CN110585489A

CN110585489A - Digestive tract submucosal injection swelling agent and application thereof

Info

Publication number: CN110585489A
Application number: CN201910977789.9A
Authority: CN
Inventors: 戴建英
Original assignee: Hangzhou Kin Kin Biotechnology Co Ltd
Current assignee: Hangzhou Kin Kin Biotechnology Co Ltd
Priority date: 2019-10-15
Filing date: 2019-10-15
Publication date: 2019-12-20

Abstract

The invention provides a digestive tract submucosal injection swelling agent, which comprises a colloidal substance and a biological adhesive; wherein the effective components of the colloid substance are colloid substance, water-soluble calcium salt and calcium ion complexing agent, the colloid substance is one or more of pectin, alginate and deacetylated gellan gum, and polylysine is used as biological adhesive; the biological adhesive is polylysine; the pH of the injected swelling agent is not less than 7. The injection swelling agent can be conveniently injected below mucosa, so that a mucosa layer is separated from a muscle layer, and the mucosa is conveniently stripped; and after the mucosa is stripped, the surgical wound is effectively protected, the bleeding is stopped, and the wound healing is promoted.

Description

Digestive tract submucosal injection swelling agent and application thereof

Technical Field

The invention relates to the technical field of biological medicines, in particular to a swelling agent suitable for submucosal injection of a digestive tract and application thereof.

Background

The endoscopic gastric mucosa resection and gastric mucosa stripping are minimally invasive surgeries for resection of early gastric cancer and gastric benign tumors, can achieve the aim of radically treating the early gastric cancer, have the advantages of small wound, small influence on the life quality of patients and the like, and gradually replace part of the traditional surgical operations. Minimally invasive surgery for early cancerous and benign tumor removal of the esophagus and colon also replaces part of traditional surgery. The endoscopic mucosal dissection requires a good endoscopic operation technology, but serious complications such as bleeding and perforation can occur during and after the operation. Therefore, how to avoid or reduce the occurrence of complications in the endoscopic mucosal dissection operation is an important problem to be solved urgently. In order to avoid intraoperative hemorrhage, it is critical to provide a good surgical field in endoscopic mucosal dissection; to avoid perforation, it is also important that the submucosa has sufficient working space; this can be achieved by injecting a suitable, sufficient submucosal injection. During the excision process, the injection liquid under the mucous membrane can keep rising for a certain time to support the mucous membrane with pathological changes to form a protective liquid pad under the mucous membrane, so that the mucous membrane layer is separated from the muscular layer, the muscular layer and the tissues below the muscular layer can be prevented from being damaged, and complications such as perforation and the like can be prevented.

The currently used submucosal injection comprises normal saline, hypertonic saline, glucose, glycerol fructose, sodium hyaluronate with different concentrations, hydroxymethyl cellulose, sodium alginate and the like. Physiological saline is a commonly used submucosal injection, an isotonic solution, and has the disadvantage of being quickly absorbed by surrounding tissues, making it difficult to create a proper mucosal elevation time and maintain the desired elevation height during resection. In general, hypertonic solutions cause higher swelling of the lesion tissue than saline. Glycerol fructose is a hypertonic solution consisting of 10% glycerol and 5% fructose, which has a higher mucosal elevation and a longer duration than physiological saline when used on the human colon, but which, due to its high osmotic pressure, is somewhat damaging to the tissue mucosa. Hyaluronic acid, a viscoelastic biopolymer found in connective tissue, is a matrix component of cell growth and tissue structure formation, has high viscosity and water-retaining ability, is not an antigen of human body and is completely non-toxic to human body. Based on current literature reports, hyaluronic acid provides the longest submucosal water-pad duration. In addition, no perforation rate occurs when using hyaluronic acid as the submucosa material for ESD, however, hyaluronic acid is not easy to obtain and expensive, and it has the disadvantages of stimulating tumor growth factors and tumor cell proliferation at the wound surface.

Disclosure of Invention

The invention aims to solve the problems, provides a compound preparation which adopts multiple materials, has good uplifting effect and good hemostatic effect, can be well combined with a digestive tract mucosa protective adhesive product into a whole, and has the protective effect on wound surfaces.

It is another object of the present invention to provide a use of an injection for treating and protecting a damaged digestive tract mucosa.

In order to achieve the purpose, the invention adopts the following technical scheme:

a digestive tract submucosal injection plumping agent comprises colloidal substance and biological adhesive; wherein the effective components of the colloid substance are colloid substance, water-soluble calcium salt and calcium ion complexing agent, the colloid substance is one or more of pectin, alginate and deacetylated gellan gum, and polylysine is used as biological adhesive; the biological adhesive is polylysine; the pH of the injected swelling agent is not less than 7.

