Adapalene gel and preparation method thereof

Abstract

The invention relates to adapalene gel and a preparation method thereof, and relates to the technical field of medicines, the adapalene gel comprises adapalene, a humectant, a bacteriostatic agent, a gel matrix, a metal chelating agent, a surfactant, a pH regulator and purified water; the preparation method comprises the following steps: adding the metal chelating agent and part of purified water into a dissolving tank, stirring and dissolving the humectant and the bacteriostatic agent, and slowly adding into the dissolving tank to obtain a mixed solution I; adding the gel matrix into the dissolving tank in a shearing state to obtain a mixed solution II; carrying out ultrasonic treatment on adapalene, a surfactant and part of purified water under the action of an ultrasonic instrument until the raw materials are uniformly dispersed, and adding into the mixed solution II to obtain a mixed solution III; stirring and shearing the mixed solution III. According to the preparation method, the gel matrix is added into the mixed solution I in a shearing state, the gel matrix can be completely swelled within 10 minutes, no obvious block mass exists, and the production efficiency is high; the ultrasonic pre-dispersion of adapalene is increased, so that the agglomeration condition of the raw materials is remarkably improved, and the content uniformity of the preparation is improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, in particular to a kind of adapalene gel and preparation method thereof. BACKGROUND

[0002] Adapalene gel is a commonly used topical tretinoin drug, mainly used for the treatment of acne (pimples) and improve skin keratosis. Its main component is adapalene (Adapalene), the chemical name is 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthalene carboxylic acid. Adapalene belongs to the third generation of tretinoin derivatives, the mechanism of action is to regulate the differentiation of hair follicle keratinocytes, reduce blockage, improve acne, closed. The indications of this product are suitable for the treatment of skin with acne, papules and pustules as the main performance of acne vulgaris, and can also be used for the treatment of acne on the face, chest and back.

[0003] Patent CN103462882B discloses a kind of adapalene gel and preparation method thereof, when preparing: (1) according to the weight of the raw material of the composition, carbomer is weighed, then soak in purified water for 24h, pass through 40 mesh screen, for standby use;(2) according to the weight of the raw material of the composition, adapalene raw material, appropriate propylene glycol is weighed into stainless steel barrel, then according to the weight, sodium hydroxide is dissolved in appropriate purified water, added into the above-mentioned stainless steel barrel, then water bath at 50 DEG C temperature for 2h, ensure that the raw material is completely dissolved;(3) according to the weight of the raw material of the composition, hydroxybenzoic acid ester, phenoxyethanol, poloxamer and the remaining propylene glycol are stirred into beaker, and dissolved to clear with water bath at 50 DEG C temperature, wait for use;(4) according to the weight of the raw material of the composition, edetate disodium is weighed into main pot, then add appropriate purified water, low speed stirring dissolves, then the solution in beaker in step (3) is poured into main pot, stirring dissolves;(5) the standby raw material of step (1) is poured into the main pot of step (4), slow stirring 15min into uniform gel matrix, open main pot, the solution of step (2) is passed through 200 mesh screen and poured into the above-mentioned gel matrix, vacuum stirring 40min, according to the weight, add essence and adjust the PH of mixed solution to 5, continue to stir 30min, vacuum degassing, discharge, in clean area, composite hose is filled, tail is sealed and packaged. In the method, carbomer is used in the way of scattering on the water surface and swelling overnight, which consumes time and has low efficiency;And the dispersion uniformity of adapalene raw material is poor, which is easy to cause the aggregation of raw materials in preparation, and the content uniformity of preparation is poor.

[0004] Therefore, it is necessary to develop a kind of adapalene gel with high production efficiency, less raw material aggregation and good content uniformity. SUMMARY

[0005] The present application aims to provide an Adapalene gel and a preparation method thereof, which has high production efficiency, less raw material aggregation, and good preparation content uniformity, and solves the problems of time-consuming, low efficiency, poor raw material dispersion uniformity, and raw material aggregation in the prior art. To achieve this goal, the present application adopts the following technical solutions:

[0006] The present application provides an Adapalene gel in the first aspect, which comprises Adapalene, a humectant, a bacteriostatic agent, a gel base, a metal chelating agent, a surfactant, a pH regulator, and purified water.

