Digestive tract mucosa protective agent powder as well as preparation method and application thereof

Abstract

The invention relates to digestive tract mucosa protective agent powder as well as a preparation method and application thereof, and the digestive tract mucosa protective agent powder contains gel and a cross-linking agent, the gel comprises any one or a combination of at least two of cellulose, modified cellulose, alginate, modified alginate, sodium polyglutamate, modified sodium polyglutamate, starch, modified starch, sodium hyaluronate, modified sodium hyaluronate, pectin or modified pectin, and the cross-linking agent comprises an ionic cross-linking agent or a nonionic cross-linking agent. The powder protective agent provided by the invention is convenient to produce and simple to use, can be adhered to the surface of a mucous membrane wound surface only through simple spraying operation, forms a hydrogel protective layer under the action of gastric juice, intestinal juice or other liquid on the surface of the wound surface, plays a role of a physical barrier, and has a good application prospect. The continuous erosion of digestible liquid or pathogenic microorganisms on the surface of the wound surface to the wound surface is effectively blocked.

Description

Technical Field

[0001] The present invention relates to the field of medical devices, and in particular to a digestive tract mucosal protective agent powder, a preparation method and an application thereof. Background Art

[0002] The gastric mucosa is the innermost layer of the stomach wall. When the stomach is empty or half full, the gastric mucosa forms many wrinkles. There are about 4 to 5 longitudinal wrinkles in the lesser curvature of the stomach, and most of them are transverse or oblique wrinkles in the greater curvature of the stomach. The wrinkles in other parts are irregular in shape. The gastric mucosa is composed of three layers: epithelium, lamina propria, and muscularis mucosa. The various types of gastritis (and ulcers) seen clinically are mainly lesions of the gastric mucosa.

[0003] Gastric mucosal injury is a common disease, and the common treatment option is mainly drug therapy. However, drug therapy usually has a long treatment cycle and is accompanied by certain side effects. In addition, non-drug medical products with related functions are mainly liquid gels or two-component gels, which have problems such as weak adhesion and poor protection, or complex and inconvenient operation, which affects the treatment effect of patients and the work efficiency of doctors. Therefore, for the symptoms of gastric mucosal injury, there is an urgent need for a gastric mucosal protective agent that is safe, has no side effects, is easy to use and has good effects.

[0004] CN101507717A discloses a compound tablet for treating peptic ulcer and a preparation method thereof, wherein the tablet core comprises a main drug and auxiliary materials, wherein the main drug is composed of an acid inhibitor, a gastric mucosal protective agent and one or two antibacterial agents, wherein the dosage range of the acid inhibitor is 10-40 mg, and cyclodextrin inclusion or self-emulsification is adopted; the dosage range of each antibacterial drug is 100-1000 mg; the dosage range of the gastric mucosal protective agent is 100-500 mg. The acid inhibitor is treated by reacting the acid inhibitor with cyclodextrin to prepare an inclusion compound or self-emulsification, and the treated acid inhibitor, antibacterial drug and an appropriate amount of auxiliary materials are compressed into a tablet core, and then the tablet core is coated with an enteric coating or compressed with an enteric coating.

[0005] CN106310205A discloses a method for preparing an oral gastric mucosa gel protective agent. Substances capable of improving the biological activity of the gastric mucosa protective agent are extracted from natural substances such as salvia miltiorrhiza, ligustrazine and codonopsis pilosula, and the substances are mixed with aloe polysaccharide to obtain a composite gel solution for later use. Leeches are cultured with clean water and duck blood respectively and then slaughtered to obtain leech blood. After sterilization, trehalose and mannitol are added to the blood to obtain a blood gel, which is mixed with the reserved composite gel solution and sodium hyaluronate to obtain an oral gastric mucosa gel protective agent.

[0006] In summary, providing a digestive tract mucosal protective agent that is safe, has no side effects, is easy to use, and has good effects has become one of the problems that need to be solved urgently in this field. Summary of the invention

[0007] In order to solve the above technical problems, the present invention provides a digestive tract mucosal protective agent powder and a preparation method and application thereof. By applying the protective agent powder to the mucosa, a hydrogel is formed on the wound surface under the action of gastric juice, intestinal juice or other liquids on the wound surface, thereby playing the role of a physical barrier, effectively reducing the continuous damage to the mucosal surface wound caused by digestive liquids or pathogenic microorganisms, and protecting the mucosal surface wound.

[0008] To achieve this object, the present invention adopts the following technical solutions:

[0009] In a first aspect, the present invention provides a digestive tract mucosal protective agent powder, which contains a gelling agent and a cross-linking agent, wherein the gelling agent includes any one of cellulose, modified cellulose, alginate, modified alginate, sodium polyglutamate, modified sodium polyglutamate, starch, modified starch, sodium hyaluronate, modified sodium hyaluronate, pectin or modified pectin, or a combination of at least two thereof, and the cross-linking agent includes an ionic cross-linking agent or a non-ionic cross-linking agent.

