Preparation method of gel

Abstract

The invention discloses an adapalene gel preparation method, which comprises: 1) preparing a carbomer phase: mixing a first solution and a second solution to obtain a mixed solution, and adding carbomer into the mixed solution, the first solution being obtained by mixing edetate disodium and water, the second solution being obtained by mixing edetate disodium and water, and the first solution being obtained by mixing edetate disodium and water; the second solution is obtained by mixing phenoxyethanol, methylparaben and propylene glycol; 2) preparation of adapalene phase: adding water into poloxamer to obtain a solution, and then adding adapalene into the solution; and 3) total mixing: mixing the adapalene phase and the carbomer phase while stirring to obtain a gel precursor, and then degassing, filling and sealing the gel precursor.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and particularly relates to a preparation method of adapalene gel. BACKGROUND

[0002] Adapalene is a widely used vitamin A acid drug for treating mild to moderate acne vulgaris. The main component of adapalene gel is adapalene, which is a vitamin A acid analogue with antibacterial and anti-inflammatory effects. Adapalene can penetrate into hair follicles and sebaceous glands, inhibit bacterial growth, reduce inflammatory reactions, and promote skin repair and regeneration. Adapalene gel can regulate the differentiation of hair follicle epithelial cells, reduce the formation of microcomedones, and inhibit the production of inflammatory mediators, thereby alleviating the inflammatory response of acne. This mechanism helps to keep pores clean and reduce local inflammation, thereby improving acne symptoms.

[0003] The preparation process of adapalene gel needs to strictly control the quality of raw materials and the preparation process to ensure the quality and efficacy of the drug. During the preparation process, it is necessary to avoid the contact of the drug with air, moisture and impurities to reduce the degradation and contamination of the drug. At the same time, strict quality control of the drug is also needed during the preparation process, including content determination, microbial limit test, etc., to ensure the safety and effectiveness of the drug.

[0004] Adapalene has very low solubility in water and is prone to form large particles during preparation, affecting drug efficacy and patient experience. Therefore, how to prepare an adapalene gel with small particle size, good stability and significant efficacy has been a research hotspot in the field of pharmaceutical preparations.

[0005] In the prior art, although there are many preparation methods of adapalene gel, there are still some problems. For example, some preparation methods use excipients or additives that may adversely affect the stability and efficacy of adapalene; or the preparation process is complex and difficult to control product quality.

[0006] Specifically, for example, CN116139071A discloses a preparation method of adapalene gel, which improves the specific process, disperses adapalene and poloxamer 188 in ethanol, and uses a spray drying method to prepare a solid dispersion. This method does not need to add additional excipients such as transdermal absorption enhancers, relies on the improvement of the preparation process to improve the transdermal rate, but needs a spray drying process, which is not only complicated, but also the stability of the obtained gel is poor.

[0007] Therefore, it is of great significance to develop a simple, efficient and stable preparation method of adapalene gel. SUMMARY

[0008] The application provides an optimized gelatinous adalaline and a preparation method thereof.

[0009] To solve the above technical problems, the technical scheme provided by the application is as follows.

[0010] A preparation method of gelatinous adalaline, comprising:

[0011] 1) Preparation of carbomer phase: a mixture solution is obtained by mixing the first solution and the second solution, and then carbomer is added into the mixture solution, wherein the first solution is obtained by mixing disodium edetate and water, and the second solution is obtained by mixing phenoxyethanol, hydroxybenzyl and propylene glycol;

[0012] 2) Preparation of adalaline phase: a solution is obtained by adding poloxamer into water, and then adalaline is added into the solution;

[0013] 3) Total mixing: the adalaline phase and the carbomer phase are mixed to obtain a gelatinous precursor, and then the gelatinous precursor is degassed, filled and sealed, wherein,

[0014] The gelatinous adalaline comprises the following raw material components in percentage by weight:

[0015] 0.1-0.3% of adalaline

[0016] 0.1-0.5% of poloxamer

[0017] 1-5% of propylene glycol

[0018] 0.1-1% of phenoxyethanol

[0019] 0.1-1% of hydroxybenzyl

[0020] 0.05-0.5% of disodium edetate

[0021] 0.5-3% of carbomer

[0022] an appropriate amount of neutralizer

[0023] purified water is added to 100%.

[0024] Further, in percentage by mass, the carbomer: disodium edetate: propylene glycol: hydroxybenzyl: phenoxyethanol in the carbomer phase is 1.1:0.1:4:0.1:0.25, and the poloxamer: adalaline in the adalaline phase is 0.2:0.1.

[0025] Further, the carbomer is selected from carbomer 980 and carbomer 940.

[0026] Further, the D90 of the adapalene is less than or equal to 6 microns.

[0027] Further, the D90 of the adapalene is 4.81-5.56 microns.

[0028] Further, the carbomer is sifted through a 40-mesh sieve and then added to the mixture.

[0029] Further, in the 3) total mixing process, the stirring conditions are as follows: the stirring speed is 50-200 rpm, the homogenization speed is 8000-12000 rpm, and the stirring time is 10-20 min.

