CN116212108B

CN116212108B - Double-layer crosslinked gel containing lidocaine and preparation method and application thereof

Info

Publication number: CN116212108B
Application number: CN202310418752.9A
Authority: CN
Inventors: 金家铸; 李成建; 盛江伟; 何柳; 朱华青; 江云东
Original assignee: Hangzhou Keteng Biological Product Co ltd
Current assignee: Hangzhou Keteng Biological Product Co ltd
Priority date: 2023-04-18
Filing date: 2023-04-18
Publication date: 2023-10-20
Anticipated expiration: 2043-04-18
Also published as: CN116212108A

Abstract

The invention provides a double-layer crosslinked gel containing lidocaine, which comprises a matrix and gel microspheres dispersed in the matrix, wherein the matrix is a mixture of sodium hyaluronate and lidocaine, the gel microspheres comprise an outer soft layer and an inner hard layer, the inner hard layer comprises crosslinked sodium hyaluronate gel particles adsorbed with the lidocaine, and the outer soft layer comprises a mixture of sodium hyaluronate and lidocaine coated on the surface of the inner hard layer; the invention also provides a preparation method of the double-layer crosslinked gel containing the lidocaine, and the double-layer crosslinked gel containing the lidocaine is obtained through repeated three-dimensional mixing and high-temperature standing after multiple crosslinking and cyclic dialysis, and the double-layer crosslinked gel containing the lidocaine has high fusion degree with tissues, good deformation resistance supporting effect, tighter structure and slow degradation rate; the invention also provides application of the double-layer crosslinked gel containing lidocaine as a supporting material and a shaping material.

Description

Double-layer crosslinked gel containing lidocaine and preparation method and application thereof

Technical Field

The invention relates to a degradable material, in particular to a double-layer crosslinked gel containing lidocaine, a preparation method and application thereof.

Background

Hyaluronic acid exists in a large amount in human skin, so that the skin is smooth and elastic, but the content of the hyaluronic acid in the skin is gradually reduced along with the increase of the age, and the phenomena of wrinkling, atrophy, dent and the like appear, and the hyaluronic acid gel can play a role in filling and beautifying, but the hyaluronic acid is degraded very rapidly in the human body. At present, in order to slow down the degradation speed, a cross-linking agent is used for cross-linking to obtain gel, but the cross-linking agent is toxic, has a large dosage or is not completely cross-linked, and can cause allergic inflammatory reaction of organisms after entering human bodies. In addition, if the swelling degree of the gel is too large, uncertainty is brought to the injection quantity, and adverse reactions such as red swelling and the like appear; if the gaps among gel particles are larger, the surface area of the gel is larger, the contact area with hyaluronidase is also increased after the gel is injected subcutaneously, the degradation speed is higher, and the maintenance time after filling is short.

Disclosure of Invention

In view of the above-mentioned drawbacks of the prior art, the present invention aims to provide a dual-layer crosslinked gel containing lidocaine, and a preparation method and application thereof, which are used for solving the problems of incomplete crosslinking, large swelling degree, weak enzymolysis resistance, short holding time, poor deformation resistance and supporting effect in the prior art.

To achieve the above and other related objects, the present invention provides a dual-layer crosslinked gel containing lidocaine, comprising a matrix and gel microspheres dispersed in the matrix, wherein the matrix is a mixture of sodium hyaluronate and lidocaine, the gel microspheres comprise an outer soft layer and an inner hard layer, the inner hard layer comprises crosslinked sodium hyaluronate gel particles adsorbed with lidocaine, and the outer soft layer comprises a mixture of sodium hyaluronate and lidocaine coated on the surface of the inner hard layer.

Further, the content of sodium hyaluronate in the double-layer crosslinked gel containing lidocaine is 20-30 mg/ml, and the content of lidocaine is 0.2-0.5 wt%.

The invention also provides a preparation method of the double-layer crosslinked gel containing lidocaine, which comprises the following steps:

s1, preparing crosslinked sodium hyaluronate gel through multiple crosslinking reactions;

s2, performing circulating dialysis on the crosslinked sodium hyaluronate gel prepared in the step S1, crushing, washing, filtering, and dehydrating to obtain dry gel particles;

s3, adding the xerogel particles obtained in the step S2 into a lidocaine solution, and sieving after the xerogel particles absorb the lidocaine to obtain wet gel particles with uniform particle sizes;

s4, mixing sodium hyaluronate with lidocaine solution to prepare a matrix;

s5, boiling and mixing the wet gel particles obtained in the step S3 with the matrix obtained in the step S4, cooling to normal temperature, repeating three-dimensional mixing for multiple times, and standing at high temperature to obtain the lidocaine-containing double-layer crosslinked gel.