[0010] The present invention provides a digestive tract mucosal protective agent in powder form. By applying the protective agent to the mucosa, the powder protective agent quickly absorbs moisture on the mucosal surface and adheres to the wound surface; then, under the action of gastric juice, intestinal juice or other liquid on the wound surface, a hydrogel is formed on the wound surface, which plays a role of a physical barrier, effectively reduces the continuous damage of the mucosal surface wound caused by digestive liquid or pathogenic microorganisms, and protects the mucosal surface wound.

[0011] The gelling agent used in the present invention is preferably a highly absorbent polymer powder that can quickly absorb wound exudate to form a gel; the cross-linking agent used in the present invention can be selected from ingredients with antibacterial effects that can inhibit bacterial growth and reduce the risk of infection.

[0012] The present invention can use a gelling agent and a cross-linking agent to form a hydrogel. In an acidic environment such as gastric juice, the powder can quickly absorb moisture on the surface of the gastric mucosa to form a physical barrier on the wound surface. The present invention can also use a gelling agent and multiple cross-linking agents to form a hydrogel. The multiple cross-linking agents synergistically accelerate the gel formation speed and increase the adhesion of the hydrogel to the mucosa, thereby expanding the application range of the protective agent to the non-acidic environment of the digestive tract mucosa. The present invention can also use multiple gelling agents and cross-linking agents for compounding. The cross-linking degree of the formed hydrogel is improved, the mechanical strength of the hydrogel is enhanced, and the hydrogel can resist the scouring of gastric juice or intestinal juice, thereby improving the protective effect on the wound surface.

[0013] Preferably, the modified cellulose comprises sodium carboxymethyl cellulose and / or sodium hydroxypropyl cellulose.

[0014] Preferably, the alginate includes any one of potassium alginate, sodium alginate or calcium alginate, or a combination of at least two of them.

[0015] Preferably, the modified alginate comprises oxidized sodium alginate and / or oxidized potassium alginate.

[0016] Preferably, the modified starch comprises carboxymethyl starch.

[0017] Preferably, the pectin comprises apple pectin.

[0018] Preferably, the modified pectin comprises high methoxyl pectin.

[0019] The present invention uses a polymer as a gelling agent. Among the polymers that can be used as gelling agents provided by the present invention, various degrees of polymerization are applicable to the present invention, and those skilled in the art can select according to the required gel strength.

[0020] Preferably, the ionic crosslinking agent includes a cationic crosslinking agent and / or an anionic crosslinking agent.

[0021] Preferably, the cationic crosslinking agent comprises an organic or inorganic calcium source, iron source or zinc source.

[0022] Preferably, the calcium source includes any one of calcium lactate, calcium carbonate, calcium gluconate, calcium chloride, zinc chloride, calcium citrate, calcium ascorbate, calcium phosphate or amino acid chelated calcium, or a combination of at least two thereof.

[0023] Preferably, the iron source comprises any one of iron dextran, ferrous succinate, ferrous fumarate, ferrous gluconate, ferrous lactate, ferrous sulfate or ferric chloride, or a combination of at least two thereof.

[0024] Preferably, the zinc source includes any one of zinc gluconate, zinc lactate or zinc chloride, or a combination of at least two thereof.

[0025] Preferably, the nonionic crosslinking agent includes chitosan substances and / or polylysine substances.

[0026] Preferably, the chitosan-based material includes any one of chitosan, carboxymethyl chitosan or sulfonated chitosan, or a combination of at least two of them.

[0027] Preferably, the polylysine-based substance comprises polylysine and / or polylysine hydrochloride.

[0028] Preferably, the digestive tract mucosal protective agent powder contains sodium alginate and calcium gluconate.

[0029] Preferably, the digestive tract mucosal protective agent powder contains potassium alginate, sodium carboxymethyl cellulose and carboxymethyl chitosan, and the mass ratio of potassium alginate to sodium carboxymethyl cellulose is (2-4):1.

[0030] The specific point values ​​of the above (2-4) can be selected as 2, 2.2, 2.4, 2.6, 2.8, 3, 3.2, 3.4, 3.6, 3.8 or 4, etc.

[0031] Preferably, the digestive tract mucosal protective agent powder contains sodium alginate, calcium carbonate and polylysine hydrochloride, and the mass ratio of calcium carbonate to polylysine hydrochloride is 1:(0.5-2).

[0032] The specific point values ​​of the above (0.5-2) can be selected from 0.5, 0.8, 1, 1.2, 1.5 or 2, etc.

[0033] Preferably, the digestive tract mucosal protective agent powder further contains a coagulant.

[0034] Preferably, the coagulant comprises gluconolactone.

[0035] The present invention can also add gluconolactone as an acidic promoter, which can be dissolved and slowly hydrolyzed into gluconic acid to release hydrogen ions. When calcium carbonate is used as a cross-linking agent in the present invention, the hydrogen ions slowly react with the calcium carbonate to release calcium ions, thereby promoting the formation of hydrogel.

[0036] Preferably, the digestive tract mucosal protective agent powder further contains auxiliary ingredients.

[0037] Preferably, the auxiliary ingredients include any one or a combination of at least two of antibacterial agents, food coloring agents, paste formers, stabilizers, antioxidants, cell growth factors, collagen, procoagulants, recombinant collagen, fibrin, vitamins, amino acids or anticancer drugs.