Further, the calcium ion complexing agent is one or more of citric acid, citrate, EDTA or EDTA sodium salt.

Further, the water-soluble calcium is one or more of calcium chloride, calcium lactate and calcium gluconate.

Further, the alginate is one or two of sodium alginate and potassium alginate.

Further, the pectin is one or two of low-methoxy pectin and amidated low-methoxy pectin. The molecules of the low methoxyl pectin and the alginate solution are crosslinked to form gel in the presence of calcium ions.

Further, the mass concentration of the calcium salt in the calcium salt solution is 0.25-5%.

Further, the weight ratio of the gel-forming substance to the polylysine is 3: 1-3.

Further, the weight ratio of the gelling substance to the calcium ion complexing agent is 3-6: 1.

Further, the weight percentage of polylysine in the calcium salt solution is 0.8-3%.

Polylysine generally has a molecular weight of 70,000-150,000, 150,000-300,000 and >300,000, and the higher the molecular weight, the stronger the adhesion force, the better the swelling effect, but is relatively viscous and not easy to inject. The invention can comprehensively select the needed polylysine according to the dissolving agent and the like.

Further, the injection swelling agent can also comprise a dissolving agent and an acid-base regulator, wherein the dissolving agent is used for dissolving the gel and the biological adhesive; the pH regulator is used for regulating the pH value of the swelling agent to be not less than 7. Preferably, the pH of the injected bulking agent is 7 to 10.

In the above injection, the mass concentration of calcium salt in calcium salt solution is 0.25% -5%, and the weight ratio of colloid-forming substance to polylysine in calcium salt solution is 3: 1-3, the weight ratio of the gelling substance to the calcium ion complexing agent in the calcium salt solution is 3-6:1, and the weight percentage of the polylysine in the calcium salt solution is 0.8-3%.

The invention also provides application of the digestive tract submucosa injection swelling agent in gastric mucosa exfoliation, esophageal mucosa exfoliation and intestinal mucosa exfoliation, and application in preparing medicines for digestive tract submucosa injection applied to the gastric mucosa exfoliation, the esophageal mucosa exfoliation and the intestinal mucosa exfoliation.

Further, the submucosal layer and the muscle layer are separated by injecting the submucosal injection-expansion agent into the lower part of the mucosa of the digestive tract.

The invention has the advantages that:

under the condition of a slightly alkaline environment, the calcium salt is dissolved to form a calcium salt solution, and calcium ions are complexed by a calcium ion complexing agent, so that the calcium salt solution cannot be crosslinked with a gel-forming substance. After the mucosa is stripped, after the injection swelling agent disclosed by the invention is contacted with digestive tract liquid such as gastric acid and the like, calcium ions cannot be in a complexing state in an acidic environment and a calcium ion complexing agent, the calcium ions are released and are crosslinked with a gel-forming substance to form a gel film, so that a protective pad is formed at a wound surface, the digestive effect of gastric acid, pepsin and the like on the mucosa is blocked, an operation wound is effectively protected, bleeding is stopped, and the wound healing is promoted.

The injection swelling agent can also be matched with other digestive tract protection glue, so that the wound can be more effectively protected after the operation.

Detailed Description

In the embodiment of the invention, if not specifically stated, the adopted chemicals are all common chemicals which can be purchased in the market. Polylysine with molecular weight of 70,000-150,000 selected in the examples, taking into account solubility and ease of injection. Polylysines of other molecular weights are also possible, as long as dissolution is achieved.

Example 1

1. Potassium alginate 12g

2. Calcium chloride 1 g

3. Sodium citrate 2g

4. Polylysine 10g

Dissolving the above components in 1500ml physiological salt solution (pH8.0 adjusted by 1mol sodium hydroxide), packaging 15ml per bottle, and sterilizing with high temperature steam to obtain injection swelling agent.

Example 2

1. Amidated low methoxyl pectin 15 g

2. Calcium chloride 1 g

3. Sodium citrate 2.5 g

4. Polylysine 12g

Dissolving the above components in 1500ml physiological salt solution (pH8.0 adjusted by 1mol sodium hydroxide), packaging 5ml per bottle, and sterilizing with high temperature steam.

Example 3

1. Sodium alginate 11 g

2. Sodium citrate 4 g

3. Calcium chloride 1.5 g

4. Polylysine 10g

Dissolving the above components in 1500ml physiological salt solution (pH8.0 adjusted by 1mol sodium hydroxide), packaging 15ml per bottle, and sterilizing with high temperature steam.

Example 4

1. Sodium alginate 11 g

2. Sodium citrate 4 g

3. Calcium gluconate 6 g

4. Polylysine 10g

Example 5

1. 10g of potassium alginate

2. Sodium citrate 4 g

3. Calcium lactate 2.8 g

4 Polylysine 10g

Dissolving the above components in 1500ml phosphate solution (pH8.0 adjusted by 1mol sodium hydroxide), packaging 15ml per bottle, and sterilizing with high temperature steam.