In step S1, the multiple crosslinking reaction is carried out for 2-6 hours at 18-26 ℃, then for 10-24 hours at 2-8 ℃ and then for 1.5-4 hours at 35-60 ℃.

Further, in step S2, the method of circulating dialysis includes: the cross-linked sodium hyaluronate gel was allowed to float up and down in a circulating buffer for dialysis.

Further, in the step S3, the dosage of the lidocaine solution is 1 to 1.2 times of the water loss amount in the gel dehydration process in the step S2.

Further, in step S3, the sieving is performed so that the gel particle size reaches 40 to 100 mesh.

Further, in step S5, the boiling mixing process includes: the wet gel particles and the lubricating liquid are filled into a closed container, heated and boiled to be fully mixed.

Further, in step S5, the three-dimensional mixing and high-temperature standing process includes: mixing in a three-dimensional mixer for 8-20 h, and then storing for 1-4 h at 35-60 ℃.

The invention also provides application of the double-layer crosslinked gel containing lidocaine as a supporting material and a shaping material.

As described above, the lidocaine-containing bilayer crosslinked gel of the invention, and the preparation method and the application thereof, have the following beneficial effects:

the crosslinked sodium hyaluronate contained in the lidocaine-containing double-layer crosslinked gel is crosslinked for multiple times, and has the advantages of high viscosity, high elasticity, high cohesive force, high crosslinking degree and less crosslinking agent residue.

According to the preparation method of the double-layer crosslinked gel containing lidocaine, the lidocaine is subjected to cyclic dialysis, and crushing and cleaning are carried out after the dialysis, so that the purification effect is achieved, impurities can be reduced, the residue of a crosslinking agent is reduced, the swelling degree of a product is low, the injection is more accurate, and edema is small; after that, the gel is compacter, easy to shape, strong in enzymolysis resistance and long in holding time, and the deformation resistance supporting effect is improved, and the lidocaine contained in the gel can make a user feel more comfortable during and after operation.

According to the preparation method of the double-layer crosslinked gel containing the lidocaine, the lidocaine is added in two steps, so that the distribution is more uniform, the postoperative comfort level is high, and the slow release effect can be ensured; and after three-dimensional mixing and high-temperature standing and repeated mixing, the formed gel microsphere is soft outside and hard inside, has high fusion degree with tissues, is compatible with human bodies, has good retention, has a tighter structure and is slow in degradation rate.

Drawings

FIG. 1 shows a micrograph of a double-layer crosslinked gel containing lidocaine according to example 1 of the present invention.

FIG. 2 shows a diagram of cohesion test experiment of a double-layer crosslinked gel containing lidocaine according to the present invention.

FIG. 3 shows an experimental graph of anti-deformation ability test of a double-layer crosslinked gel containing lidocaine according to the present invention.

FIG. 4 shows a supporting experimental test chart of a dual layer crosslinked gel containing lidocaine according to the present invention.

FIG. 5 is a chart showing the experimental tack and retention test of a dual layer crosslinked gel containing lidocaine according to the present invention.

FIG. 6 shows a graph of experimental push force test of a dual layer crosslinked gel containing lidocaine according to the present invention.

Detailed Description

Other advantages and effects of the present invention will become apparent to those skilled in the art from the following disclosure, which describes the embodiments of the present invention with reference to specific examples. The invention may be practiced or carried out in other embodiments that depart from the specific details, and the details of the present description may be modified or varied from the spirit and scope of the present invention.

The first aspect of the invention provides a lidocaine-containing bilayer crosslinked gel, comprising a matrix and gel microspheres dispersed in the matrix, wherein the matrix is a mixture of sodium hyaluronate and lidocaine, the gel microspheres comprise an outer soft layer and an inner hard layer, the inner hard layer comprises crosslinked sodium hyaluronate gel particles adsorbed with lidocaine, and the outer soft layer comprises a mixture of sodium hyaluronate and lidocaine coated on the surface of the inner hard layer.

The content of sodium hyaluronate in the double-layer crosslinked gel containing the lidocaine is 20-30 mg/ml (comprising sodium hyaluronate participating in crosslinking in gel microspheres and sodium hyaluronate in a matrix), and the content of the lidocaine is 0.2-0.5 wt% (based on the content of lidocaine substances).

The second aspect of the invention provides a method for preparing a double-layer crosslinked gel containing lidocaine, comprising the following steps:

s4, mixing sodium hyaluronate with lidocaine solution to prepare a matrix;

Sodium hyaluronate is an acidic mucose with the widest distribution in human bodies, exists in the matrix of connective tissues, and has good moisturizing effect. Sodium hyaluronate is an inherent biological substance of the skin, and exogenous sodium hyaluronate is an endogenous supplement to the skin. The smaller sodium hyaluronate can permeate into skin epidermis layer to promote skin nutrition supply and waste excretion, thereby preventing skin aging and caring skin. Sodium hyaluronate can promote regeneration of injured skin by promoting proliferation and differentiation of epidermal cells and scavenging oxygen free radicals, and has certain preventive effect when used in advance.

