CN112870455B

CN112870455B - Gel preparation containing hyaluronic acid, preparation method and application thereof in endoscopy

Info

Publication number: CN112870455B
Application number: CN202110160887.0A
Authority: CN
Inventors: 耿凤; 邵萌; 王静; 郭学平
Original assignee: Bloomage Biotech Co Ltd
Current assignee: Bloomage Biotech Co Ltd
Priority date: 2021-02-05
Filing date: 2021-02-05
Publication date: 2022-05-24
Anticipated expiration: 2041-02-05
Also published as: CN112870455A

Abstract

The invention provides a gel preparation which is characterized by comprising hyaluronic acid or a salt thereof, ectoin, polyethylene glycol, polyvinyl alcohol, an anesthetic and an antifoaming agent. The gel preparation contains hyaluronic acid and ectoin, can improve the lubrication degree of an endoscope and ensure that the endoscope smoothly enters the body when being applied to endoscopy, and the hyaluronic acid and the ectoin are compounded and applied to match with polyethylene glycol and polyvinyl alcohol, so that the hydrophilic performance of the gel is improved, the lens is effectively prevented from being infected by grease, the cleanness of the lens in the endoscopy process is ensured, the inspection visual field is clear, and the diagnosis accuracy of diseases is greatly improved.

Description

Gel preparation containing hyaluronic acid, preparation method and application thereof in endoscopy

Technical Field

The invention belongs to the field of biomedicine, and particularly relates to a gel preparation containing hyaluronic acid, a preparation method and application thereof in endoscopy.

Background

The endoscope is an optical instrument, and is sent into the body from the outside of the body through a natural cavity of the human body to examine internal diseases, so that the pathological changes of the internal cavity of the viscera can be directly observed, the position and the range of the pathological changes can be determined, and photographing, biopsy or brushing can be carried out, thereby greatly improving the diagnosis accuracy of the diseases and being capable of carrying out certain treatments. Endoscopes are now in wide-ranging use, such as gastroscopes, enteroscopes, bronchoscopes, esophagoscopes, sigmoidoscopes, cystoscopes, laryngoscopes, nasoscopes, colposcopes, and the like.

Since the endoscope needs to be delivered into the body from the outside of the body through the natural orifice of the human body, the endoscope needs to be inserted smoothly, less in stimulation, free of pain, convenient to operate and the like when passing through the orifice of the human body, so that a lubricant needs to be taken orally or smeared on the surface of the endoscope before endoscopy. At present, most of lubricants are glycerin, silicone oil, liquid paraffin and the like, but the lubricants are fat-soluble components, are heavy in greasy feeling and easy to cause discomfort of patients, and are not easy to clean the endoscope body, and the fat-soluble lubricants are easy to contaminate the grease in the body, so that the lens of the endoscope is blurred, and certain influence is caused on the safety, continuity and efficiency of the operation. And the endoscopy can stimulate or damage the cavity or the tissue more or less, and the endoscope gel with the repairing function can effectively solve the problem.

Patent CN105342985B discloses a gel preparation and application thereof, comprising cellulose derivatives, glycerin and more than one selected from polyethylene glycol and propylene glycol, wherein the cellulose derivatives are used as gel substrates, which can increase the viscosity of the preparation, easily adhere to endoscopic instruments, and slowly slide to the surface of mucosa, so that an endoscope can easily enter the cavity channel. However, the patent still does not solve the problem that the endoscope lens is easy to blur in the body.

Disclosure of Invention

Aiming at the problems in the prior art, the invention provides a gel preparation and a preparation method and application thereof. Specifically, the present invention relates to the following aspects:

1. a gel formulation comprising hyaluronic acid or a salt thereof, ectoin, polyethylene glycol, polyvinyl alcohol, an anesthetic, and an antifoaming agent.

2. The gel preparation according to item 1, wherein the hyaluronic acid or the salt thereof is 0.1% to 9%, preferably 1% to 5%, the ectoin is 0.1% to 5%, preferably 1% to 4%, the polyethylene glycol is 1% to 20%, preferably 10% to 20%, the polyvinyl alcohol is 1% to 15%, preferably 5% to 15%, the anesthetic is 0.5% to 2.0%, and the antifoaming agent is 1% to 5% by mass of the gel preparation.