[0007] The humectant comprises one or more of propylene glycol, glycerol, sorbitol, and polyethylene glycol; the bacteriostatic agent comprises one or more of methylparaben, ethylparaben, phenoxyethanol, potassium sorbate, and sodium benzoate; the gel base comprises one or more of Carbomer homopolymer type C 980 NF, hydroxypropyl methylcellulose, and sodium carboxymethylcellulose; the metal chelating agent comprises one or more of disodium edetate, calcium disodium edetate, sodium citrate, and sodium gluconate; the surfactant comprises poloxamer 182; and the pH regulator comprises sodium hydroxide.

[0008] As an embodiment of the present application, the humectant is propylene glycol; the bacteriostatic agent is methylparaben and phenoxyethanol; the gel base is Carbomer homopolymer type C 980 NF; the metal chelating agent is disodium edetate; the surfactant is poloxamer 182; and the pH regulator is sodium hydroxide.

[0009] As an embodiment of the present application, the weight content of each component of the Adapalene gel is as follows: 1 part of Adapalene, 35-45 parts of the humectant, 2-6 parts of the bacteriostatic agent, 10-15 parts of the gel base, 1-3 parts of the metal chelating agent, 1-3 parts of the surfactant, 1-3 parts of the pH regulator, and 900-1000 parts of purified water.

[0010] As an embodiment of the present application, the weight content of each component of the Adapalene gel is as follows: 1 part of Adapalene, 35-45 parts of propylene glycol, 1-3 parts of methylparaben, 1-3 parts of phenoxyethanol, 10-15 parts of Carbomer homopolymer type C 980 NF, 1-3 parts of disodium edetate, 1-3 parts of poloxamer 182, 1-3 parts of sodium hydroxide, and 900-1000 parts of purified water.

[0011] The present application provides a preparation method of an Adapalene gel in the second aspect, which comprises the following steps:

[0012] Step one: adding the metal chelating agent and part of the purified water into a dissolving tank and stirring until complete dissolution;

[0013] Step two, stirring and dissolving the prescription amount of moisturizer and bacteriostatic agent completely, slowly adding to the dissolving tank to obtain mixed solution one;

[0014] Step three, adding the gel matrix to the dissolving tank in a shearing state, shearing and swelling completely to obtain mixed solution two; vacuum transferring mixed solution two to the emulsifying tank;

[0015] Step four, under the action of the ultrasonic instrument, ultrasonic dispersing the prescription amount of adapalene, surfactant and part of purified water until the raw materials are uniformly dispersed, and then adding them to mixed solution two to obtain mixed solution three;

[0016] Step five, starting stirring and shearing of mixed solution three in the emulsifying tank;

[0017] Step six, mixing and completely dissolving sodium hydroxide and the remaining purified water, and adjusting the pH to 5.00±0.25.

[0018] As an embodiment of the present application, in step three, the shearing speed is 1400-1600 rpm, preferably 1500 rpm; the shearing time is 10-15 min, preferably 12 min.

[0019] As an embodiment of the present application, in step four: the ultrasonic frequency is 25-30 kHz, preferably 27.5 kHz; the ultrasonic time is 25-35 min, preferably 30 min.

[0020] As an embodiment of the present application, in step five, the shearing speed is 1800-2200 rpm, preferably 2000 rpm; the stirring speed is 40-60 rpm, preferably 50 rpm; the stirring time is 20-30 min, preferably 25 min.

[0021] As an embodiment of the present application, in step one: the amount of purified water added is 70%.

[0022] As an embodiment of the present application, in step four: the amount of purified water added is 20%.

[0023] Compared with the prior art, the present application has the following beneficial effects:

[0024] 1. In the present application, the metal chelating agent and part of purified water are first stirred and dissolved, then the moisturizer and bacteriostatic agent are stirred and dissolved, and then the gel matrix is added to the mixed solution one in a shearing state, which is swollen completely within 10 min, has good properties, no obvious carbomer lumps, and high production efficiency.

[0025] 2、The adapalene gel prepared in the application is a suspension gel. The structure of adapalene has strong hydrophobicity, and adapalene is easy to agglomerate in the gel matrix of the aqueous phase. Moreover, the raw material is micronized and has a large specific surface area, and the electrostatic effect is obvious, so it is not easy to disperse. The application increases the step of ultrasonic pre-dispersion of adapalene, so that the agglomerated lumps are obviously dispersed and improved, thereby significantly improving the agglomeration of the raw material in the preparation, avoiding the agglomeration of adapalene after long-term storage, and being beneficial to improving the content uniformity of the preparation.