Lidocaine has anesthetic effect and can be used for surface anesthesia, local infiltration anesthesia and nerve block anesthesia.

According to the preparation method of the double-layer crosslinked gel containing the lidocaine, the gel crosslinking degree is high through multiple crosslinking, the crosslinked sodium hyaluronate gel is subjected to cyclic dialysis, then the crosslinked sodium hyaluronate gel is crushed, washed, filtered and dehydrated, so that the residual quantity of a crosslinking agent in the obtained crosslinked gel is less, the gel is more compact and easy to shape, the dehydrated gel is added into a lidocaine solution, a certain amount of lidocaine is adsorbed, wet gel particles with uniform particle sizes are obtained through sieving and screening, and finally the wet gel particles and a substrate containing the lidocaine are subjected to boiling mixing and repeated three-dimensional mixing, and the double-layer crosslinked gel containing the lidocaine and containing gel microspheres with soft outside and hard inside is obtained through high-temperature standing.

In the preparation method of the lidocaine-containing double-layer crosslinked gel, in the step S1, crosslinked sodium hyaluronate gel is prepared by crosslinking reaction of sodium hyaluronate and a crosslinking agent in alkali liquor.

Wherein the alkaline solution is sodium hydroxide solution with pH of more than 13. The concentration of the sodium hydroxide solution is 0.5 to 3.5 weight percent. For example 0.5 to 1.0wt%, 1.0 to 1.5wt%, 1.5 to 2.0wt%, 2.0 to 2.5wt%, 2.5 to 3.0wt% or 3.0 to 3.5wt%. In a preferred embodiment of the invention, the concentration of the sodium hydroxide solution is 1% by weight.

The cross-linking agent is 1, 4-butanediol diglycidyl ether (BDDE).

The mass ratio of the cross-linking agent to the sodium hyaluronate is 1:20-1:8. For example, 1:20 to 1:15, 1:15 to 1:10 or 1:10 to 1:8. In a preferred embodiment of the invention, the mass ratio of the cross-linking agent to sodium hyaluronate is 1:12.5.

The crosslinking reaction is carried out under stirring.

In the step S1, the multiple crosslinking reaction is carried out for 2-6 hours at 18-26 ℃, then for 10-24 hours at 2-8 ℃ and then for 1.5-4 hours at 35-60 ℃. Namely, the multiple crosslinking reaction can be carried out at 18-20 ℃, 20-22 ℃, 22-24 ℃ or 24-26 ℃ for 2-4 or 4-6 hours, then at 2-4 ℃, 4-6 ℃ or 6-8 ℃ for 10-14 hours, 14-18 hours, 18-22 hours or 22-24 hours, and then at 35-40 ℃, 40-45 ℃, 45-50 ℃, 50-55 ℃, 55-60 ℃ or 60-65 ℃ for 1.5-2 hours, 2-2.5 hours, 2.5-3 hours, 3-3.5 hours or 3.5-4 hours. In a preferred embodiment of the invention, the multiple crosslinking reaction is carried out 3 hours prior to 25℃and then 16 hours at 6℃and then 2 hours at 50 ℃.

In the preparation method of the lidocaine-containing double-layer crosslinked gel, in the step S2, the method for circulating dialysis comprises the following steps: the crosslinked sodium hyaluronate gel was dialyzed by floating it up and down in a circulating buffer. The method specifically comprises the following steps: and (3) placing the gel in a hollowed container, and enabling the container to float up and down in a circulating buffer solution to complete circulating dialysis.

Wherein the buffer solution is prepared from disodium hydrogen phosphate, sodium dihydrogen phosphate and sodium chloride. The pH of the buffer solution is 6.6-7.6. For example 6.6 to 6.8, 6.8 to 7.0, 7.0 to 7.2, 7.2 to 7.4 or 7.4 to 7.6. In a preferred embodiment of the invention, the pH of the buffer is 6.86.

The osmotic pressure of the buffer is 270mOsm/L to 330mOsm/L. For example 270mOsm/L to 280mOsm/L, 280mOsm/L to 290mOsm/L, 290mOsm/L to 300mOsm/L, 300mOsm/L to 310mOsm/L, 310mOsm/L to 320mOsm/L or 320mOsm/L to 330mOsm/L. In a preferred embodiment of the invention, the buffer has an osmotic pressure of 300mOsm/L.