3. The gel formulation according to item 1, wherein the hyaluronic acid or a salt thereof is composed of an oligomeric hyaluronic acid or a salt thereof having a molecular weight of 1k-50kDa, preferably 1k-10kDa, and a cross-linked hyaluronic acid or a salt thereof cross-linked from hyaluronic acid or a salt thereof having a molecular weight of 500k-2000kDa, preferably 500k-1000kDa, with a degree of cross-linking of 3-5%.

4. The gel formulation according to item 3, wherein the mass ratio of the oligomeric hyaluronic acid or salt thereof to the crosslinked hyaluronic acid or salt thereof is 1:1-10, preferably 1: 2-4.

5. The gel formulation according to claim 1, wherein the polyethylene glycol is one or more selected from the group consisting of polyethylene glycol-200, polyethylene glycol-400, polyethylene glycol-1000, polyethylene glycol-1500, polyethylene glycol-2000, and polyethylene glycol-3000.

6. The gel preparation according to item 1, wherein the anesthetic is a local anesthetic selected from one or more of lidocaine, procaine, benzocaine, bupivacaine, and dyclonine.

7. The gel formulation according to item 1, wherein the antifoaming agent is a nonionic surfactant selected from one or two of polyoxyethylene polyoxypropylene pentaerythritol ether and polyoxyethylene alkylolamide.

8. The gel formulation of claim 1, further comprising a preservative and a pH adjuster.

9. A method of preparing a gel formulation, comprising the steps of:

adding hyaluronic acid or its salt, polyethylene glycol, and polyvinyl alcohol into water for swelling to obtain a first solution;

dissolving ectoin, anesthetic, defoamer and preservative in water to obtain a second solution;

adding the second solution into the first solution, adjusting pH to 5.5-7.0, and performing wet heat sterilization to obtain gel preparation.

10. Use of the gel formulation of any one of items 1 to 8, the gel formulation prepared by the method of item 9, in endoscopy.

The invention has the following beneficial effects: the gel preparation contains hyaluronic acid and ectoine, can improve the lubrication degree of an endoscope when being applied to endoscopy, ensures that the endoscope smoothly enters the body, is compounded and applied by the hyaluronic acid and the ectoine, and improves the hydrophilic performance of the gel by matching polyethylene glycol and polyvinyl alcohol, effectively avoids grease from contaminating a lens, ensures the cleanness of the lens in the endoscopy process, ensures clear inspection visual field, and greatly improves the diagnosis accuracy of diseases. Meanwhile, the cross-linked hyaluronic acid in the gel can be quickly formed into a film on a cavity, so that the cavity is protected from being damaged by an endoscope, the oligomeric hyaluronic acid, the ectoine, the anesthetic and the like are uniformly dispersed in a net structure formed by the cross-linked hyaluronic acid gel, and can be uniformly adhered to the cavity during and after examination, the anesthesia speed is high and uniform, the oligomeric hyaluronic acid and the ectoine are cooperatively compounded, the quick anti-inflammation and repair effects on epidermal cells of the cavity can be realized, and the uncomfortable symptoms such as mucositis edema and the like caused by endoscopy are reduced.

Detailed Description

The present invention is further illustrated by the following examples, which are intended to be purely exemplary of the invention and are not intended to be limiting.

Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can be used in experimental or practical applications, the materials and methods are described below. In case of conflict, the present specification, including definitions, will control, and the materials, methods, and examples are illustrative only and not intended to be limiting. The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.

The invention provides a gel preparation which comprises hyaluronic acid or a salt thereof, ectoin, polyethylene glycol, polyvinyl alcohol, an anesthetic and an antifoaming agent.

