A method for preparing a hyaluronic acid sodium gel for injection containing lidocaine hydrochloride

Abstract

The application discloses a preparation method of a hyaluronic acid sodium gel containing lidocaine hydrochloride for injection, and the method comprises the following steps: obtaining a hyaluronic acid sodium alkali solution at room temperature, controlling the adding proportion of a crosslinking agent, the reaction temperature, the reaction time, elution and impurity removal, granulation and other steps to obtain the hyaluronic acid sodium gel, preparing a non-crosslinked hyaluronic acid sodium solution, dissolving the lidocaine hydrochloride in the non-crosslinked hyaluronic acid sodium solution, and mixing the lidocaine hydrochloride with the crosslinked hyaluronic acid sodium gel by using a self-rotation and revolution stirring mode. The crosslinked hyaluronic acid sodium gel obtained by the method avoids the damage of mechanical stirring to the gel, the risk of product contamination is reduced, and the safety is better. The preparation method improves the uniformity of the distribution of the lidocaine hydrochloride in the gel, and is easier to realize industrialized production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biomedical materials, and particularly relates to a preparation method of a hyaluronic acid sodium gel for injection containing lidocaine hydrochloride. BACKGROUND

[0002] Hyaluronic acid (HA) is a polysaccharide belonging to glycosaminoglycans, which is composed of disaccharide units of N-acetylglucosamine and D-glucuronic acid, and has significant moisturizing and anti-aging effects. By using different modification methods, the physicochemical properties of hyaluronic acid sodium can be changed, and the retention time in the body can be prolonged.

[0003] In order to improve the comfort of consumers during the injection process, lidocaine hydrochloride is added to the hyaluronic acid sodium gel to relieve the pain at the injection site. The commonly used methods are mixing lidocaine hydrochloride with the gel by stirring or adding by dialysis. When the mechanical stirring is operated at a low speed, the hyaluronic acid sodium gel with high viscosity may not be stirred, and the dispersion effect is poor. High-speed shearing has a strong shearing effect on the material, which finally affects the physicochemical properties of the gel. The dialysis method adds lidocaine hydrochloride to the buffer solution, which causes waste of lidocaine hydrochloride, and the overall process time is long, and the pollution risk is increased. How to efficiently add lidocaine hydrochloride to the cross-linked hyaluronic acid sodium gel and make it uniformly distributed, reduce the structural damage to the hyaluronic acid sodium, and obtain a hyaluronic acid sodium gel with uniformly distributed lidocaine hydrochloride is a technical problem to be solved. SUMMARY

[0004] The purpose of the present application is to overcome the defects of the prior art, and to provide a preparation method of a hyaluronic acid sodium gel for injection containing lidocaine hydrochloride. The lidocaine hydrochloride is first dissolved in a non-cross-linked hyaluronic acid sodium solution, and then a self-rotation and revolution stirring method is used to make it uniformly dispersed, so as to improve the uniformity of the distribution of lidocaine hydrochloride in the gel, and to make it easier to realize industrialized production.

[0005] The technical solution for realizing the above-mentioned purpose is as follows: a preparation method of a hyaluronic acid sodium gel for injection containing lidocaine hydrochloride, comprising the following steps:

[0006] S1, a dissolving step: dissolving hyaluronic acid sodium in a sodium hydroxide solution at room temperature to obtain a hyaluronic acid sodium alkali solution;

[0007] S2, a cross-linking step: adding a cross-linking agent to the hyaluronic acid sodium alkali solution, stirring and mixing, and then performing a cross-linking reaction to obtain a hyaluronic acid sodium gel;

[0008] S3, elution step: the cross-linking reaction obtained sodium hyaluronate gel is broken into blocks, and is eluted with a PB (phosphate buffer solution) buffer solution having a pH of 8-10 and an osmotic pressure of 400-1000 mOsm / L, the elution temperature is 30-70°C, and the elution time is 1-4 days; after elution, the blocky sodium hyaluronate gel is filtered out;