The mass ratio of the buffer solution to the sodium hyaluronate dry powder which participates in forming gel in the crosslinked sodium hyaluronate gel is 500:1-1000:1. For example 500:1 to 550:1, 550:1 to 600:1, 600:1 to 650:1, 650:1 to 700:1, 700:1 to 750:1, 750:1 to 800:1, 800:1 to 850:1, 850:1 to 900:1, 900:1 to 950:1 or 950:1 to 1000:1. In a preferred embodiment of the invention, the mass ratio of the buffer solution to the sodium hyaluronate dry powder is 750:1.

the circulating dialysis time is 16-48 h. For example, 16 to 20 hours, 20 to 24 hours, 24 to 28 hours, 28 to 32 hours, 32 to 36 hours, 36 to 40 hours, 40 to 44 hours or 44 to 48 hours. In a preferred embodiment of the invention, the cycle dialysis time is 32 hours.

The buffer solution is replaced for 3-8 times in the circulating dialysis process.

The crushing method in the step S2 comprises the following steps: and (3) crushing the dialyzed gel through a 2-8-mesh screen. Specifically, a stainless steel extrusion device is adopted, gel after dialysis is enabled to pass through a screen with the aperture of 2-8 meshes under the condition of positive pressure of 0.05-0.5 MPa, and the gel is crushed into viscoelasticity microgel. Wherein, the pressure adopted in the stainless steel extrusion device can be 0.05MPa to 0.1MPa, 0.1MPa to 0.15MPa, 0.15MPa to 0.2MPa, 0.2MPa to 0.25MPa, 0.25MPa to 0.3MPa, 0.3MPa to 0.35MPa, 0.35MPa to 0.4MPa, 0.4MPa to 0.45MPa or 0.45MPa to 0.5MPa. In a preferred embodiment of the invention, a pressure of 0.4MPa is used.

In the step S2, sterilized water for injection is used for washing. After washing, the liquid is filtered out and repeatedly washed for 2 to 6 times.

In the step S2, the dehydration adopts a vacuum drying method. The vacuum drying time is 2-6 h, the vacuum drying temperature is 25-45 ℃, and the vacuum degree is less than or equal to-0.085 mpa. Wherein, the vacuum drying time can be 2-3 h, 3-4 h, 4-5 h or 5-6 h. In a preferred embodiment of the invention, the vacuum drying time is 5 hours. The vacuum drying temperature may be 25 to 30 ℃, 30 to 35 ℃, 35 to 40 ℃ or 40 to 45 ℃. In a preferred embodiment of the invention, the vacuum drying temperature is 37 ℃.

The degree of dehydration in step S2 is: the gel is dehydrated by 5 to 15 weight percent (namely the mass ratio of water loss to gel before dehydration). For example, 5wt% to 10wt% or 10wt% to 15wt%. In a preferred embodiment of the invention, the gel loses 10% by weight.

In the preparation method of the double-layer crosslinked gel containing lidocaine, in the step S3 and the step S4, the lidocaine solution is as follows: adding sodium bicarbonate into lidocaine hydrochloride solution with the concentration of 6-15 wt% to regulate the pH value to 6.8-7.6. The 6-15 wt% lidocaine hydrochloride solution is 100g solution and contains 6-15 g lidocaine hydrochloride, wherein the solvent is sterilization injection water.

In the preparation method of the double-layer crosslinked gel containing the lidocaine, in the step S3, the dosage of the lidocaine solution is 1-1.2 times of the water loss rate in the gel dehydration process in the step S2. For example 1 to 1.1 times or 1.1 to 1.2 times. In a preferred embodiment of the invention, the lidocaine solution is used in an amount 1 times, i.e. equal, the water loss during the gel dehydration in step S2.

Sieving to make the gel particle size reach 40-100 mesh. The sieving process may pass the gel through the primary and secondary screens of the secondary sieving device in sequence. The secondary screening device is a gel granulating device disclosed in patent number 2016208941192. The first-level screen mesh and the second-level screen mesh are 40-100 meshes. The specific operation of sieving is as follows: loading gel particles on a first-stage screening screen, closing a first-stage and second-stage middle partition plate, opening an exhaust valve between the screen and the partition plate, and pressing the gel particles through the first-stage screen by using 0.2-0.6mpa pressure to enable the gel to fall on the partition plate; closing the air, opening the partition plate to enable the gel to fall on the secondary screen, closing the partition plate, opening an air inlet valve (pressure is 0.2-0.6 mpa) between the secondary screen and the partition plate, enabling the gel to pass through the screen and fall in a container below the discharge port.

In the step S3, the content of the lidocaine in the wet gel particles is 0.2-0.5 wt%. The xerogel particles are soaked in the lidocaine solution, so that the content of the lidocaine in the gel is 0.2 to 0.5 weight percent of the total mass after the xerogel particles absorb the lidocaine. For example 0.2wt% to 0.3wt%, 0.3wt% to 0.4wt% or 0.4wt% to 0.5wt%. In a preferred embodiment of the invention, the lidocaine content of the wet gel pellet is 0.3wt%.