[0038] Preferably, the digestive tract mucosal protective agent powder contains, by mass, 70 to 100 parts (for example, 70 parts, 75 parts, 80 parts, 85 parts, 90 parts, 95 parts or 100 parts, etc.) of gelling agent and 5 to 30 parts (for example, 5 parts, 7 parts, 10 parts, 15 parts, 20 parts, 25 parts or 30 parts, etc.) of cross-linking agent.

[0039] Preferably, the digestive tract mucosal protective agent powder further contains 5 to 15 parts (for example, 5 parts, 7 parts, 9 parts, 10 parts, 11 parts, 13 parts or 15 parts, etc.) of a coagulant, by weight.

[0040] Preferably, the digestive tract mucosal protective agent powder further contains 0.5 to 2 parts (for example, 0.5 parts, 1 parts, 1.5 parts or 2 parts, etc.) of auxiliary ingredients by weight.

[0041] Preferably, the gelling agent, cross-linking agent, coagulant and auxiliary components are uniform fine powders.

[0042] Preferably, the mesh size of the powder particles of the gelling agent, cross-linking agent, coagulant and auxiliary component is independently ≥80 mesh (for example, it can be 80 mesh, 90 mesh, 100 mesh, 150 mesh, 200 mesh, 300 mesh, 400 mesh or 500 mesh, etc.), preferably ≥150 mesh (for example, it can be 150 mesh, 200 mesh, 300 mesh, 400 mesh or 500 mesh, etc.).

[0043] In a second aspect, the present invention provides a method for preparing a gastrointestinal mucosal protective agent powder as described in the first aspect, the preparation method comprising: mixing the powders of the gelling agent and the cross-linking agent, and vacuum drying at 55-65°C (for example, 55°C, 57°C, 59°C, 60°C, 61°C, 63°C or 65°C, etc.) for 5-7h (for example, 5h, 5.5h, 6h, 6.5h or 7h, etc.) to obtain the gastrointestinal mucosal protective agent powder.

[0044] In a third aspect, the present invention provides a hydrogel adhered to the surface of the digestive tract mucosa, wherein the hydrogel is obtained by allowing the digestive tract mucosa protective agent powder described in the first aspect to act on the mucosa surface liquid.

[0045] Preferably, the method for preparing the hydrogel comprises: applying the digestive tract mucosal protective agent powder described in the first aspect to the mucosal surface, and forming the hydrogel under the action of liquid on the mucosal surface.

[0046] Preferably, the mucosa includes gastric mucosa or digestive tract mucosa.

[0047] Preferably, the mucosal surface fluid comprises gastric juice or intestinal juice.

[0048] Preferably, the dosage of the digestive tract mucosal protective agent powder is 0.1 to 1.5 g / cm 2 (For example, it can be 0.1g / cm 2 , 0.2g / cm 2 , 0.5g / cm 2 , 0.8g / cm 2 , 1g / cm 2 , 1.2g / cm 2 or 1.5g / cm 2 wait).

[0049] In a fourth aspect, the present invention provides a digestive tract mucosal protective agent solution, wherein the digestive tract mucosal protective agent solution contains the digestive tract mucosal protective agent powder described in the first aspect, glycerol and water.

[0050] Preferably, the ratio of the digestive tract mucosal protective agent powder, glycerin and water in the digestive tract mucosal protective agent solution is 1 g: (1-2) mL: (15-20) mL.

[0051] The specific point value of the above (1-2) mL may be selected from 1 mL, 1.2 mL, 1.4 mL, 1.5 mL, 1.6 mL, 1.8 mL or 2 mL, etc.

[0052] The specific point value of the above (15-20) mL can be selected from 15 mL, 16 mL, 16.5 mL, 17 mL, 17.5 mL, 18 mL, 19 mL or 20 mL, etc.

[0053] Preferably, the pH of the digestive tract mucosal protective agent solution is 7 to 8.5 (for example, it may be 7, 7.2, 7.5, 7.8, 8, 8.2 or 8.5, etc.).

[0054] Preferably, the preparation method of the digestive tract mucosal protective agent solution comprises: completely dissolving the gelling agent in water, adjusting the solution pH to 7-8.5, adding a cross-linking agent, stirring evenly, adding glycerol, and further mixing evenly to obtain the digestive tract mucosal protective agent solution.

[0055] In a fifth aspect, the present invention provides use of the digestive tract mucosal protective agent solution as described in the fourth aspect in the preparation of a submucosal swelling agent.

[0056] In endoscopic mucosal dissection (ESD) / endoscopic mucosal resection (EMR) surgery, the conventional ESD / EMR scheme is usually to inject air or glucose solution into the submucosal layer to separate the mucosa and raise the lesion. However, due to the fluidity of the injected material, this scheme can easily cause changes in the morphology of the raised area during the operation, such as lowering the raised area, or the loss of the injected material during the incision process, resulting in a loss of the raised effect, affecting the operation and increasing the risk of the operation.