Among them, Hyaluronic Acid (HA) is a high molecular polysaccharide naturally present in human interstitial tissue, and HAs been widely used in the fields of cosmetics, health products, and medicines because it HAs excellent moisture retention, lubricity, and viscoelasticity, and HAs various biological activities. The hyaluronic acid HAs various different molecular weights, HA with each molecular weight HAs different effects and performances, the high molecular weight HA HAs excellent film forming and water locking effects, the low molecular hydrolyzed HA can permeate the skin to deeply replenish water for the skin, and the low molecular hyaluronic acid also HAs certain effects of inhibiting inflammatory reaction, resisting tumors, promoting bone and angiogenesis and the like.

Ectoin, also known as tetrahydropyrimidine, is called 2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid, and tetrahydropyrimidine is not only an important osmotic pressure compensation solute, but also has a good protection effect on cells and biological macromolecules (biological membranes, proteins, enzymes and nucleic acids) under adverse environmental stimuli such as high temperature, high salt, freezing, drying, radiation and the like. The ring structure of the tetrahydropyrimidine molecule has stronger electronegativity, is easy to form hydrogen bonds with water molecules, enhances the association capability of the water molecules, ensures that the water molecules are directionally arranged around the ring structure, changes the spatial arrangement of the water molecules and has long-acting moisturizing effect.

In a specific embodiment, the hyaluronic acid or a salt thereof is 0.1% to 9% by mass of the gel formulation, for example, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, preferably 1% to 5%; the ectoin is 0.1% to 5%, for example, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, preferably 1% to 4%; the polyethylene glycol is 1% to 20%, for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, preferably 10% to 20%; the polyvinyl alcohol is 1% to 15%, for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, preferably 5% to 15%; the anesthetic is 0.5% to 2.0%, for example, 0.5%, 1%, 1.5%, 2%; the defoaming agent is 1% to 5%, and may be, for example, 1%, 2%, 3%, 4%, 5%.

In a specific embodiment, the hyaluronic acid or a salt thereof is composed of an oligomeric hyaluronic acid or a salt thereof and a cross-linked hyaluronic acid or a salt thereof, wherein the molecular weight of the oligomeric hyaluronic acid or a salt thereof is 1k-50kDa, such as 1kDa, 2kDa, 5kDa, 10kDa, 20kDa, 30kDa, 40kDa, 50kDa, preferably 1k-10 kDa.

The cross-linked hyaluronic acid or the salt thereof is a derivative formed by chemically modifying hyaluronic acid, and the molecular weight of the cross-linked hyaluronic acid or the salt thereof can be improved, so that the physicochemical properties such as viscoelasticity, lubricity, water solubility and the like can be changed. The cross-linked hyaluronic acid or a salt thereof is cross-linked with hyaluronic acid or a salt thereof having a molecular weight of 500k to 2000kDa, and for example, it may be cross-linked with hyaluronic acid or a salt thereof having a molecular weight of 500kDa, 600kDa, 700kDa, 800kDa, 900kDa, 1000kDa, 1100kDa, 1200kDa, 1300kDa, 1400kDa, 1500kDa, 1600kDa, 1700kDa, 1800kDa, 1900kDa, 2000kDa, preferably 500k to 1000 kDa.

The crosslinking degree refers to the degree of modification of hyaluronic acid molecules by a crosslinking agent, and is the ratio of oligosaccharide chromatographic peak area to total chromatographic peak area detected by liquid chromatography after the crosslinked hyaluronic acid or salt thereof is subjected to enzymolysis by hyaluronidase. The physicochemical properties of the crosslinked hyaluronic acid are closely related to the degree of crosslinking. The crosslinked hyaluronic acid or a salt thereof may have a degree of crosslinking of 3 to 5%, for example, 3%, 4%, or 5%.

Further, the crosslinked hyaluronic acid or a salt thereof may be obtained by:

(1) dissolving hyaluronic acid or its salt in sodium hydroxide aqueous solution premixed with cross-linking agent, dissolving uniformly, and performing cross-linking reaction at 37-42 deg.C for 12-36 hr;

(2) after the reaction is finished, adjusting the pH value of the reaction solution to be neutral;

(3) adding organic solvent or its water solution under stirring to precipitate the reaction product in microsphere form, collecting the precipitate, washing the precipitate, and drying to obtain crosslinked hyaluronic acid powder.