In the step S3, the content of sodium hyaluronate in the wet gel particles is 1-3.2 wt%. For example 1wt% to 1.2wt%, 1.2wt% to 1.6wt%, 1.6wt% to 2.0wt%, 2.0wt% to 2.4wt%, 2.4wt% to 2.8wt% or 2.8wt% to 3.2wt%. In a preferred embodiment of the invention, the sodium hyaluronate content of the wet gel particles is 2 wt.%.

In the preparation method of the double-layer crosslinked gel containing the lidocaine, in the step S4, the content of the lidocaine in the matrix is 0.2-0.5 wt%. For example 0.2wt% to 0.3wt%, 0.3wt% to 0.4wt% or 0.4wt% to 0.5wt%. In a preferred embodiment of the invention, the lidocaine content of the matrix is 0.3wt%.

Wherein the content of lidocaine in the matrix is 0.2-0.5 wt%.

The content of sodium hyaluronate in the matrix is 1wt% to 3.2wt%. For example 1wt% to 1.2wt%, 1.2wt% to 1.6wt%, 1.6wt% to 2.0wt%, 2.0wt% to 2.4wt%, 2.4wt% to 2.8wt% or 2.8wt% to 3.2wt%. In a preferred embodiment of the invention, the sodium hyaluronate content of the matrix is 2% by weight

In the preparation method of the lidocaine-containing double-layer crosslinked gel, in the step S5, the boiling mixing process comprises the following steps: the wet gel particles and the lubricating liquid are filled into a closed container, heated and boiled to be fully mixed.

Wherein the mass ratio of the wet gel particles to the matrix is 5:1-15:1. For example, 5:1 to 7:1, 7:1 to 9:1, 9:1 to 11:1, 11:1 to 13:1 or 13:1 to 15:1. In a preferred embodiment of the invention, the mass ratio of wet gel particles to matrix is 10:1.

The boiling mixing temperature is 110-125 ℃. For example, 110 to 115 ℃, 112 to 120 ℃ or 120 to 125 ℃. In a preferred embodiment of the invention, the temperature of the boiling mixture is 121 ℃.

The boiling mixing time is 15-45 min. For example 15 to 20 minutes, 20 to 25 minutes, 25 to 30 minutes, 30 to 35 minutes, 35 to 40 minutes or 40 to 45 minutes. In a preferred embodiment of the invention, the boiling mixing time is 30 minutes.

In step S5, the three-dimensional mixing and high-temperature standing process includes: mixing in a three-dimensional mixer for 8-20 h, and then storing for 1-4 h at 35-60 ℃. For example, mixing for 8 to 12 hours, 12 to 16 hours or 16 to 20 hours in a three-dimensional mixer, and then storing for 1 to 2g, 2 to 3 hours or 3 to 4 hours at 35 to 40 ℃, 40 to 45 ℃, 45 to 50 ℃, 50 to 55 ℃ or 55 to 60 ℃. In a preferred embodiment of the invention, the three-dimensional mixing and high temperature rest process is to mix for 14 hours in a three-dimensional mixer and then store for 2 hours at 42 ℃.

In the step S5, the three-dimensional mixing and high-temperature standing repetition times are 2-7 times. For example, 2 to 3 times, 3 to 4 times, 4 to 5 times, 5 to 6 times or 6 to 7 times. In a preferred embodiment of the invention, the three-dimensional mixing and high temperature rest repetition times are 4 times. The three-dimensional mixing and high-temperature standing process has a certain self-crosslinking effect, so that the mixed solution of the matrix is wrapped outside the gel particles to form gel microspheres with soft outside and hard inside.

In a third aspect, the present invention provides the use of the above-described lidocaine-containing bilayer crosslinked gel as a support material and a shaping material. The double-layer crosslinked gel containing lidocaine obtained by the method contains gel microspheres with soft outside and hard inside, has high fusion degree with tissues, is compatible with human bodies, has good retention, more compact structure, slow degradation rate and good anti-deformation supporting effect. The lidocaine-containing double-layer crosslinked gel is injected subcutaneously, has uniform particle size, smooth pushing and low swelling degree, generates little edema, has high fusion degree with tissues, is compatible with human bodies, has strong enzymolysis resistance, has long retention time, is simple and safe to use, and does not need a repair period.

Example 1

Preparing a lidocaine-containing bilayer crosslinked gel:

s1, mixing BDDE and a 1wt% NaOH solution to obtain a mixed solution, adding sodium hyaluronate into the mixed solution (the mass ratio of the sodium hyaluronate to the BDDE is 12.5:1), stirring and dissolving at room temperature, reacting for 3 hours at room temperature, then reacting for 16 hours at 6 ℃, then heating to 50 ℃, reacting for 2 hours, cooling to room temperature, and cooling to 6 ℃ for 20 hours to obtain the crosslinked sodium hyaluronate gel.