[0057] In recent years, some medical device products used to assist mucosal separation, such as mucosal separation fluid, usually have low viscosity and are easily lost from the peeling wound or wound surface. They usually have no protective ability or require additional operations or additional fixatives to achieve the purpose of protection. This prolongs the patient's recovery period, affects the quality of life, and also increases the number of surgical steps and prolongs the operation time due to the need for additional operations.

[0058] The digestive tract mucosal protective agent solution provided by the present invention can separate the mucosa at the lesion from the basal layer of the stomach wall during ESD surgery, ensuring the smooth progress of the surgery, reducing the risk of touching the basal layer of the stomach wall during surgery, and reducing the risk of gastric perforation. And there is no need to perform special treatment on the wound surface after surgery. The gel remaining on the wound surface will form a hydrogel protective layer under the action of gastric juice and adhere to the surface of the wound surface, protecting the wound surface as a physical barrier, reducing the continuous erosion damage of gastric juice to the wound surface, creating favorable conditions for the growth and recovery of the gastric mucosa, and helping the recovery of the wound mucosa.

[0059] The digestive tract mucosal protective agent solution provided by the present invention may contain a gelling agent and a cross-linking agent, and is used as a mucosal lifting agent in gastric mucosal stripping. In use, the solution only needs to inject the product into the submucosal layer of the target area to separate the mucosa and lift the mucosa. After surgery, the lifting agent remaining on the surface of the affected area can form a hydrogel in situ under the action of gastric acid, which plays a role in physically blocking gastric juice from eroding the wound surface. In addition, the solution can also be used in other acidic parts of the digestive tract to lift and protect the mucosa, and can only separate the mucosa for non-acidic parts of the digestive tract.

[0060] The digestive tract mucosal protective agent solution provided by the present invention may also contain a gelling agent and multiple cross-linking agents, wherein the multiple cross-linking agents synergistically increase the adhesion of the hydrogel to the mucosa, thereby expanding the application range of the protective agent to the non-acidic environment of the digestive tract mucosa.

[0061] Preferably, the digestive tract mucosal protective agent solution also contains methylene blue and / or edible brilliant blue coloring agent.

[0062] When the digestive tract mucosal protective agent solution provided by the present invention is used in ESD / EMR surgery, methylene blue or other edible brilliant blue colorants need to be added to dye the gastric mucosa so that the operator can better observe the tissue morphology of the gastric mucosa.

[0063] Other specific point values ​​within the above numerical ranges can be selected and will not be described in detail here.

[0064] Compared with the prior art, the present invention has the following beneficial effects:

[0065] The digestive tract mucosal protective agent powder provided by the present invention is composed of a uniform mixture of multiple functional fine powders, is easy to produce, and is simple to use. It can adhere to the surface of the mucosal wound surface through a simple spraying operation. At the same time, the product powder adheres to the wound surface and forms a hydrogel protective layer on the wound surface under the action of the liquid on the mucosal surface, which plays the role of a physical barrier, effectively blocking the continuous erosion of the wound surface by gastric juice, and the product has a certain antibacterial effect and the function of promoting cell growth. Therefore, this product effectively reduces the continuous damage of the mucosal surface wound surface to the digestive liquid or pathogenic microorganisms through the joint action of multiple functions, protects the mucosal surface wound surface, promotes wound healing, shortens the course of the disease, and achieves a safe and side-effect-free therapeutic effect. DETAILED DESCRIPTION

[0066] To further illustrate the technical means and effects of the present invention, the present invention is further described below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention, rather than to limit the present invention.

[0067] If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the field or the product instructions are used. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0068] Example 1

[0069] In this embodiment, a digestive tract mucosal protective agent powder is prepared, which is composed of 80 parts of gelling agent, 15 parts of cross-linking agent and 1 part of vitamin E by weight. The gelling agent is potassium alginate and sodium carboxymethyl cellulose, and the mass ratio is 3:1. The cross-linking agent is carboxymethyl chitosan. After the above powders are mixed evenly, they are vacuum dried at 60° C. for 6 hours. The dried powders are packaged in spring bottles with a powder mesh size of 150. After packaging, they are sterilized for use.

[0070] Example 2

[0071] In this embodiment, a digestive tract mucosal protective agent powder is prepared, which is composed of 100 parts of gelling agent, 5 parts of cross-linking agent and 0.5 parts of vitamin C by mass. The gelling agent is sodium alginate and the cross-linking agent is calcium gluconate. After the above powders are mixed evenly, they are vacuum dried at 55° C. for 7 hours. The dried powders are packaged in spring bottles with a powder mesh size of 80. After packaging, they are sterilized for use.

[0072] Example 3

[0073] In this embodiment, a digestive tract mucosal protective agent powder is prepared, which is composed of 70 parts of gelling agent, 30 parts of cross-linking agent and 2 parts of sucralfate in terms of mass. The gelling agent is sodium alginate, and the cross-linking agent is calcium carbonate and polylysine hydrochloride, with a mass ratio of 1:1. After the above powders are mixed evenly, they are vacuum dried at 65° C. for 5 hours. The dried powders are packaged in spring bottles with a powder mesh size of 200 meshes. After packaging, they are sterilized for use.

