fill the particles with a particle size of 50 μm to 500 μm into gastric-soluble capsule shells to obtain capsule preparations #4 and #5.

[0093] 2.1 Viscosity test

[0094] 2.1.1 Measurement purpose:

[0095] Test the viscosity of the particles encapsulated in capsule preparations #4 and #5 under the condition of 5% wt concentration.

[0096] 2.1.2 Test method:

[0097] Test according to the method specified in "Polyethylene Oxide" in the Pharmacopoeia of the People's Republic of China (2020 Edition, Volume IV): Weigh precisely 30 g of the granules in the capsule shell and place them in an 800-ml beaker. Add 125 ml of anhydrous isopropanol, stir at high speed (400 r / min) to disperse evenly, add 570 ml of carbon dioxide-free water, continue to stir at high speed for 1 minute (splashing of the solution should be avoided), then continue to stir slowly (60 r / min) for 3 hours until there is no gelatinous substance in the solution (prevent the evaporation 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 law (Method 3 of General Rule 0633 in the Pharmacopoeia of the People's Republic of China).

[0098] 2.1.3 Test Results:

[0099] Table 5 Viscosity Values of the Granules Used in Capsule Preparations #4 and #5

[0100] #4 #5 Viscosity (mPa·s) 4080 4900

[0101] As can be seen from Table 5, the viscosities of the granules encapsulated in capsule preparations #4 and #5 at a concentration of 5% wt are also within the range of 3000 - 6000 mPa·s.

[0102] 2.2 Adhesion Force Test on Digestive Tract Mucosa

[0103] 2.2.1 Test Purpose:

[0104] Evaluate the adhesion performance of capsule preparations #4 and #5 through the adhesion force test.

[0105] 2.2.2 Test Method:

[0106] The test method is the same as that in Example 1, and the test is carried out using the tester as shown in Figure 1 . Take the excised pig stomach or intestine, lay its mucosal layer outwards and fix it to the robotic arms at both ends of the adhesion force tester. Spread the prepared granules (0.3 g) of capsule preparations #4 and #5 evenly on the mucosa (about 2 cm 2 ), and then after about 10 seconds, it can be observed that a colloid (i.e., a viscous film) is formed 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 test the adhesion force.

[0107] 2.2.3 Test Results:

[0108] The adhesion forces of the viscous films formed by capsule preparations #4 and #5 on the digestive tract mucosa are shown in Table 6 below.

[0109] Table 6 Test Results of the Adhesion of Capsule Preparations #4 and #5 to the Digestive Tract Mucosa

[0110] #4 #5 Adhesion force (N) 0.89 0.88

[0111] 2.3 Test of the Adhesion Effect on the Digestive Tract Mucosa and Tolerance to the Digestive Tract Environment

[0112] 2.3.1 Test Purpose:

[0113] Detect the adhesion force of the viscous films formed by the above-mentioned capsule preparations #4 and #5 through the adhesion performance test, the tolerance to the in vivo environment (artificial gastric juice and artificial intestinal juice), and the protective effect on the gastrointestinal mucosa. 2.3.2 Test Method:

[0114] Similar to Example 1, use the inclined plate device as shown in Figure 2 to simulate the digestive tract environment for the tolerance test. Take the excised pig stomach or intestine, spread the mucosal layer outwards on the Figure 2 inclined plate device, and evenly scatter the content particles (0.3 g) of the above-mentioned capsule preparations #4 and #5 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 a colloid, i.e., a viscous film, 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 rate of 2.5 L / 24 h, and observe the residence time of the colloid formed on the mucosal surface under the flushing condition on the mucosal surface.

[0115] 2.3.3 Test Results:

[0116] The flushing experiment results of the content particles of capsule preparations #4 and #5 are as shown in Figure 6 . According to Figure 6 , after the capsule preparation of the present invention is orally administered to the stomach, the PEO particles in the capsule shell are released, and they can quickly and timely form a viscous protective film on the surface of the digestive tract mucosa. This viscous protective film has sufficient tolerance to artificial gastric juice and artificial intestinal juice and stays on the mucosal surface for up to 4 - 6 hours, which is sufficient to exert a protective effect on the digestive tract mucosa.

[0117] 2.4 Test of the Protective Effect of the Capsule on Ulcers

[0118] 2.4.1 Test Purpose:

[0119] Explore the preventive and protective effects of gastric-soluble capsules on rat gastric ulcers

[0120] 2.4.2 Test Method:

[0121] The rats were randomly divided into 4 groups, namely the sham operation group, the model group, and 2 dosing groups. The rats were fasted for 24 h in advance, and then the rats in the dosing groups were orally administered capsule preparations #4 and #5. After 2 h, the rats in the model group and the dosing groups were intragastrically administered absolute ethanol (15 mL / kg), and the rats in the sham operation group were intragastrically administered an equal amount of normal saline. 2 h after intragastric administration of absolute ethanol, the rats were anesthetized and dissected, and the gastric ulcers of the rats in each group were observed macroscopically for gastric ulcer scoring. 2.4.3 Test results:

[0122] The gastric ulcer conditions of each group were as Figure 7 shown. Figure 7 The gastric ulcers of the rats in each group visible to the naked eye were shown. According to the degree of ulcer, the scores were divided into four grades: none (0 points), mild (1 point), moderate (2 points), and severe (3 points). The gastric ulcer scoring results of the rats in each group are shown in Table 7.