[0009] S4, swelling step: the eluted blocky sodium hyaluronate gel is swelled at room temperature with a PBS (phosphate buffered saline) buffer solution having a pH of 6.0-8.0 and an osmotic pressure of 250-320 mOsm / L, and the operation is repeated 2-3 times to adjust the osmotic pressure and pH of the blocky sodium hyaluronate gel;

[0010] S5, granulation step: the blocky sodium hyaluronate gel obtained after swelling is removed of excess water, is sieved, and sodium hyaluronate gel particles are obtained;

[0011] S6, non-cross-linked sodium hyaluronate solution preparation step: a non-cross-linked sodium hyaluronate solution containing sodium hyaluronate, lidocaine hydrochloride, sodium chloride, disodium hydrogen phosphate, and sodium dihydrogen phosphate is prepared, wherein the content of sodium hyaluronate is 10-25 mg / ml, and the content of lidocaine hydrochloride is 10-700 mg / ml;

[0012] S7, mixing step: the sodium hyaluronate gel particles obtained in step S5 and the non-cross-linked sodium hyaluronate solution obtained in step S6 are mixed uniformly in a ratio of 3-200:1 by mass using a self-rotation and revolution stirrer to obtain a lidocaine hydrochloride-containing sodium hyaluronate gel semi-finished product for injection.

[0013] The above method for preparing a lidocaine hydrochloride-containing sodium hyaluronate gel for injection, in step S1, the mass fraction of sodium hyaluronate in the sodium hyaluronate alkali solution is 8%-15%, the molecular weight of sodium hyaluronate is 1 x 10 6 -3 x 10 6 Da, and the mass fraction of sodium hydroxide solution is 0.5-2%.

[0014] The above method for preparing a lidocaine hydrochloride-containing sodium hyaluronate gel for injection, in step S2, the cross-linking agent is one or more of 1,4-butanediol diglycidyl ether (BDDE), divinyl sulfone (DVS), and a polyepoxy compound.

[0015] The preparation method of the above-mentioned lidocaine hydrochloride-containing sodium hyaluronate gel for injection, in step S2, the amount of the crosslinking agent added is 5-25% of the weight of the sodium hyaluronate; the crosslinking reaction temperature is 20-50 DEG C, and the crosslinking time is 12-48 h.

[0016] The preparation method of the above-mentioned lidocaine hydrochloride-containing sodium hyaluronate gel for injection, in step S6, the molecular weight of the sodium hyaluronate in the non-crosslinked sodium hyaluronate solution is 1x10 6 ~ 3x10 6 Da.

[0017] The preparation method of the above-mentioned lidocaine hydrochloride-containing sodium hyaluronate gel for injection, in step S7, the rotation speed of the rotation-revolution agitator is 100-3000 rpm, and the revolution speed is 100-3000 rpm.

[0018] The preparation method of the lidocaine hydrochloride-containing sodium hyaluronate gel for injection of the present application has a simple preparation process, the lidocaine hydrochloride and the lubricant are mixed in advance, then the self-rotation and revolution mixing mode is adopted to mix the gel particles, the time for adding the lidocaine hydrochloride is greatly shortened, the lidocaine hydrochloride is uniformly distributed in the gel, the complex process of dialysis and then adding the lubricant is avoided, the waste of the lidocaine hydrochloride in the dialysate is reduced, the pollution risk in the gel production process is reduced, and the gel structure and the physical and chemical properties are not damaged due to the introduction of mechanical stirring. DETAILED DESCRIPTION

[0019] In order for those skilled in the art to better understand the technical solutions of the present application, the specific embodiments thereof are described in detail below, and all the following examples are used to better illustrate and explain the core idea of the present application, and cannot limit the protection scope of the present application. Other researchers in the field can make any changes and improvements on the basis of the core idea, and such similar changes are also within the protection scope of the present application.