[0074] Example 4

[0075] This embodiment prepares a digestive tract mucosal protective agent powder, which is different from Example 1 in that, by weight, it consists of 100 parts of gelling agent, 5 parts of cross-linking agent and 0.5 parts of vitamin E, the gelling agent is potassium alginate and sodium carboxymethyl cellulose, the mass ratio is 2:1, and the cross-linking agent is carboxymethyl chitosan.

[0076] Example 5

[0077] This embodiment prepares a digestive tract mucosal protective agent powder, which is different from Example 1 in that, by weight, it consists of 100 parts of gelling agent, 5 parts of cross-linking agent and 0.5 parts of vitamin E, the gelling agent is potassium alginate and sodium carboxymethyl cellulose, the mass ratio is 4:1, and the cross-linking agent is carboxymethyl chitosan.

[0078] Example 6

[0079] This example prepares a digestive tract mucosal protective agent powder, which is different from Example 1 only in that potassium alginate is not added, and the proportion of potassium alginate is replaced by an equal amount of sodium carboxymethyl cellulose.

[0080] Example 7

[0081] This example prepares a digestive tract mucosal protective agent powder, which is different from Example 1 only in that sodium carboxymethyl cellulose is not added, and the proportion of sodium carboxymethyl cellulose is replaced by an equal amount of potassium alginate.

[0082] Example 8

[0083] This example prepares a digestive tract mucosal protective agent powder, which is different from Example 1 only in that potassium alginate is not added, and the proportion of potassium alginate is replaced by an equal amount of oxidized potassium alginate.

[0084] Example 9

[0085] This example prepares a digestive tract mucosal protective agent powder, which is different from Example 1 only in that sodium carboxymethyl cellulose is not added, and the proportion of sodium carboxymethyl cellulose is replaced by an equal amount of sodium hydroxypropyl cellulose.

[0086] Example 10

[0087] This embodiment prepares a digestive tract mucosal protective agent powder, which is different from Example 3 in that, by mass, it consists of 85 parts of gelling agent, 20 parts of cross-linking agent and 1 part of sucralfate, the gelling agent is sodium alginate, and the cross-linking agent is calcium carbonate and polylysine hydrochloride, with a mass ratio of 1:0.5.

[0088] Embodiment 11

[0089] This embodiment prepares a digestive tract mucosal protective agent powder, which is different from the embodiment 3 in that, by weight, it is composed of 100 parts of gelling agent, 5 parts of cross-linking agent and 0.5 parts of sucralfate, the gelling agent is sodium alginate, and the cross-linking agent is calcium carbonate and poly-lysine hydrochloride, with a mass ratio of 1:2.

[0090] Example 12

[0091] This example prepares a digestive tract mucosal protective agent powder, which is different from Example 3 only in that calcium carbonate is not added, and the calcium carbonate is replaced by an equal amount of poly-lysine hydrochloride.

[0092] Example 13

[0093] This example prepares a digestive tract mucosal protective agent powder, which is different from Example 3 only in that polylysine hydrochloride is not added, and the proportion of polylysine hydrochloride is replaced by an equal amount of calcium carbonate.

[0094] Embodiment 14

[0095] This example prepares a digestive tract mucosal protective agent powder, which is different from Example 3 only in that calcium carbonate is not added, and the proportion of calcium carbonate is replaced by an equal amount of zinc chloride.

[0096] Embodiment 15

[0097] This example prepares a digestive tract mucosal protective agent powder, which is different from Example 3 only in that poly-lysine hydrochloride is not added, and the proportion of poly-lysine hydrochloride is replaced by an equal amount of chitosan.

[0098] Example 16

[0099] This example prepares a digestive tract mucosal protective agent powder, which is different from Example 3 only in that it also contains 10 parts of a coagulant, which is gluconolactone.

[0100] Embodiment 17

[0101] This example prepares a digestive tract mucosal protective agent powder, which is different from Example 16 only in that the coagulant gluconolactone is 5 parts.

[0102] Embodiment 18

[0103] This example prepares a digestive tract mucosal protective agent powder, which is different from Example 16 only in that the coagulant gluconolactone is 15 parts.

[0104] Embodiment 19

[0105] In this embodiment, a digestive tract mucosal protective agent solution is prepared. The digestive tract mucosal protective agent powder prepared in Example 3 is mixed with glycerol and water. The ratio of digestive tract mucosal protective agent powder, glycerol and water is 1g: 1.7mL: 17mL. The pH is adjusted to 7.5 and sterilized after packaging. The specific preparation method is as follows: first, the gelling agent sodium alginate is completely dissolved in water, and the pH of the solution is adjusted to 7.5 with NaOH, and then the cross-linking agent calcium carbonate and polylysine hydrochloride are added. After stirring evenly, glycerol is added and further mixed evenly.

[0106] Embodiment 20

[0107] This example prepares a digestive tract mucosa protective agent solution, which is different from Example 19 only in that the digestive tract mucosa protective agent powder of Example 12 is used to prepare the digestive tract mucosa protective agent solution.