[0026] 3、The application increases the shearing swelling operation when the gel matrix is added to the dissolving tank, so that the dispersion uniformity of adapalene is double guaranteed. BRIEF DESCRIPTION OF DRAWINGS

[0027] Figure 1 is the microscope photograph of the finished product of Example 1;

[0028] Figure 2 is the microscope photograph of the finished product of Comparative Example 2. DETAILED DESCRIPTION

[0029] The application will be further described below in combination with examples, but the embodiments of the application are not limited thereto.

[0030] The raw and auxiliary materials reagents / materials / equipment used in the examples can be purchased through commercial channels.

[0031] Example 1

[0032] In this embodiment, an adapalene gel and a preparation method thereof are provided, and the preparation method comprises the following steps:

[0033] Step one, 1 part of edetate disodium and 665 parts of 70% purified water are added to a dissolving tank, and stirring and dissolving are completed;

[0034] Step two, 40 parts of propylene glycol, 1 part of hydroxybenzyl alcohol and 2.5 parts of phenoxyethanol are stirred and dissolved completely, and then slowly added to the dissolving tank to obtain a mixed solution one;

[0035] Step three, 11 parts of carbomer homopolymer type C 980 NF are added to the dissolving tank under shearing, the shearing rotation speed is 1500 rpm, and the shearing time is 12 min, and the shearing swelling is completed to obtain a mixed solution two; the mixed solution two is vacuum transferred to an emulsifying tank;

[0036] Step four, 1 part of adapalene and 2 parts of poloxamer 182 are added to 20% purified water (190 parts) under the action of an ultrasonic instrument, and ultrasonic treatment is performed until the raw materials are uniformly dispersed, the ultrasonic frequency is 27.5 kHz, and the ultrasonic time is 30 min, and then the mixture is added to the mixed solution two to obtain a mixed solution three;

[0037] Step five, open the stirring and shearing of the mixed solution three in the emulsification tank, the shearing speed is 2000 rpm, the stirring speed is 50 rpm, and the time is 25 min;

[0038] Step six, mix sodium hydroxide with the remaining purified water (95 parts) to completely dissolve, and adjust the pH to 5.00±0.25.

[0039] Example 2

[0040] In this embodiment, an adapalene gel and a preparation method thereof are provided, and the preparation method comprises the following steps:

[0041] Step one, add 2 parts of edetate disodium and 630 parts of 70% purified water into a dissolving tank and stir to completely dissolve;

[0042] Step two, stir 35 parts of propylene glycol, 2 parts of hydroxybenzoic acid ester and 1 part of phenoxyethanol to completely dissolve, and slowly add them into the dissolving tank to obtain a mixed solution one;

[0043] Step three, add 10 parts of carbomer homopolymer type C 980 NF into the dissolving tank under shearing, the shearing speed is 1400 rpm, the shearing time is 10 min, and the shearing is completely swollen to obtain a mixed solution two; the mixed solution two is vacuum-transferred to an emulsification tank;

[0044] Step four, under the action of an ultrasonic instrument, ultrasonic the 1 part of adapalene and 1 part of poloxamer 182 and 180 parts of 20% purified water to be uniformly dispersed, the ultrasonic frequency is 25 kHz, the ultrasonic time is 25 min, and the mixture is added into the mixed solution two to obtain a mixed solution three;

[0045] Step five, open the stirring and shearing of the mixed solution three in the emulsification tank, the shearing speed is 1800 rpm, the stirring speed is 40 rpm, and the time is 20 min;

[0046] Step six, mix sodium hydroxide with the remaining purified water (90 parts) to completely dissolve, and adjust the pH to 5.00±0.25.