Further, the mass ratio of the oligomeric hyaluronic acid or salt thereof to the crosslinked hyaluronic acid or salt thereof is 1:1-10, and may be, for example, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, and preferably 1: 2-4.

Further, the oligomeric hyaluronate is a soluble salt of hyaluronic acid, and may be, for example, sodium hyaluronate, potassium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, or a combination thereof.

Further, the crosslinked hyaluronate salt is a soluble salt of crosslinked hyaluronic acid, and may be, for example, crosslinked sodium hyaluronate, crosslinked potassium hyaluronate, crosslinked calcium hyaluronate, crosslinked magnesium hyaluronate, crosslinked zinc hyaluronate, or a combination thereof.

In a specific embodiment, the polyethylene glycol is selected from one or more of polyethylene glycol-200, polyethylene glycol-400, polyethylene glycol-1000, polyethylene glycol-1500, polyethylene glycol-2000, and polyethylene glycol-3000.

In a specific embodiment, the anesthetic is a local anesthetic selected from one or more of lidocaine, procaine, benzocaine, bupivacaine, and dyclonine.

Lidocaine (Lidocaine), a local anesthetic and antiarrhythmic drug, is a derivative of cocaine, but has no components of cocaine that produce hallucinations and addiction. The hydrochloride of the lidocaine is white crystalline powder, is easy to dissolve in water, has toxicity equivalent to that of procaine, has stronger and lasting local anesthesia effect and good surface penetration, and can be injected and used for surface anesthesia. Lidocaine is a very good local anaesthetic, generally acting after one to three minutes of administration, with the effect remaining for one to three hours.

Procaine is a local anesthetic. The hydrochloride is commonly used in clinic and is also called Novicine. White crystals or crystalline powder, easily soluble in water. Has lower toxicity than cocaine. The injection can prolong the action time by adding a small amount of adrenalin. Can be used for infiltration anesthesia, lumbar anesthesia, and closed therapy. Except for the reaction of the central nervous system and the cardiovascular system caused by excessive administration, the skin allergy test should be performed before the administration of the medicine, if the anaphylactic reaction is happened. The metabolite of the compound, aminobenzoic acid (PABA), can reduce the antibacterial effect of sulfonamides.

Ethyl p-aminobenzoate, also known as benzocaine, of formula C₉H₁₁NO₂Is an organic compound. It is colorless rhombohedral crystal, and odorless and tasteless. Is easily soluble in alcohol, ether and chloroform, can be dissolved in oleum Armeniacae amarum, oleum Olivarum and dilute acid, and is hardly soluble in water. It is clinically used for relieving pain and itching of wound surfaces, ulcer surfaces, burns, skin chapping and hemorrhoids.

Bupivacaine, chemical name is 1-n-butyl-2- (2, 6-dimethylaminoformyl) piperidine, and hydrochloride thereof is commonly used, is white crystalline powder, and has no odor and bitter taste. It is easily soluble in ethanol, soluble in water, slightly soluble in chloroform, and hardly soluble in ether. The pH value of the water solution is 4.5-6.0. Clinically, it belongs to the category of narcotics.

Dyclonine, an English name of dyclonine, has the effects of blocking the conduction of various nerve impulses or stimuli, inhibiting touch and pain, and relieving pain, itching and bacteria on skin.

In a specific embodiment, the defoaming agent is a nonionic surfactant, preferably selected from one or two of polyoxyethylene polyoxypropylene pentaerythritol ether and polyoxyethylene alkylolamide.

Further, the gel formulation further comprises a preservative and a pH adjuster.

In a specific embodiment, the preservative is selected from one or two of sodium benzoate and sodium ethylparaben, and the pH regulator is selected from one or two of sodium hydroxide, sodium bicarbonate and hydrochloric acid.

The invention also provides a gel preparation which is composed of hyaluronic acid or a salt thereof, ectoin, polyethylene glycol, polyvinyl alcohol, an anesthetic, an antifoaming agent, a preservative, a pH regulator and water.

The mass contents of hyaluronic acid or a salt thereof, ectoin, polyethylene glycol, polyvinyl alcohol, an anesthetic, an antifoaming agent, a preservative, and a pH adjuster are as described above.