[0108] Embodiment 21

[0109] This example prepares a digestive tract mucosa protective agent solution, which is different from Example 19 only in that the digestive tract mucosa protective agent powder of Example 13 is used to prepare the digestive tract mucosa protective agent solution.

[0110] Test Example 1

[0111] This test example tests the gelling performance of the digestive tract mucosal protective agent powder prepared in Examples 1-18, including the following steps:

[0112] Weigh a certain amount of the prepared finished powder and put it into a small filter tea bag. Place the filter tea bag flat on the table and use a resin stick to flatten the powder in the tea bag so that it forms a powder cake with a thickness of about 2mm and a height of about 1.5cm at the bottom of the filter tea bag. Clamp the top of the tea bag with a clip and hang the tea bag in a beaker with a cotton thread. Then add artificial gastric juice prepared according to the pharmacopoeia to the beaker so that it soaks the upper edge of the powder cake to simulate the situation when the product powder is soaked in gastric juice. After soaking for 2 minutes, observe whether the powder of each experimental group has gelled. Thereafter, observe every 30 seconds. The experimental group will no longer be observed after gelling. When observing at the preset time node, if it has not yet gelled, it will not be recorded. If it has gelled, it will be recorded as the gelling time is less than this time. For example, if a certain experimental group has not gelled at 2 minutes, but has gelled when observed at 2.5 minutes, it will be recorded as the gelling time <2.5 minutes. The gelling time is shown in Table 1.

[0113] Table 1

[0114]

[0115]

[0116] It can be seen from Table 1 that:

[0117] (1) Comparing Example 1 with Examples 6-9, it can be seen that the gelling agents potassium alginate and sodium carboxymethyl cellulose have a synergistic effect of accelerating the gelation rate. The lack or replacement of any one of them will increase the gelation time.

[0118] (2) Comparing Example 3 with Examples 12-15, it can be seen that using sodium alginate as a gelling agent and using calcium carbonate and poly-lysine hydrochloride as two cross-linking agents can synergistically accelerate the gelation rate. The lack or replacement of any one of the two cross-linking agents will increase the gelation time.

[0119] (3) Comparing Example 3 with Examples 16-18, it can be seen that the coagulant gluconolactone can accelerate the gelation rate.

[0120] Test Example 2

[0121] This test example tests the protective effect of the digestive tract mucosal protective agent powder prepared in Examples 1-18, including the following steps:

[0122] Method 1: Cut the gastric wall tissue sample into a circle with a diameter of 1.5 cm, place the tissue sample in a culture dish filled with powder, turn it over and cover it with powder, so that the tissue sample is completely wrapped with the protective agent powder, and record it as the experimental group. Take another sample as the control group without wrapping any components, record it as the injury group. Take another sample without wrapping any sample, record it as the PBS group. Put the experimental group and injury group samples into culture dishes containing the same sufficient amount of simulated gastric fluid, soak the PBS group samples in the same amount of PBS, cover them with plastic wrap, and place them in a constant temperature incubator for 6 hours, 24 hours, 48 ​​hours, and 72 hours. Observe the sample status at the specified time point to judge the protective effect of the product.

[0123] The observation results showed that all samples could form hydrogels on the surface of pig stomach samples. The samples in the experimental group could still maintain the basic morphology of the tissue for 72 hours because they were wrapped in the protective layer of hydrogel. The samples in the PBS group swelled and turned white on the surface after immersion, but they could still maintain a certain tissue morphology at 72 hours. Compared with the gastric wall tissues in the experimental group and the PBS group, the gastric wall tissue samples in the injury group were observed to turn white and swell in 6 hours under the corrosion of artificial gastric juice; the solution became turbid at 24 hours, and the edge tissue of some gastric wall samples fell off; the gastric wall tissue was observed to be deeply corrupted at 48 hours, and could not maintain its complete shape even with slight force, and the sample liquid was turbid; the gastric wall tissue samples lost their basic tissue morphology and broke and corrupted into mud at 72 hours.

[0124] Method 2: Cut the gastric wall tissue sample into 2cm×4cm strips. Spray half of the cut tissue sample with powder evenly on the mucosal surface to completely cover it. Then soak the pig stomach sample in a culture dish filled with sufficient simulated gastric fluid for 3 hours, 6 hours, and 24 hours. Observe the covered and uncovered areas of the pig stomach sample product at the corresponding time points, compare the color and tissue state, and judge the product protection effect.

[0125] The observation results showed that among all the immersed samples, the tissue area not covered by the protective powder turned white after more than 3 hours, the tissue swelled after more than 6 hours, and the solution became slightly turbid after more than 24 hours. After peeling off the protective powder gel, the covered area could still maintain the original red surface of the tissue after 6 hours, and the tissue surface turned slightly white and swollen after 24 hours, but it was lower than the 24-hour immersion effect of the PBS group in method 1.

[0126] Based on the above two test methods, it is shown that the digestive tract mucosal protective agent powder provided by the present invention has a good gastric mucosal protective effect.