[0047] Example 3

[0048] In this embodiment, an adapalene gel and a preparation method thereof are provided, and the preparation method comprises the following steps:

[0049] Step one, add 3 parts of edetate disodium and 700 parts of 70% purified water into a dissolving tank and stir to completely dissolve;

[0050] Step two, stir 45 parts of propylene glycol, 3 parts of hydroxybenzoic acid ester and 3 parts of phenoxyethanol to completely dissolve, and slowly add them into the dissolving tank to obtain a mixed solution one;

[0051] Step three, 15 parts of Carbomer homopolymer type C 980 NF is added into the dissolving tank under shearing, the shearing speed is 1600 rpm, the shearing time is 15 min, and the shearing is completely swollen to obtain mixed solution two; the mixed solution two is vacuum transferred to the emulsifying tank;

[0052] Step four, 1 part of adapalene, 3 parts of poloxamer 182 and 20% purified water (200 parts) are ultrasonically treated under the action of an ultrasonic instrument until the raw materials are uniformly dispersed, the ultrasonic frequency is 30 kHz, the ultrasonic time is 35 min, and the mixture is added to the mixed solution two to obtain mixed solution three;

[0053] Step five, the mixed solution three in the emulsifying tank is opened for stirring and shearing, the shearing speed is 2200 rpm, the stirring speed is 60 rpm, and the time is 30 min;

[0054] Step six, sodium hydroxide and the remaining purified water (100 parts) are mixed and dissolved completely, and the pH is adjusted to 5.00±0.25.

[0055] Example 4

[0056] The present embodiment provides a kind of adapalene gel and its preparation method, the preparation method includes the following steps:

[0057] Step one, 1 part of calcium disodium ethylenediaminetetraacetate and 70% purified water (665 parts) are added into the dissolving tank and stirred to dissolve completely;

[0058] Step two, 40 parts of glycerol and 2 parts of potassium sorbate are stirred and dissolved completely, and then slowly added into the dissolving tank to obtain mixed solution one;

[0059] Step three, 11 parts of hydroxypropyl methyl cellulose is added into the dissolving tank under shearing, the shearing speed is 1500 rpm, the time is 12 min, and the shearing is completely swollen to obtain mixed solution two; the mixed solution two is vacuum transferred to the emulsifying tank;

[0060] Step four, 1 part of adapalene, 2 parts of poloxamer 182 and 20% purified water (190 parts) are ultrasonically treated under the action of an ultrasonic instrument until the raw materials are uniformly dispersed, the ultrasonic frequency is 27.5 kHz, the ultrasonic time is 30 min, and the mixture is added to the mixed solution two to obtain mixed solution three;

[0061] Step five, the mixed solution three in the emulsifying tank is opened for stirring and shearing, the shearing speed is 2000 rpm, the stirring speed is 50 rpm, and the time is 25 min;

[0062] Step six, sodium hydroxide and the remaining purified water (95 parts) are mixed and dissolved completely, and the pH is adjusted to 5.00±0.25.

[0063] Example 5

[0064] The present embodiment provides an Adapalene gel and a preparation method thereof, the preparation method comprising the following steps:

[0065] Step one, add 1 part of sodium citrate and 665 parts of 70% purified water into a dissolving tank and stir to dissolve completely;

[0066] Step two, stir to dissolve 40 parts of sorbitol and 5 parts of sodium benzoate completely, and then slowly add them into the dissolving tank to obtain a mixed solution one;

[0067] Step three, add 11 parts of sodium carboxymethyl cellulose into the dissolving tank under shearing, with a shearing rotation speed of 1500 rpm for 12 minutes, so as to be completely sheared and swelled to obtain a mixed solution two; and then the mixed solution two is transferred into an emulsifying tank under vacuum;

[0068] Step four, under the action of an ultrasonic instrument, ultrasonically disperse 1 part of Adapalene, 2 parts of poloxamer 182 and 190 parts of 20% purified water for 30 minutes at an ultrasonic frequency of 27.5 kHz, and then add them into the mixed solution two to obtain a mixed solution three;

[0069] Step five, start stirring and shearing of the mixed solution three in the emulsifying tank, with a shearing rotation speed of 2000 rpm and a stirring rotation speed of 50 rpm for 25 minutes;

[0070] Step six, mix and dissolve sodium hydroxide and the remaining purified water (95 parts) completely, and adjust the pH to 5.00±0.25.