[0020] Example 1

[0021] A lidocaine hydrochloride-containing sodium hyaluronate gel for injection, the preparation method comprising the following steps:

[0022] S1, dissolving step: at room temperature, 88 mL of 1 wt% NaOH solution is prepared, 12 g of sodium hyaluronate dry powder with a molecular weight of 1.5x10 6 Da is added thereto and stirred until dissolved uniformly to obtain a sodium hyaluronate alkali solution;

[0023] S2, cross-linking step: 1200 μL of BDDE was added to the sodium hyaluronate alkali solution, and after uniform stirring, it was placed in a 25°C environment for 24 h of reaction to obtain a sodium hyaluronate gel;

[0024] S3, elution step: the sodium hyaluronate gel obtained by cross-linking reaction was crushed into 1 cm 3 squares, and elution was performed with a PB buffer solution having a pH of 8.5 and an osmotic pressure of 500 mOsmol / L, the elution temperature was set to 40°C, and the elution time was 48 h, and after elution, the blocky sodium hyaluronate gel was filtered out;

[0025] S4, swelling step: the blocky sodium hyaluronate gel after elution was swelled with a PBS buffer solution having a pH of 7.2 and an osmotic pressure of 280 mOsmol / L, and the PBS buffer solution was replaced twice to adjust the osmotic pressure and pH of the blocky sodium hyaluronate gel;

[0026] S5, granulation step: the blocky sodium hyaluronate gel obtained after swelling was removed of excess water, and passed through a 45-mesh sieve to obtain sodium hyaluronate gel particles;

[0027] S6, non-cross-linked sodium hyaluronate solution preparation step: 1.5 x 10 6 Da sodium hyaluronate dry powder and lidocaine hydrochloride were added to a PBS solution and stirred until dissolved to make the sodium hyaluronate (HA) content 12 mg / ml and the lidocaine hydrochloride content 300 mg / ml;

[0028] S7, mixing step: the sodium hyaluronate gel particles obtained in step S5 and the non-cross-linked sodium hyaluronate solution obtained in step S6 were mixed uniformly in a ratio of 99:1 by mass using a self-rotation and revolution stirrer, the self-rotation speed was 1500 rpm, the revolution speed was 300 rpm, the time was controlled for 20 min, and a lidocaine hydrochloride-containing sodium hyaluronate gel semi-finished product for injection of Example 1 was obtained.

[0029] Example 2:

[0030] A lidocaine hydrochloride-containing sodium hyaluronate gel for injection, the preparation method comprising the following steps:

[0031] S1, dissolving step: at room temperature, 88 mL of 1 wt% NaOH solution was prepared, and 12 g of 1.5 x 10 6 Da sodium hyaluronate dry powder was added and stirred until dissolved to obtain a sodium hyaluronate alkali solution;

[0032] S2, cross-linking step: 1560 μL of BDDE was added to the sodium hyaluronate alkali solution, and after uniform stirring, it was placed in a 25°C environment for 24 h of reaction to obtain a sodium hyaluronate gel;

[0033] S3, elution step: the cross-linked hyaluronic acid sodium gel obtained in the cross-linking step was crushed into 1 cm 3 sized blocks, and eluted with a PB buffer solution having a pH of 8.5 and an osmotic pressure of 500 mOsmol / L, the elution temperature was set to 40°C, and the elution time was 48 h, and the blocky hyaluronic acid sodium gel was filtered out after elution;

[0034] S4, swelling step: the blocky hyaluronic acid sodium gel after elution was swelled with a PBS buffer solution having a pH of 7.2 and an osmotic pressure of 280 mOsmol / L, and the PBS buffer solution was replaced twice to adjust the osmotic pressure and pH of the blocky hyaluronic acid sodium gel;

[0035] S5, granulation step: the blocky hyaluronic acid sodium gel after swelling was removed of excess water, and passed through a 45-mesh sieve to obtain hyaluronic acid sodium gel particles;

[0036] S6, non-cross-linked hyaluronic acid sodium solution preparation step: 13 g of hyaluronic acid sodium dry powder having a molecular weight of 1.5 x 10 6 Da and 0.5 g of lidocaine hydrochloride were stirred until dissolved to make the hyaluronic acid sodium (HA) content 14 mg / ml and the lidocaine hydrochloride content 100 mg / ml;