[0127] Test Example 3

[0128] This test example tests the residual effect on the gastric mucosal surface of the digestive tract mucosal protective agent powder prepared in Examples 1 and 4-9, including the following steps:

[0129] The gastric wall tissue sample was cut into a sheet of about 3cm×3cm, and the upper mucosal layer of about 1cm×1cm in the middle of the tissue sample sheet was peeled off, and then the prepared powder was evenly sprayed on the wound surface where the upper mucosal layer was peeled off, and the powder that was not adhered and fixed on the surface was gently shaken off. The prepared gastric wall tissue sample was fixed on a 45° inclined surface, and the outlet pipe of the peristaltic pump was set at a position about 10cm above, and the flow rate of the peristaltic pump was adjusted to 20mL / min. Artificial gastric juice was applied to the surface of the pig stomach wall sample, and the sample was continuously flushed for 0.5 hours, and the protective agent on the surface of the pig stomach sample was observed. The powder sprayed on the tested pig stomach wall sample can gradually form a hydrogel patch under the flushing of artificial gastric juice, and the powder will hardly fall off from the wound surface. In addition, the hydrogel sheet formed after one hour of flushing is still stably adhered to the original position, and a certain pulling force is obviously required when manually trying to peel it off. In addition, this test example also measured the mass loss rate of the hydrogel after one hour of flushing, and the mass loss rate = test results are shown in Table 2.

[0130] Table 2

[0131] Group Mass loss rate (%) Example 1 3.6 Example 4 4.3 Example 5 4.1 Example 6 9.3 Example 7 5.0 Example 8 5.7 Example 9 7.0

[0132] As can be seen from Table 2, by comparing Example 1 with Examples 4-9, it can be seen that potassium alginate and sodium carboxymethyl cellulose can synergistically improve the cross-linking degree of the hydrogel, enhance the mechanical strength of the hydrogel, resist the scouring of gastric juice, and improve the protective effect on the wound surface. Replacing or removing any one component will reduce the protective effect on the wound surface.

[0133] Test Example 4

[0134] This test example tests the submucosal injection ridge effect of the digestive tract mucosal protective agent solution prepared in Examples 19-21, including the following steps:

[0135] Fresh pig stomach was selected and cut into slices with a side length of about 3 cm. Then the prepared mucosal separation liquid was loaded into a 1 mL syringe (needle specification: 0.45×16). The pig stomach wall tissue sample was fixed on the horizontal base surface, and the syringe needle was inserted into the mucosal layer at a 45° angle with the pig stomach wall tissue sample (so that the needle penetrated the mucosal layer but not the basal layer), and the separation liquid was slowly pushed in to separate the upper mucosa from the basal layer, and the height and shape of the mucosal bulge were observed. Then the upper mucosa was peeled off with dissecting scissors, and the outflow of the separation liquid during the peeling process was observed, as well as the stability of the separation liquid on the wound surface after the mucosa was peeled off. The peeled wound surface was soaked in a sufficient amount of artificial gastric juice for 30 minutes, and the changes of the residual separation liquid under the action of artificial gastric juice were observed.

[0136] The experimental results show that all the tested samples can make the mucosal layer locally bulge, with low diffusion effect; all the tested samples can be injected smoothly without blocking the syringe needle; when peeling the mucosa, the amount of separation liquid injected into the submucosal layer is small, which has little effect on the morphology of the raised mucosal tissue; after peeling the raised mucosal layer, there is separation liquid remaining on the wound surface, and it remains on the wound surface for a period of time; under the action of gastric juice, the separation liquid can form a hydrogel film, adhere to the wound surface, form a physical barrier, and protect the wound from gastric juice and pepsin erosion for a certain period of time. Among them, Example 19 has the best bulge effect, the highest mucosal bulge height, less outflow when shearing the mucosa, and the formed hydrogel has the highest mechanical strength and stability.

[0137] In summary, the present invention provides a powder dosage form of a digestive tract mucosal protective agent, which is composed of a uniform mixture of multiple functional fine powders and can adhere to the surface of the digestive tract mucosal wound through a simple spraying operation. At the same time, the product powder adheres to the wound surface to form a hydrogel protective layer on the wound surface under the action of gastric juice, intestinal juice or other liquids on the wound surface, which acts as a physical barrier, effectively blocking the continuous erosion of the wound surface by digestive liquids or pathogenic microorganisms on the wound surface, protecting the digestive tract mucosal surface wound, promoting wound healing, shortening the course of the disease, and achieving a safe and side-effect-free treatment effect.

[0138] The applicant declares that the above is only a specific implementation mode of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed by the present invention shall fall within the protection scope and disclosure scope of the present invention.

Claims

1. A digestive tract mucosal protective agent powder, characterized in that: The digestive tract mucosal protective agent powder contains a gelling agent and a cross-linking agent, wherein the gelling agent includes any one of cellulose, modified cellulose, alginate, modified alginate, sodium polyglutamate, modified sodium polyglutamate, starch, modified starch, sodium hyaluronate, modified sodium hyaluronate, pectin or modified pectin, or a combination of at least two thereof, and the cross-linking agent includes an ionic cross-linking agent or a non-ionic cross-linking agent.