[0071] Example 6

[0072] The present embodiment provides an Adapalene gel and a preparation method thereof, the preparation method comprising the following steps:

[0073] Step one, add 1 part of sodium citrate and 665 parts of 70% purified water into a dissolving tank and stir to dissolve completely;

[0074] Step two, stir to dissolve 40 parts of sorbitol and 5 parts of sodium benzoate completely, and then slowly add them into the dissolving tank to obtain a mixed solution one;

[0075] Step three, add 11 parts of sodium carboxymethyl cellulose into the dissolving tank under shearing, with a shearing rotation speed of 1500 rpm for 12 minutes, so as to be completely sheared and swelled to obtain a mixed solution two; and then the mixed solution two is transferred into an emulsifying tank under vacuum;

[0076] Step four, 1 part of adapalene, 2 parts of poloxamer 182 and 20% purified water (190 parts) are ultrasonically dispersed under the action of an ultrasonic instrument, the ultrasonic frequency is 27.5 kHz, the ultrasonic time is 30 min, and then they are added to the mixed solution two to obtain a mixed solution three;

[0077] Step five, the mixed solution three in the emulsification tank is stirred and sheared at a shearing speed of 2000 rpm and a stirring speed of 50 rpm for 25 min.

[0078] Step six, sodium hydroxide and the remaining purified water (95 parts) are mixed and dissolved completely, and the pH is adjusted to 5.00±0.25.

[0079] Comparative example 1

[0080] The embodiment provides an adapalene gel and a preparation method thereof, and the preparation method comprises the following steps:

[0081] Step one, 1 part of edetate disodium and 70% purified water (665 parts) are added into a dissolving tank and stirred and dissolved completely.

[0082] Step two, 40 parts of propylene glycol, 1 part of hydroxybenzoic acid methyl ester and 2.5 parts of phenoxyethanol are stirred and dissolved completely, and then slowly added into the dissolving tank to obtain a mixed solution one.

[0083] Step three, 11 parts of carbomer homopolymer type C 980 NF are added into the dissolving tank under shearing at a shearing speed of 1500 rpm for 12 min, and then sheared and swelled completely to obtain a mixed solution two; the mixed solution two is vacuum-transferred into an emulsification tank.

[0084] Step four, 1 part of adapalene, 2 parts of poloxamer 182 and 20% purified water (190 parts) are ultrasonically dispersed under the action of an ultrasonic instrument, the ultrasonic frequency is 27.5 kHz, the ultrasonic time is 30 min, and then they are added to the mixed solution two to obtain a mixed solution three.

[0085] Step five, the mixed solution three in the emulsification tank is stirred at a stirring speed of 50 rpm for 25 min.

[0086] Step six, sodium hydroxide and the remaining purified water (95 parts) are mixed and dissolved completely, and the pH is adjusted to 5.00±0.25.

[0087] Comparative example 2

[0088] The embodiment provides an adapalene gel and a preparation method thereof, and the preparation method comprises the following steps:

[0089] Step one, 1 part of edetate disodium and 70% purified water (665 parts) are added into a dissolving tank and stirred and dissolved completely.

[0090] Step two, propylene glycol 40 parts, hydroxybenzoic acid ester 1 part, phenoxyethanol 2.5 parts were stirred and dissolved completely, slowly added to the dissolution tank to obtain mixed solution one;

[0091] Step three, carbomer homopolymer type C 980 NF 11 parts were added to the dissolution tank under shearing at a shearing speed of 1500 rpm for 12 min, and shearing was completed to obtain mixed solution two. The mixed solution two was vacuum transferred to the emulsification tank;

[0092] Step four, adapalene 1 part, poloxamer 182 2 parts and 20% purified water (190 parts) were mixed and stirred and dispersed, and then added to the mixed solution two to obtain mixed solution three;

[0093] Step five, the mixed solution three in the emulsification tank was stirred and sheared at a shearing speed of 2000 rpm and a stirring speed of 50 rpm for 25 min;

[0094] Step six, sodium hydroxide and the remaining purified water (95 parts) were mixed and dissolved completely, and the pH was adjusted to 5.00±0.25.

[0095] Content uniformity test

[0096] The gels prepared in Examples 1-6 and Comparative Examples 1-2 were taken to measure the content of the preparation in different parts (sample numbers 1-3 were the upper part of the preparation container, sample numbers 4-6 were the middle part, and 7-10 were the lower part). In Examples 1-6, the RSD was less than or equal to 2%, which was within the acceptable standard of 2%, and the content uniformity was good. In Comparative Examples 1-2, the RSD was greater than 2%, which was greater than the acceptable standard of 2%, indicating that there were differences in the content of the upper, middle and lower parts of the tank, the content uniformity was lacking, and it was indicated that the removal of the shearing step and the ultrasonic step of the raw materials had a significant effect on the content uniformity of the preparation. The content uniformity results of each example and comparative example are shown in Tables 1-8 below.