S2, placing the crosslinked sodium hyaluronate gel prepared in the step S1 in a hollowed container, enabling the container to float up and down in a circulating buffer solution (the buffer solution is prepared from disodium hydrogen phosphate, sodium dihydrogen phosphate and sodium chloride, the pH value is 6.86, the osmotic pressure is 300 mOsm/L), the mass ratio of the buffer solution to the sodium hyaluronate dry powder raw material forming the crosslinked sodium hyaluronate gel is 750:1, and circularly dialyzing for 32h, wherein the buffer solution is replaced for 5 times. After dialysis, a stainless steel extrusion device is adopted, gel after dialysis is enabled to pass through a screen mesh with the pore diameter of 2-8 meshes under the condition of positive pressure of 0.4MPa, and the gel is crushed into viscoelasticity microgel. Washing the microgel with sterilized water for injection, filtering to remove liquid, repeatedly washing for 3 times, and vacuum drying at 37deg.C for 5 hr to vacuum degree of less than or equal to-0.085 mpa to make gel lose water 10wt% to obtain xerogel particles (shown in figure 1 b).

S3, adding the xerogel particles obtained in the step S2 into a lidocaine solution, wherein the dosage of the neutral lidocaine solution is equal to the water loss rate in the gel dehydration process, sieving the xerogel particles in a secondary sieving device (a sieve is 40-100 meshes) after the xerogel particles completely absorb the lidocaine to obtain wet gel particles with uniform particle diameters, wherein the content of the lidocaine in the wet gel particles is 0.3wt% and the content of sodium hyaluronate (namely sodium hyaluronate participating in crosslinking) is 2wt%. Wherein, the lidocaine solution is: sodium bicarbonate is added into the lidocaine hydrochloride solution with the concentration of 6-15%, and the pH value of the lidocaine hydrochloride solution is adjusted to 6.86, so that the neutral lidocaine solution is obtained.

S4, diluting the neutral lidocaine solution in the step S3 with water, adding sodium hyaluronate, and mixing to obtain a matrix (shown in figure 1 a); the content of lidocaine in the matrix is 0.3wt%, and the content of sodium hyaluronate in the matrix is 2wt%;

s5, filling the wet gel particles obtained in the step S3 and the substrate obtained in the step S4 into a closed container according to the mass ratio of 10:1, heating to 121 ℃, fully mixing the wet gel particles by boiling, and keeping the boiling mixing time to be 30min; boiling, mixing, cooling to room temperature, mixing in a three-dimensional mixer for 14h, storing at 42deg.C for 2h, repeatedly three-dimensional mixing, and standing at 42deg.C for 4 times to obtain a double-layer crosslinked gel containing lidocaine and containing gel microspheres with soft outside and hard inside (shown in figure 1 c); the content of lidocaine in the double-layer crosslinked gel containing lidocaine is 0.3wt%, and the content of sodium hyaluronate is 2wt% (including sodium hyaluronate participating in crosslinking and non-crosslinked sodium hyaluronate); the particle size of gel microsphere in the double-layer crosslinked gel containing lidocaine is not less than 70% of the particle size of 100-2000 μm.

Example 2

Preparing common hemp-containing gel:

the cross-linked sodium hyaluronate was prepared in the same ratio as in example 1, and the obtained cross-linked sodium hyaluronate was dialyzed in a buffer, and the gel was prepared into microgel after dialysis, and then was uniformly mixed with a matrix (prepared by mixing sodium hyaluronate with lidocaine), to obtain a general fibrilia-containing gel. The difference is that: the crosslinking process is carried out by stirring uniformly at normal temperature and then crosslinking reaction for 2 hours at 50 ℃; the dialysis procedure is not the cyclic dialysis in example 1, but a conventional dialysis procedure; the microgel prepared after dialysis is not subjected to the processes of filtration, washing and dehydration; the microgel is mixed with the matrix without repeated boiling mixing and three-dimensional mixing processes. The obtained common hemp-containing gel contains 0.3wt% of lidocaine and 2wt% of sodium hyaluronate.

Example 3

Cohesive force test

Taking one gram of the lidocaine-containing double-layer crosslinked gel prepared in example 1 and one gram of the general hemp-containing gel prepared in example 2, spreading the double-layer crosslinked gel on a plane of a universal tensile tester, starting the tester, pressing the gel to the bottom, slowly lifting the tester, observing the breaking condition of the gel, and ensuring that the gel has high cohesive force and is not easy to break. As shown in fig. 2.