[0037] S7, mixing step: the hyaluronic acid sodium gel particles obtained in step S5 and the non-cross-linked hyaluronic acid sodium solution obtained in step S6 were mixed uniformly in a ratio of 97:3 by mass using a self-rotation and revolution stirrer, the self-rotation speed was 1500 rpm, the revolution speed was 300 rpm, and the time was controlled to 20 min, to obtain the hyaluronic acid sodium gel semi-finished product for injection containing lidocaine hydrochloride of Example 2.

[0038] Example 3

[0039] A hyaluronic acid sodium gel for injection containing lidocaine hydrochloride, the preparation method comprising the following steps:

[0040] S1, dissolving step: 87 mL of 1 wt% NaOH solution was prepared at room temperature, and 13 g of hyaluronic acid sodium dry powder having a molecular weight of 1.5 x 10 6 Da was added and stirred until dissolved uniformly to obtain a hyaluronic acid sodium alkali solution;

[0041] S2, cross-linking step: 1690 μL of BDDE was added to the hyaluronic acid sodium alkali solution, and after stirring uniformly, it was placed in a 25°C environment for 24 h to obtain a hyaluronic acid sodium gel;

[0042] S3, elution step: the cross-linked hyaluronic acid sodium gel obtained in the cross-linking step was crushed into 1 cm 3The block-shaped sodium hyaluronate gel is eluted with PB buffer solution with pH 8.5 and osmotic pressure 500 mOsmol / L, the elution temperature is set to 40 DEG C, and the elution time is 48 h; and the block-shaped sodium hyaluronate gel is filtered after elution;

[0043] S4, swelling step: the eluted block-shaped sodium hyaluronate gel is swelled with PBS buffer solution with pH 7.2 and osmotic pressure 280 mOsmol / L, and the PBS buffer solution is replaced twice to adjust the osmotic pressure and pH of the block-shaped sodium hyaluronate gel;

[0044] S5, granulation step: the block-shaped sodium hyaluronate gel obtained after swelling is removed of excess water and filtered through a 45-mesh screen to obtain sodium hyaluronate gel particles;

[0045] S6, non-crosslinked sodium hyaluronate solution preparation step: 1.5*10 6 The sodium hyaluronate dry powder with a molecular weight of 1.5*10

[0046] S7, mixing step: the sodium hyaluronate gel particles obtained in step S5 and the non-crosslinked sodium hyaluronate solution obtained in step S6 are mixed uniformly in a ratio of 99:1 by mass using a self-rotation and revolution stirrer, the self-rotation speed is 1500 rpm, the revolution speed is 300 rpm, and the time is controlled to be 20 min, to obtain the lidocaine hydrochloride-containing sodium hyaluronate gel semi-finished product of example 3.

[0047] Test experiment:

[0048] The HA and lidocaine hydrochloride contents of the material bodies of one point in each of the upper, middle and lower three layers of the sodium hyaluronate gel semi-finished products of examples 1-3 are determined, and the results are shown in table 1.

[0049] Table 1, HA and lidocaine hydrochloride content determination results of each sampling point of examples 1-3:

[0050]

[0051]

[0052] The results in table 1 show that the non-crosslinked sodium hyaluronate solution and the sodium hyaluronate gel particles are mixed uniformly under the self-rotation and revolution stirring for 20 min, compared with the mixing of the dialysis and the addition of lidocaine and the lubricant, a large amount of time is saved, the process is simplified, the risk of product contamination is reduced, the difficulty of mechanical stirring of the high viscoelastic fluid is avoided, and the non-uniform dispersion of the crosslinked phase is avoided.

[0053] The preparation method of the hyaluronic acid sodium gel for injection containing lidocaine hydrochloride can obtain the hyaluronic acid sodium gel with uniform distribution of lidocaine hydrochloride, and the process steps are simple.