[0123] Table 7 Gastric ulcer scores of rats in each group

[0124] #4 #5 Model group Sham operation group Ulcer score 1.8 1.7 2.7 0

[0125] From Figure 7 and Table 7, it can be seen that the gastric mucosa of the sham operation group was intact and smooth, without congestion, edema, ulceration, etc.; compared with the sham operation group, the model group showed mucosal damage, bleeding, and ulceration of the gastric tissue, indicating successful modeling; compared with the model group, the mucosal damage, ulceration, and bleeding of the gastric mucosa in each dosing group were significantly improved.

[0126] In order to further illustrate the effect of the capsule preparation containing PEO particles with specific physicochemical properties of the present invention relative to the capsule preparation containing PEO particles with other physicochemical properties, the following comparative examples are further provided herein.

[0127] In this comparative example, PEO particles with the physicochemical parameters listed in Table 8 below were used as raw materials, and a control capsule preparation #6 was prepared according to the same preparation steps as in Example 1.

[0128] Table 8 Physicochemical parameters of the control capsule preparation and the PEO contained therein

[0129] Capsule number Physicochemical parameters of PEO #6 Weight-average molecular weight: 1 million; Particle size: 0.5 μm to 2000 μm;

[0130] According to the same method as in Example 1, the adhesion effect and tolerance of the viscous film formed by the control capsule preparation #6 on the digestive tract mucosa and the effect of promoting the repair of the digestive tract mucosa were detected, as follows: 3.1 Test of the adhesion force of the viscous film on the digestive tract mucosa:

[0131] The adhesion force of the viscous film formed by the control capsule preparation #6 on the digestive tract membrane was measured to be 1.35 N according to the same test method as in Example 1.

[0132] 3.2 Adhesion effect on digestive tract mucosa and tolerance to digestive tract environment:

[0133] According to the same method as in Example 1, in the inclined plate flushing experiment, under the flushing of artificial gastric juice or artificial intestinal juice, observe the colloidal adhesion residence time formed by the control capsule preparation #6 on the surface of the digestive tract mucosa. The colloidal states before flushing and after 6 hours of flushing are as Figure 8 shown. It can be seen from the figure that the adhesion residence time of the formed colloid on the digestive tract mucosa is greater than 6 hours, while the residence time of alcohol in the digestive tract is usually less than 6 hours. Therefore, in the capsule preparation of the present invention, by controlling the weight average molecular weight of the PEO encapsulated in the capsule within a suitable range (i.e., 400,000 - 800,000), the viscosity of PEO makes the adhesion force and duration on the digestive tract mucosa within a suitable range, thereby effectively reducing and preventing the damage of alcohol to the digestive tract mucosa.

[0134] 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. A capsule preparation for reducing and preventing alcohol-induced damage to the digestive tract mucosa, comprising a capsule shell and polyoxyethylene particles encapsulated therein, wherein: The capsule shell is gastric-soluble and / or enteric-soluble; The weight-average molecular weight of polyoxyethylene is from 400,000 to 800,000 Daltons; The average particle size of the polyoxyethylene particles is from 0.5 μm to 2000 μm; The capsule is configured such that after oral administration of the capsule preparation to a mammal, the polyoxyethylene particles encapsulated by the capsule shell are released into the digestive tract and form a viscous film covering the digestive tract mucosa in the digestive tract, and the duration of adhesion of the viscous film to the digestive tract mucosa corresponds to the residence time of alcohol in the digestive tract.

2. The capsule preparation according to claim 1, wherein The viscous film adheres to the digestive tract mucosa for 4 - 6 hours.

3. The capsule preparation according to claim 2, wherein, The capsule shell is gastric-soluble, and the polyoxyethylene particles encapsulated by the capsule shell form a viscous film covering the gastric mucosa.

4. The capsule preparation according to claim 1, wherein, The capsule preparation further comprises at least one of polysaccharide and povidone.

5. The capsule preparation according to claim 4, wherein, The capsule preparation comprises a polysaccharide, and the mass ratio of polyoxyethylene to the polysaccharide is from 9:1 to 1:

1.

6. The capsule preparation according to claim 4, wherein The capsule preparation comprises povidone, and the mass ratio of polyoxyethylene to povidone is from 9:1 to 1:

1.

7. The capsule preparation according to claim 1, wherein, The viscosity of the polyoxyethylene particles at a concentration of 5% wt is 3000 - 6000 mPa·s.

8. The capsule preparation according to any one of claims 4 to 6, wherein, The polysaccharide is selected from: sodium carboxymethyl starch granules and hydroxypropyl cellulose granules, and their average particle size is from 0.5 μm to 2000 μm.

9. The capsule preparation according to claim 1, wherein, The capsule shell is made of gelatin.

10. Use of the capsule preparation according to any one of claims 1 to 9 in the preparation of a drug for reducing alcohol-induced damage to the digestive tract mucosa.

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