2. The digestive tract mucosa protective agent powder according to claim 1, characterized in that: The modified cellulose includes sodium carboxymethyl cellulose and / or sodium hydroxypropyl cellulose; Preferably, the alginate comprises any one of potassium alginate, sodium alginate or calcium alginate, or a combination of at least two thereof; Preferably, the modified alginate comprises oxidized sodium alginate and / or oxidized potassium alginate; Preferably, the modified starch comprises carboxymethyl starch; Preferably, the pectin comprises apple pectin; Preferably, the modified pectin comprises high methoxyl pectin.

3. The digestive tract mucosa protective agent powder according to claim 1 or 2, characterized in that: The ionic crosslinking agent includes a cationic crosslinking agent and / or an anionic crosslinking agent; Preferably, the cationic crosslinking agent comprises an organic or inorganic calcium source, iron source or zinc source; Preferably, the calcium source includes any one of calcium lactate, calcium carbonate, calcium gluconate, calcium chloride, zinc chloride, calcium citrate, calcium ascorbate, calcium phosphate or amino acid chelated calcium, or a combination of at least two thereof; Preferably, the iron source comprises any one or a combination of at least two of ferrous dextran, ferrous succinate, ferrous fumarate, ferrous gluconate, ferrous lactate, ferrous sulfate or ferric chloride; Preferably, the zinc source comprises any one of zinc gluconate, zinc lactate or zinc chloride, or a combination of at least two thereof; Preferably, the nonionic crosslinking agent includes chitosan and / or polylysine substances; Preferably, the chitosan-based material includes any one of chitosan, carboxymethyl chitosan or sulfonated chitosan, or a combination of at least two thereof; Preferably, the polylysine-based substance comprises polylysine and / or polylysine hydrochloride.

4. The digestive tract mucosa protective agent powder according to any one of claims 1 to 3, characterized in that: The digestive tract mucosal protective agent powder also contains a coagulant; Preferably, the coagulant comprises gluconolactone; Preferably, the digestive tract mucosal protective agent powder further contains auxiliary ingredients; Preferably, the auxiliary ingredients include any one or a combination of at least two of antibacterial agents, food coloring agents, paste formers, stabilizers, antioxidants, cell growth factors, collagen, procoagulants, recombinant collagen, fibrin, vitamins, amino acids or anticancer drugs.

5. The digestive tract mucosa protective agent powder according to any one of claims 1 to 4, characterized in that: The digestive tract mucosal protective agent powder contains 70 to 100 parts of gelling agent and 5 to 30 parts of cross-linking agent by weight; Preferably, the digestive tract mucosal protective agent powder further contains 5 to 15 parts of a coagulant by weight; Preferably, the digestive tract mucosal protective agent powder further contains 0.5 to 2 parts of auxiliary ingredients by weight; Preferably, the gelling agent, cross-linking agent, coagulant and auxiliary components are uniform fine powders; Preferably, the mesh size of the powder particles of the gelling agent, cross-linking agent, coagulant and auxiliary component is independently ≥80 mesh, preferably ≥150 mesh.

6. A method for preparing the digestive tract mucosal protective agent powder according to any one of claims 1 to 5, characterized in that: The preparation method comprises: mixing the powders of the gelling agent and the cross-linking agent, and vacuum drying at 20 to 65° C. for 4 to 24 hours to obtain the digestive tract mucosal protective agent powder.

7. A hydrogel adherent to the surface of the digestive tract mucosa, characterized in that: The hydrogel is obtained by reacting the digestive tract mucosal protective agent powder according to any one of claims 1 to 5 with a mucosal surface liquid.

8. The hydrogel according to claim 7, characterized in that The method for preparing the hydrogel comprises: applying the digestive tract mucosal protective agent powder according to any one of claims 1 to 6 to the mucosal surface, and forming the hydrogel under the action of the liquid on the mucosal surface; Preferably, the mucosa includes gastric mucosa or digestive tract mucosa; Preferably, the mucosal surface fluid comprises gastric juice or intestinal juice; Preferably, the dosage of the digestive tract mucosal protective agent powder is 0.1 to 1.5 g / cm 2 .

9. A digestive tract mucosal protective agent solution, characterized in that: The digestive tract mucosa protective agent solution contains the digestive tract mucosa protective agent powder according to any one of claims 1 to 5, glycerin and water; Preferably, the ratio of the digestive tract mucosal protective agent powder, glycerol and water in the digestive tract mucosal protective agent solution is 1 g: (1-2) mL: (15-20) mL; Preferably, the pH of the digestive tract mucosal protective agent solution is 7 to 8.5; Preferably, the preparation method of the digestive tract mucosal protective agent solution comprises: completely dissolving the gelling agent in water, adjusting the solution pH to 7-8.5, adding a cross-linking agent, stirring evenly, adding glycerol, and further mixing evenly to obtain the digestive tract mucosal protective agent solution.

10. Use of the digestive tract mucosal protective agent solution according to claim 9 in the preparation of a submucosal swelling agent; Preferably, the digestive tract mucosal protective agent solution also contains methylene blue and / or edible brilliant blue coloring agent.

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