The invention also provides a preparation method of the gel preparation, which is characterized by comprising the following steps of:

In a specific embodiment, the hyaluronic acid or a salt thereof is composed of an oligomeric hyaluronic acid or a salt thereof and a cross-linked hyaluronic acid or a salt thereof, wherein the molecular weight of the oligomeric hyaluronic acid or a salt thereof is 1k-50kDa, such as 1kDa, 2kDa, 5kDa, 10kDa, 20kDa, 30kDa, 40kDa, 50kDa, preferably 1k-10 kDa. The cross-linked hyaluronic acid or a salt thereof is cross-linked with hyaluronic acid or a salt thereof having a molecular weight of 500k to 2000kDa, and may be cross-linked with hyaluronic acid or a salt thereof having a molecular weight of 500kDa, 600kDa, 700kDa, 800kDa, 900kDa, 1000kDa, 1100kDa, 1200kDa, 1300kDa, 1400kDa, 1500kDa, 1600kDa, 1700kDa, 1800kDa, 1900kDa, 2000kDa, preferably 500k to 1000kDa, and has a cross-linking degree of 3 to 5%. In the preparation process of the first solution, oligomeric hyaluronic acid or salt thereof and cross-linked hyaluronic acid or salt thereof are added into water together with polyethylene glycol and polyvinyl alcohol for swelling.

Wherein the wet heat sterilization is performed at 121 ℃ for 20-30 min.

The invention also provides the application of the gel preparation or the gel preparation prepared by the method in endoscopy. Specifically, the composition can be used as a lubricant, an antifoaming agent, an anesthetic, and a visibility-improving agent in endoscopy.

The gel preparation has good gel adhesion, the vertical adhesion of the gel is over 11.23g, and the gel can be well adhered to an endoscope; the gel preparation has good lubrication degree, and can ensure that an endoscope smoothly enters a body; the gel prepared by the embodiment of the invention is not easy to be stained with adhesive grease, and can ensure that the lens of the endoscope coated with the gel of the embodiment is clean after entering the body; the gel samples of the embodiments 1 to 6 of the invention show stronger human epidermal cell migration capacity, and the cell migration rate reaches more than 60 percent, which indicates that the samples have good wound repair function.

The sodium hyaluronate and the ectoin used in the application are purchased from Huaxi biotechnology limited company, and other materials, reagents and the like can be obtained from commercial sources if no special description is provided.

Example 1

(1) Preparation of crosslinked sodium hyaluronate

Dissolving 10g of sodium hyaluronate (Mw is 1000kDa) in 100mL of 1 wt% sodium hydroxide solution, adding a crosslinking agent BDDE, wherein the dosage of the crosslinking agent is 4 wt% of the mass of the hyaluronic acid, uniformly mixing, and crosslinking in a water bath at 40 ℃ for 24 hours; after the reaction is finished, adjusting the pH value of the reaction solution to be neutral; adding organic solvent or its water solution under stirring to precipitate the reaction product in the form of microsphere, collecting the precipitate, washing and drying the precipitate to obtain cross-linked sodium hyaluronate powder with cross-linking degree of 3.1%.

(2) Preparation of gel formulations

Adding 2g of the cross-linked sodium hyaluronate prepared in the step (1), 1g of oligomeric sodium hyaluronate (Mw ═ 5kDa), 15g of polyethylene glycol-2000 (PEG-2000), and 10g of polyvinyl alcohol into water, and swelling for 20min under stirring to obtain a first solution; adding 3g of ectoin, 1g of lidocaine, 2g of polyoxyethylene polyoxypropylene pentaerythritol ether and 0.2g of sodium benzoate into water, and stirring to dissolve the materials to obtain a second solution; adding the second solution into the first solution under stirring, adding water to 100g, stirring for 20min, adjusting pH to 6.5 with sodium hydroxide, and wet-heat sterilizing at 121 deg.C for 25min to obtain gel preparation.

Examples 2 to 6 and comparative examples 1 to 8 are different from example 1 in the content of crosslinked sodium hyaluronate, oligomeric sodium hyaluronate, polyethylene glycol, ectoine and the molecular weight of oligomeric sodium hyaluronate, which are specifically shown in table 1.