As can be seen from fig. 2: FIGS. 2a, 2b, 2c and 2d show the double crosslinked lidocaine-containing gel of example 1 of the present invention, and FIGS. 2e, 2f, 2g and 2h show the general tingling gel of example 2; the difficulty in breaking the lidocaine-containing bilayer crosslinked gel of example 1 of the present invention while the conventional tingling-containing gel of example 2 easily broken in the same pressing and lifting, demonstrated that the lidocaine-containing bilayer crosslinked gel of example 1 of the present invention had higher cohesive force.

Example 4

Deformation resistance test

The double-layer crosslinked gel containing lidocaine prepared in example 1 and the common hemp-containing gel prepared in example 2 are respectively added into two identical test tubes, small steel balls with the same mass are respectively put into the two identical test tubes, and the time for the steel balls to fall to the bottom of the test tubes is observed, so that the longer the time is, the stronger the deformation resistance is. As shown in fig. 3.

As can be seen from fig. 3: FIGS. 3a, 3b and 3c show a double-layer crosslinked gel containing lidocaine according to example 1 of the present invention, and FIGS. 3d and 3e show a general fibrilia-containing gel of example 2; the steel balls in the lidocaine-containing double-layer crosslinked gel of the embodiment 1 of the invention fall to the bottom of the test tube for 84s, and the steel balls in the ordinary hemp-containing gel of the embodiment 2 fall to the bottom of the test tube for 37s, which shows that the deformation resistance of the lidocaine-containing double-layer crosslinked gel of the embodiment 1 of the invention is better than that of the ordinary hemp-containing gel of the embodiment 2.

Example 5

Experiment of supporting Property

The lidocaine-containing bilayer crosslinked gel prepared in example 1 and the general hemp-containing gel of example 2 were each taken at 0.5g in a petri dish, a cotton swab of 5cm was inserted, and the falling time was observed, and the longer the falling time of the small swab, the more supportive was. As shown in fig. 4.

As can be seen from fig. 4: FIGS. 4a, 4b, 4c show a double-layer crosslinked gel containing lidocaine according to example 1 of the present invention, and FIGS. 4d, 4e show a general fibrilia-containing gel of example 1; the falling time of the small rod on the lidocaine-containing double-layer crosslinked gel of the embodiment 1 of the invention is 102s, and the falling time of the small rod on the common hemp-containing gel of the embodiment 2 is 60s, which indicates that the plasticity and the supporting force of the lidocaine-containing double-layer crosslinked gel of the embodiment 1 of the invention are stronger.

Example 6

Viscosity and retention experiments

The double-layer crosslinked gel containing lidocaine prepared in example 1 and the common hemp-containing gel prepared in example 2 were respectively taken and placed at the upper end of a slide glass inclined at 35 degrees, respectively placing small steel balls with the diameter of 8mm on the gel, and observing the time for the balls to roll down to the plane, wherein the longer the time is, the stronger the viscosity and retention of the gel are. As shown in fig. 5.

As can be seen from fig. 5: FIGS. 5a, 5b, 5c are double crosslinked lidocaine-containing gels of example 1 of the present invention, and FIGS. 5d, 5e are conventional hemp-containing gels of example 2; the rolling time of the pellets on the lidocaine-containing double-layer crosslinked gel of the embodiment 1 of the invention is 8s, and the rolling time of the pellets on the common hemp-containing gel of the embodiment 2 is 3s, which indicates that the lidocaine-containing double-layer crosslinked gel of the embodiment 1 of the invention has stronger viscosity and retention.

Example 7

Experiment of the pushing force

The lidocaine-containing bilayer crosslinked gel of example 1 was tested using an XBD4000 series universal tester as shown in fig. 6: the peak height difference is small during pushing, and the pushing force is stable, which indicates that pushing is smooth.

In summary, the preparation of the double-layer crosslinked gel containing lidocaine provided by the invention is characterized in that crosslinking is more thorough through crosslinking at different temperatures, then the redundant crosslinking agent is removed through cyclic dialysis, the impurities are removed through crushing and washing, the gel is more compact through dehydration, the plasticity is stronger, the lidocaine is absorbed through swelling, the particles are uniform through sieving, the lubricant is added, the particles are boiled and mixed, and then the double-layer crosslinked gel containing lidocaine containing gel microspheres with external softness and internal hardness is obtained through three-dimensional mixing and high-temperature standing processes at room temperature repeatedly; the double-layer crosslinked gel tissue containing lidocaine prepared by the method has the advantages of high fusion degree, human body affinity, good retention, compact structure, slow degradation rate and improved anti-deformation supporting effect. Therefore, the invention effectively overcomes various defects in the prior art and has high industrial utilization value.