[0054] In conclusion, the preparation method of the hyaluronic acid sodium gel for injection containing lidocaine hydrochloride of the present application can dissolve lidocaine hydrochloride into non-crosslinked hyaluronic acid sodium solution first, and then uniformly disperse it by self-rotation and revolution stirring, so as to improve the uniformity of distribution of lidocaine hydrochloride in the gel, and more easily realize industrialized production.

[0055] Those skilled in the art of the present technology should recognize that the above embodiments are only used to illustrate the present application, and are not used as a limitation of the present application, and as long as the above described embodiments are changed and modified within the scope of the spirit of the present application, they will fall within the scope of the claims of the present application.

Claims

1. A process for the preparation of a lidocaine hydrochloride containing sodium hyaluronate gel for injection, characterized in that, The method comprises the following steps: S1, dissolving step: sodium hyaluronate is dissolved in sodium hydroxide solution to prepare an alkali solution of sodium hyaluronate at room temperature; the mass fraction of sodium hyaluronate in the alkali solution of sodium hyaluronate is 8% to 15%, the molecular weight of sodium hyaluronate is 1 x 10 6 ~ 3 x 10 6 Da, and the mass fraction of sodium hydroxide solution is 0.5 to 2%. S2, a cross-linking step: adding a cross-linking agent to the sodium hyaluronate alkali solution, stirring and mixing, and then performing a cross-linking reaction to obtain a sodium hyaluronate gel; the cross-linking agent is added in an amount of 5-25% by weight of the sodium hyaluronate, the cross-linking reaction temperature is 20-50°C, and the cross-linking time is 12-48 hours; S3, an elution step: crushing the sodium hyaluronate gel obtained by the cross-linking reaction into blocks, and eluting the blocks with a PB buffer solution having a pH of 8-10 and an osmotic pressure of 400-1000 mOsm / L, at an elution temperature of 30-70°C and an elution time of 1-4 days; after the elution is completed, the block-shaped sodium hyaluronate gel is filtered out; S4, a swelling step: swelling the block-shaped sodium hyaluronate gel obtained after the elution with a PBS buffer solution having a pH of 6.0-8.0 and an osmotic pressure of 250-320 mOsm / L at room temperature, repeating the operation 2-3 times, and adjusting the osmotic pressure and pH of the block-shaped sodium hyaluronate gel; S5, a granulation step: removing excess water from the block-shaped sodium hyaluronate gel obtained after the swelling, sieving, and obtaining sodium hyaluronate gel particles; S6, the non-crosslinked sodium hyaluronate solution preparation step: preparing a non-crosslinked sodium hyaluronate solution containing sodium hyaluronate, lidocaine hydrochloride, sodium chloride, disodium hydrogen phosphate and sodium dihydrogen phosphate, wherein the content of sodium hyaluronate is 10-25 mg / ml, the content of lidocaine hydrochloride is 10-700 mg / ml; the molecular weight of sodium hyaluronate in the non-crosslinked sodium hyaluronate solution is 1 x 10 6 ~3 x 10 6 Da; S7, a mixing step: uniformly mixing the sodium hyaluronate gel particles obtained in step S5 and the non-cross-linked sodium hyaluronate solution obtained in step S6 in a ratio of 3-200:1 by mass using a self-rotation and revolution stirring machine, and obtaining a lidocaine hydrochloride-containing sodium hyaluronate gel semi-finished product for injection.

2. A process for the preparation of a lidocaine hydrochloride containing sodium hyaluronate gel for injection according to claim 1, characterized in that, In step S2, the cross-linking agent is one or more of 1,4-butanediol diglycidyl ether, divinyl sulfone, and a polyepoxide compound.

3. A process for the preparation of a lidocaine hydrochloride containing sodium hyaluronate gel for injection according to claim 1, characterized in that, In step S7, the revolution speed of the self-rotation and revolution stirring machine is 100-3000 rpm, and the rotation speed is 100-3000 rpm.

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