TABLE 1

Verification example 1 gel adhesion

(1) Tangential adhesion

0.1g of each of the gels prepared in the above examples and comparative examples was placed on a 7cm by 7cm glass plate, and a 2.5cm by 2.5cm rigid plastic sheet was placed on the sample and pressed against the rigid plastic sheet with a 500g weight for 5min to spread the sample between the rigid plastic sheet and the glass plate. Fixing glass plate vertically, mounting small hook, fine wire and plastic cup on plastic sheet, opening control valve of dripping device, and dripping at 20 mL/min^-1And (4) enabling the flow rate to enter the small plastic cup until the sheet starts to slide, and recording the weight of the sheet, the hook line, the small plastic cup and the water to obtain the tangential adhesion of the gel. The results are shown in Table 2.

(2) Vertical adhesion

0.1g of each of the gels prepared in the above examples and comparative examples was placed on a 7cm by 7cm glass plate, and a 2.5cm by 2.5cm rigid plastic sheet was placed on the sample and pressed against the rigid plastic sheet with a 500g weight for 5min to spread the sample between the rigid plastic sheet and the glass plate. Fixing the glass plate horizontally, mounting small hook, fine wire and plastic cup on the plastic sheet, opening the control valve of dripping device, and dripping at 20 mL/min^-1And (4) enabling the liquid to flow into the small plastic cup at a flow speed until the sheet starts to slide, and recording the weight of the sheet, the hook line, the small plastic cup and the water to obtain the vertical adhesion of the lidocaine hydrochloride gel. The results are shown in Table 2.

TABLE 2

	Tangential adhesion force/g	Perpendicular adhesion force/g
			Example 1	2.68	13.12
Example 2	2.20	11.78
			Example 3	2.35	12.01
Example 4	2.50	12.65
			Example 5	2.49	12.58
Example 6	2.21	11.23
			Comparative example 1	1.89	9.55
Comparative example 2	2.20	11.07
			Comparative example 3	2.02	10.81
Comparative example 4	1.68	9.44
			Comparative example 5	0.76	7.13
Comparative example 6	0.86	7.21
			Comparative example 7	2.02	10.21
Comparative example 8	0.77	8.02

And (4) conclusion: the adhesion force is the performance which the endoscope gel needs to have when the endoscope gel plays a role, and the vertical adhesion force is large to ensure that the gel is well adhered to the endoscope. As can be seen from the above table, the tangential adhesion force of the gels prepared in the examples and the comparative examples is not much different, but the vertical adhesion force of the gels prepared in the examples of the present invention is much different, the vertical adhesion force of the gels prepared in the examples of the present invention is more than 11.23, especially the vertical adhesion force of the gels prepared in the example 1 is improved by more than 2.05-5.99 compared with the comparative examples, and the gels can be ensured to be well adhered to the endoscope.

Verification example 2 lubricity

Lubricity was measured by an MXD-01 friction coefficient meter.

The friction coefficient instrument mainly comprises a stainless steel water plane, a slide block with constant quality and a force value sensor. The method comprises the steps of respectively fixing a PE film and a fiber film on the bottom surface of a sliding block and a horizontal plane, coating the gel preparation prepared in the embodiment and the comparative example between the PE film and the fiber film, taking the coating water as a contrast, connecting the sliding block and a force value sensor during measurement, placing the sliding block on the horizontal plane, pulling the sliding block to move for a certain distance by the force value sensor at a constant speed, stopping the movement, measuring the friction coefficient between the sliding block and the horizontal plane, and automatically obtaining an average value by an instrument after measuring for three times.