[0097] Table 1: Content uniformity results of Example 1

[0098]

[0099] Table 2: Content uniformity results of Example 2

[0100]

[0101]

[0102] Table 3: Content uniformity results of Example 3

[0103]

[0104] Table 4: Example 4 content uniformity results

[0105]

[0106] Table 5: Example 5 content uniformity results

[0107]

[0108] Table 6: Example 6 content uniformity results

[0109]

[0110] Table 7: Comparative Example 1 content uniformity results

[0111]

[0112]

[0113] Table 8: Comparative Example 2 content uniformity results

[0114]

Claims

1. An adapalene gel, characterized in that: Including adapalene, humectants, antibacterial agents, gel matrix, metal chelating agents, surfactants, pH adjusters, and purified water; The humectant includes one or more of propylene glycol, glycerin, sorbitol, and polyethylene glycol; the antibacterial agent includes one or more of methylparaben, ethylparaben, phenoxyethanol, potassium sorbate, and sodium benzoate; the gel matrix includes one or more of carbomer homopolymer C-type 980NF, hydroxypropyl methylcellulose, and sodium carboxymethyl cellulose; the metal chelating agent includes one or more of disodium edetate, calcium disodium EDTA, sodium citrate, and sodium gluconate; the surfactant includes poloxamer 182; and the pH adjuster includes sodium hydroxide.

2. The adapalene gel according to claim 1, characterized in that: The humectant is propylene glycol; the antibacterial agent is methylparaben and phenoxyethanol; the gel matrix is ​​carbomer homopolymer C-type 980NF; the metal chelating agent is disodium edetate; the surfactant is poloxamer 182; and the pH adjuster is sodium hydroxide.

3. An adapalene gel according to claim 2, characterized in that, The weight contents of each component of the adapalene gel are as follows: 1 part adapalene, 35-45 parts humectant, 2-6 parts antibacterial agent, 10-15 parts gel matrix, 1-3 parts metal chelating agent, 1-3 parts surfactant, 1-3 parts pH adjuster, and 900-1000 parts purified water.

4. An adapalene gel according to claim 3, characterized in that, The weight contents of each component of the adapalene gel are as follows: adapalene 1 part, propylene glycol 35-45 parts, methylparaben 1-3 parts, phenoxyethanol 1-3 parts, carbomer homopolymer C type 980NF 10-15 parts, disodium edetate 1-3 parts, poloxamer 182 1-3 parts, sodium hydroxide 1-3 parts, and purified water 900-1000 parts.

5. A method for preparing adapalene gel according to any one of claims 1-4, characterized in that, The preparation method includes the following steps: Step 1: Add the metal chelating agent and some purified water to the dissolving tank and stir until completely dissolved; Step 2: Stir and dissolve the prescribed amount of moisturizer and antibacterial agent completely, then slowly add them to the dissolving tank to obtain mixed solution one; Step 3: Add the gel matrix to the dissolving tank under shear conditions, and allow it to swell completely to obtain mixed solution 2; transfer mixed solution 2 to the emulsifying tank under vacuum. Step 4: Under the action of an ultrasonic instrument, the prescribed amount of adapalene, surfactant and part of purified water are ultrasonically dispersed until the raw materials are evenly dispersed, and then added to mixed solution 2 to obtain mixed solution 3; Step 5: Start stirring and shearing the mixed solution in the emulsification tank. Step 6: Mix sodium hydroxide with the remaining purified water until completely dissolved, and adjust the pH to 5.00±0.

25.

6. The preparation method according to claim 5, characterized in that: In step three, the shearing speed is 1400-1600 rpm, preferably 1500 rpm; the shearing time is 10-15 min, preferably 12 min.

7. The preparation method according to claim 5, characterized in that, In step four: the ultrasonic frequency is 25-30 kHz, preferably 27.5 kHz; the ultrasonic time is 25-35 min, preferably 30 min.

8. The preparation method according to claim 5, characterized in that, In step five, the shearing speed is 1800-2200 rpm, preferably 2000 rpm; the stirring speed is 40-60 rpm, preferably 50 rpm; and the stirring time is 20-30 min, preferably 25 min.

9. The preparation method according to claim 5, characterized in that, In step one: the amount of purified water added is 70%.

10. The preparation method according to claim 5, characterized in that, In step four: the amount of purified water added is 20%.

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