The above embodiments are merely illustrative of the principles of the present invention and its effectiveness, and are not intended to limit the invention. Modifications and variations may be made to the above-described embodiments by those skilled in the art without departing from the spirit and scope of the invention. Accordingly, it is intended that all equivalent modifications and variations of the invention be covered by the claims, which are within the ordinary skill of the art, be within the spirit and scope of the present disclosure.

Claims

1. The double-layer crosslinked gel containing the lidocaine is characterized by comprising a matrix and gel microspheres dispersed in the matrix, wherein the matrix is a mixture of sodium hyaluronate and the lidocaine, the gel microspheres comprise an outer soft layer and an inner hard layer, the inner hard layer comprises crosslinked sodium hyaluronate gel particles adsorbed with the lidocaine, the crosslinked sodium hyaluronate gel particles adsorbed with the lidocaine are obtained by circularly dialyzing the crosslinked sodium hyaluronate gel, then crushing, washing, filtering and dehydrating the dehydrated gel, and adding the dehydrated gel into a lidocaine solution; the outer soft layer comprises a mixture of sodium hyaluronate and lidocaine coated on the surface of the inner hard layer, and the outer soft layer is prepared by three-dimensional mixing and high-temperature standing of a mixed solution of sodium hyaluronate and lidocaine.

2. The lidocaine-containing bilayer crosslinked gel of claim 1 wherein the content of sodium hyaluronate in the lidocaine-containing bilayer crosslinked gel is 1wt% to 3.2wt% and the content of lidocaine is 0.2wt% to 0.5wt%.

3. A method for preparing a lidocaine-containing bilayer crosslinked gel according to any one of claims 1 to 2 comprising the steps of:

s4, mixing sodium hyaluronate with lidocaine solution to obtain a matrix;

4. The method for preparing a double-layer crosslinked gel containing lidocaine according to claim 3, wherein in step S1, the crosslinked sodium hyaluronate gel is obtained by crosslinking reaction of sodium hyaluronate and a crosslinking agent in an alkali solution;

and/or in the step S1, the multiple crosslinking reaction is carried out for 2-6 hours at 18-26 ℃, then for 10-24 hours at 2-8 ℃ and then for 1.5-4 hours at 35-60 ℃.

5. The method for preparing a lidocaine-containing bilayer crosslinked gel according to claim 3, wherein in step S2, the method for cyclic dialysis comprises: allowing the crosslinked sodium hyaluronate gel to float up and down in a circulating buffer solution for dialysis;

and/or, the crushing method in step S2 comprises: breaking the dialyzed gel through a 2-8 mesh screen;

and/or, the washing in the step S2 adopts sterilized water for injection;

and/or, the dehydration in the step S2 adopts a vacuum drying method;

and/or, the degree of dehydration in step S2 is: the gel is dehydrated by 5 to 15 weight percent.

6. The method for preparing a double-layer crosslinked gel containing lidocaine according to claim 3, wherein in step S3 and step S4, the lidocaine solution is: adding sodium bicarbonate into lidocaine hydrochloride solution with the concentration of 6-15 wt% to adjust the pH value to 6.8-7.6;

and/or, in the step S3, the dosage of the lidocaine solution is 1-1.2 times of the water loss amount in the gel dehydration process in the step S2;

and/or, in the step S3, sieving to enable the particle size of the gel to reach 40-100 meshes;

and/or, in the step S3, the content of the lidocaine in the wet gel particles is 0.2-0.5 wt%;

and/or, in the step S3, the content of sodium hyaluronate in the wet gel particles is 1-3.2 wt%.

7. The method for preparing a double-layer crosslinked gel containing lidocaine according to claim 3, wherein in step S4, the content of lidocaine in the matrix is 0.2wt% to 0.5wt%;

and/or, in the step S4, the content of the sodium hyaluronate in the matrix is 1-3.2 wt%.

8. The method for preparing a lidocaine-containing bilayer crosslinked gel according to claim 3 wherein in step S5, the boiling mixing process comprises: placing the wet gel particles and the substrate into a closed container, and heating and boiling to fully mix the wet gel particles and the substrate;

and/or, in step S5, the three-dimensional mixing and high-temperature standing process includes: mixing in a three-dimensional mixer for 8-20 h, and then storing for 1-4 h at 35-60 ℃;

and/or, in the step S5, the three-dimensional mixing and high-temperature standing repetition times are 2-7 times.

9. The method for preparing a lidocaine-containing bilayer crosslinked gel according to claim 3 wherein in step S5 the mass ratio of the wet gel particles to the matrix is 5:1 to 15:1, a step of;

and/or, in the step S5, the boiling mixing temperature is 110-125 ℃;

and/or in the step S5, the boiling mixing time is 15-45 min.

10. Use of a lidocaine-containing bilayer crosslinked gel according to any one of claims 1 to 2 as support material and shaping material.