TABLE 3

	Coefficient of kinetic friction (μ)
		Example 1	0.023
Example 2	0.041
		Example 3	0.533
Example 4	0.030
		Example 5	0.035
Example 6	0.687
		Comparative example 1	1.105
Comparative example 2	0.967
		Comparative example 3	1.032
Comparative example 4	1.211
		Comparative example 5	1.175
Comparative example 6	1.164
		Comparative example 7	0.995
Comparative example 8	1.134
		Control	1.387

And (4) conclusion: the gel endows the endoscope with certain lubrication degree, so that the endoscope can be ensured to enter the body smoothly. The smaller the coefficient of dynamic friction, the stronger the lubricating properties of the gel. As can be seen from the above table, the coefficient of dynamic friction between the PE film and the fiber film after the gel is applied is significantly smaller than that of the control group applied with water, which indicates that the friction between the PE film and the fiber film is reduced by the presence of the gel, and especially the friction reduction is more excellent after the gel of the embodiment of the present invention is applied.

Verification example 3 evaluation of adhesion of oil and fat

The gels of examples and comparative examples were uniformly applied to 15cm by 10cm glass plates, respectively, the glass plates were placed on a horizontal surface, a drop of blood was applied 10cm from one side, the glass plates were stood up after 5 seconds, the infiltration and rolling of blood were observed, and the time taken for the blood to roll to the other side was recorded.

TABLE 4

	Wetting and rolling conditions	Time/s
			Example 1	Does not infiltrate and rolls easily	8.1
Example 2	Does not infiltrate and rolls easily	9.5
			Example 3	Does not infiltrate and rolls easily	9.9
Example 4	Does not infiltrate and rolls easily	8.9
			Example 5	Does not infiltrate and rolls easily	9.0
Example 6	Does not infiltrate and rolls easily	10.0
			Comparative example 1	Slight infiltration and not easy to roll	18.7
Comparative example 2	Slight infiltration and not easy to roll	17.8
			Comparative example 3	Slight infiltration and not easy to roll	18.4
Comparative example 4	Wetting without rolling	——
			Comparative example 5	Wetting without rolling	——
Comparative example 6	Wetting without rolling	——
			Comparative example 7	Wetting without rolling	——
Comparative example 8	Wetting without rolling	——

Note: indicating that the gel did not roll to the other side during the observation period or that the gel was fully soaked during the rolling process

And (4) conclusion: as can be seen from the data in the above table, the blood does not infiltrate into the glass plate coated with the gel prepared in the embodiment of the present invention, and is easy to roll, and the rolling time on the glass plate is below 10s, which indicates that the gel prepared in the embodiment of the present invention is not easy to be stained with adhering grease, and can ensure that the lens of the endoscope coated with the gel of the embodiment is clean after entering the body.

Verification example 4 wound repair experiment

1. Preparation of gel extract

According to the national standard of the people's republic of China, part 12 of the biological evaluation of medical instruments: sample preparation and reference samples. And (3) disinfecting the gel through an ultraviolet ozone box, putting the material into a sterile leaching container in a sterile ultra-clean workbench, completely soaking the disinfected material in the solution, and adopting a serum-free DMEM medium as a medium for leaching the material. Leaching for 48h, filtering and sterilizing the leaching liquor, sealing, and storing at 4 ℃ for later use.

2. Cell culture

Cell wound repair regular scratch regions were formed in 24-well culture plates using ibidi chambers, and the effect of the samples on the ability of human epidermal keratinocytes (HaCaT) to migrate to the scratch regions was examined to evaluate whether the samples had the ability to repair wounds.

In a new 24-well plate, an ibidi cell was placed, and human epidermal keratinocytes HaCaT in logarithmic growth phase were taken at 3X 10⁵one/mL of the cells were inoculated in an ibidi chamber in a 24-well plate, 70. mu.L of each cell suspension was added to each of the left and right wells of the chamber, 400. mu.L of complete medium was supplemented outside the chamber, 5% CO at 37 ℃%₂Culturing for 24h under the condition. The chamber was removed, the old culture medium was aspirated off, and 1mL of sample solution was added. The sample solution is extracted from experimental example and comparative example, and DMEM high-sugar culture solution is usedWas prepared at a concentration of 10% (v/v) and used after being sterilized by filtration through a 0.22 μm filter. The control group was replaced with culture medium without sample. After further incubation for 24h, photographs were observed. Results mobility was calculated by analysis using Image J software.