Experimental examples evaluation of Effect

The products of the above examples were used directly in the tests.

1 safety study test

The injection-molded swelling agents prepared in examples 1 to 5 were subjected to the following biological tests

1) Stimulation of oral mucosa: the test solution was prepared by adding physiological saline at a ratio of 0.2 g/ml. The experimental liquid of the sample is made into a cotton ball with the diameter not more than 5mm and soaked in the cheek capsule on one side of 3 golden yellow mice. The contact time is minimum 5min each time, once a day, 4 times totally, after the last contact, the cheek sacs are observed visually 24h, the mice are killed painlessly, tissue samples of representative parts of the cheek sacs are taken and put into 4% formaldehyde solution for fixation, and histological evaluation is carried out after tissue sections are made. The stimulation indexes are all 0, and the tested sample has no oral mucosa irritation.

2) Cytotoxicity: the test solution was prepared by adding the medium at a ratio of 0.2 g/ml. Then, the cytotoxicity is measured by MTT method according to the cytotoxicity test specified in GB/T16886.5, and the cytotoxicity is in the range of 0-1 grade.

3) Sensitization test: the test solution was prepared by adding physiological saline at a ratio of 0.2 g/ml. Then, no sensitization was observed in any of the skin sensitization tests as specified in GB/T16886.10.

2 mucosal bulging Effect test

1) Test materials:

(1) 3 in vitro fresh pig stomachs are purchased from supermarkets, and are stored in a refrigerator at 4 ℃ when being used, and the experimental time is not more than 12 hours from the pig slaughtering time.

(2) Laboratory bench, syringe, time-recorder, pin, silk thread, camera, ruler, white cystosepiment. 23G and 25G (Gauge, G for short) injection needles.

2) Test method

Fixing the stomach of a pig on a square foam plate by using a pin, injecting 1ml of a swelling agent and a physiological saline (contrast) solution of 6 groups of liquid of No. 1-5 embodiment under the mucous membrane, respectively, forming a swelling immediately under the mucous membrane of the stomach of the pig, measuring the height (0min) of each group of swelling by using a ruler and a silk thread, taking a picture perpendicular to the plane of the stomach by using a digital camera, and accurately recording the height of each group of mucous membrane swelling; 5. after 15 min, 30 min and 60min, the height of the ridge was measured at the same position and recorded by taking a picture with a digital camera. The porcine gastric submucosa injection experiments were repeated independently 3 times each. The results show that the invention has good mucosa uplift effect. The test results are shown in Table 1.

Table 1: test results

The specific embodiments described herein are merely illustrative of the spirit of the invention. Various modifications or additions may be made to the described embodiments or alternatives may be employed by those skilled in the art without departing from the spirit of the invention.

Claims

1. A digestive tract submucosal injection bulking agent, said injection bulking agent comprising a colloidal material and a bioadhesive; wherein the effective components of the colloid substance are colloid substance, water-soluble calcium salt and calcium ion complexing agent, the colloid substance is one or more of pectin, alginate and deacetylated gellan gum, and polylysine is used as biological adhesive; the biological adhesive is polylysine; the pH of the injected swelling agent is not less than 7.

2. The alimentary tract submucosal injection upcomer ment according to claim 1, wherein the calcium ion complexing agent is one or more of citric acid, citrate, EDTA or sodium EDTA.

3. The digestive tract submucosa injection enhancer of claim 1, wherein the pectin is one or both of low methoxy pectin and amidated low methoxy pectin.

4. The alimentary tract submucosal injection upcomer ment of claim 1, wherein the alginate is one or both of sodium alginate or potassium alginate.

5. The intestinal submucosal injection spreader according to claim 1, wherein the calcium salt is present in the calcium salt solution in a concentration of from 0.25% to 5% by weight.

6. The digestive tract submucosa injection bulking agent of claim 1, wherein the weight ratio of gel-forming substance to polylysine is from 3: 1-3.

7. The alimentary submucous injection spreading agent according to claim 1 wherein the weight ratio of the gel-forming substance to the calcium ion complexing agent is 3-6: 1.

8. The digestive tract submucosa injection bulking agent of claim 1, wherein the polylysine is present in the calcium salt solution in an amount of 0.8 to 3% by weight.

9. Use of a swelling agent for injection submucosa of digestive tract according to any one of claims 1 to 8 in gastric mucosa dissection, esophageal mucosa dissection and intestinal mucosa dissection.

10. The use of the digestive tract submucosal injection enhancer according to claim 9, wherein the digestive tract submucosal injection enhancer is injected below the mucosa to separate the mucosal layer from the muscle layer.