Mobility ═ area of scratched area of experimental group/area of scratched area of control group × 100%

TABLE 5

	Mobility (%)
		Example 1	68.43
Example 2	65.00
		Example 3	64.78
Example 4	66.13
		Example 5	66.12
Example 6	62.21
		Comparative example 1	45.34
Comparative example 2	47.22
		Comparative example 3	46.31
Comparative example 4	38.13
		Comparative example 5	38.11
Comparative example 6	48.25
		Comparative example 7	37.32
Comparative example 8	48.11
		Control group	23.43

And (4) conclusion: high cell mobility indicates greater wound repair capacity. As can be seen from the data in the table above, the gel samples of examples 1 to 6 of the present invention show strong human epidermal cell migration ability, and the cell migration rates all reach more than 60%, indicating that the above samples have a good wound repair function. Among them, the wound repair effect is the best in example 1, and the mobility is significantly better than that of the comparative sample data. The mobility of the comparative examples is obviously reduced, and particularly the mobility of the comparative examples 4,5 and 7 is the lowest and is below 40%, which shows that the cross-linked hyaluronic acid, the oligomeric hyaluronic acid and the ectoin achieve better effect on the wound repair function by the synergistic action, and the defect is not all right.

Claims

1. A gel formulation comprising hyaluronic acid or a salt thereof, ectoin, polyethylene glycol, polyvinyl alcohol, an anesthetic, and an antifoaming agent,

the hyaluronic acid or salt thereof is composed of oligomeric hyaluronic acid or salt thereof and cross-linked hyaluronic acid or salt thereof, wherein the molecular weight of the oligomeric hyaluronic acid or salt thereof is 1k-50 kDa;

the mass ratio of the oligomeric hyaluronic acid or the salt thereof to the cross-linked hyaluronic acid or the salt thereof is 1: 1-10.

2. The gel formulation of claim 1, wherein the hyaluronic acid or salt thereof is 0.1-9%, the ectoin is 0.1-5%, the polyethylene glycol is 1-20%, the polyvinyl alcohol is 1-15%, the anesthetic is 0.5-2.0%, and the antifoaming agent is 1-5% by mass of the gel formulation.

3. The gel formulation of claim 1, wherein the hyaluronic acid or salt thereof is 1% to 5%, the ectoine is 1% to 4%, the polyethylene glycol is 10% to 20%, and the polyvinyl alcohol is 5% to 15% by mass of the gel formulation.

4. The gel formulation of claim 1, wherein the oligomeric hyaluronic acid or a salt thereof has a molecular weight of 1k-10kDa, and the cross-linked hyaluronic acid or a salt thereof is cross-linked from hyaluronic acid or a salt thereof having a molecular weight of 500k-2000kDa, and the degree of cross-linking is 3-5%.

5. The gel formulation of claim 4, wherein the cross-linked hyaluronic acid or salt thereof is cross-linked with hyaluronic acid or salt thereof having a molecular weight of 500k-1000 kDa.

6. The gel formulation of claim 1, wherein the mass ratio of the oligomeric hyaluronic acid or salt thereof to the cross-linked hyaluronic acid or salt thereof is 1: 2-4.

7. The gel formulation of claim 1, wherein the polyethylene glycol is selected from one or more of polyethylene glycol-200, polyethylene glycol-400, polyethylene glycol-1000, polyethylene glycol-1500, polyethylene glycol-2000, and polyethylene glycol-3000.

8. The gel preparation according to claim 1, wherein the anesthetic is a local anesthetic selected from one or more of lidocaine, procaine, benzocaine, bupivacaine, and dyclonine.

9. The gel formulation of claim 1, wherein the antifoaming agent is a nonionic surfactant selected from one or both of polyoxyethylene polyoxypropylene pentaerythritol ether and polyoxyethylene alkylolamide.

10. The gel formulation of claim 1, further comprising a preservative and a pH adjuster.

11. A method of preparing a gel formulation, comprising the steps of:

adding the second solution into the first solution, adjusting the pH value to 5.5-7.0, and performing moist heat sterilization to obtain a gel preparation;

12. Use of a gel formulation according to any one of claims 1 to 10 or a gel formulation prepared by a method according to claim 11 in the preparation of an endoscopic article.