[0030] Further, in the 3) total mixing process, the sodium hydroxide solution is added while stirring, and the pH value is adjusted to 4.5-5.0.

[0031] The present application also provides an adapalene gel prepared by the above-mentioned method for preparing an adapalene gel.

[0032] Compared with the prior art, the method for preparing the adapalene gel has the following advantages:

[0033] Small particle size: through specific raw material ratio and fine preparation process, the prepared adapalene gel has small particle size, is easy to be absorbed by the skin, and improves the drug efficacy;

[0034] Good stability: appropriate excipients and preparation process are used to ensure that the adapalene gel has good stability during storage and use;

[0035] Good absorbability: the optimized adapalene gel shows significant absorbability in clinical application, and is suitable for the treatment of mild to moderate acne vulgaris. DETAILED DESCRIPTION

[0036] The technical solutions in the embodiments of the present application will be clearly described below in combination with the embodiments of the present application. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art belong to the scope of protection of the present application.

[0037] The terms "first", "second", etc. in the specification and claims of the present application are used to distinguish similar objects, and are not used to describe a particular order or sequence. It should be understood that the data thus used can be interchanged under appropriate circumstances so that the embodiments of the present application can be implemented in an order other than that described herein, and the objects distinguished by "first", "second", etc. are generally a class and do not limit the number of objects, for example, the first object can be one or more. In addition, "and / or" in the specification and claims indicates at least one of the connected objects, and the character " / ", generally indicates that the front and rear associated objects are in an "or" relationship.

[0038] Example 1

[0039] Formulation

[0040]

[0041] 1) Preparation of Carbomer Phase

[0042] Sodium edetate was added to water and stirred to dissolve, to obtain a first solution. Phenoxyethanol, hydroxybenzoic acid methyl ester, and propylene glycol were mixed and stirred to dissolve, to obtain a second solution. The first solution and the second solution were mixed, washed with solution 1, to obtain a mixture. Carbomer was passed through a 40-mesh sieve and allowed to stand for 24 hours, then added to the solution, and soaked for 24 hours, and then slowly stirred to swell and added to the above mixture.

[0043] 2) Preparation of Adapalene Phase

[0044] Poloxamer was added to water and stirred to dissolve, then adapalene was added and stirred to disperse uniformly.

[0045] 3) Total Mixing

[0046] The prescribed amount of 0.18% sodium hydroxide was weighed and added to water and stirred to dissolve. The adapalene phase was added while stirring, and the carbomer phase was used to rinse, wherein the stirring speed was 100 rpm, the homogenization speed was 10,000 rpm, and the stirring time was 15 min. The sodium hydroxide solution was added while stirring, and the pH value was adjusted to 4.75, then washed with the remaining water, to obtain a gel precursor, wherein the vacuum degree was -0.08 MPa, the stirring speed was 100 rpm, and the stirring time was 30 min. Sampling was performed to detect the content uniformity of the upper, middle, and lower portions. The gel precursor was transferred to a vacuum stirring tank, the vacuum pump was turned on for degassing treatment to remove air bubbles. The degassed gel precursor was transferred to a filling device, and filling, sealing, and other operations were performed, to obtain an adapalene gel.

[0047] Stability test

[0048] The impurities of the obtained adapalene gel were detected by the following method:

[0049] 1. Preparation of Test Solution

[0050] Accurately weigh 4.0 g of Adapalene Gel into a 20 ml volumetric flask.

[0051] Add tetrahydrofuran 10 ml, shake vigorously (vortex if necessary).

[0052] Ultrasonic for 10 minutes to disperse, then cool.

[0053] Add solvent acetonitrile-tetrahydrofuran-water (37:20:43) to dilute to the mark, shake well.

[0054] Centrifuge, and filter using 0.45 μm PTFE filter membrane.

[0055] 2. Preparation of Control Solution and Other Solutions

[0056] Control Solution: Accurately pipette 1 ml of Test Solution into a 200 ml volumetric flask, dilute to the mark with solvent, and shake well.

[0057] System Suitability Solution: Prepared using Impurity C Reference Standard and Adapalene Reference Standard to ensure that the resolution between Impurity C and Adapalene peaks is greater than 4.5, and the signal-to-noise ratio is greater than 10.

[0058] Blank Vehicle Solution: Another blank vehicle is prepared according to the Test Solution preparation method.

[0059] Sensitivity Solution: Accurately pipette the System Suitability Solution and dilute according to a certain proportion to ensure that the signal-to-noise ratio of the Adapalene peak is not less than 10.

[0060] 3. Chromatographic Condition Setting

[0061] Use phenyl-bonded silica gel as the filler (such as Aglient ZORBAX SB-Phenyl, 4.6 x 250 mm, 5 μm or a chromatographic column with equivalent performance).

[0062] Mobile phase A is 0.1% glacial acetic acid, mobile phase B is acetonitrile-tetrahydrofuran (65:35), and gradient elution is performed.

[0063] The column temperature is set to 30°C, the flow rate is 1.2 ml / min, the detection wavelength is 270 nm, and the injection volume is 25 μl.

[0064] 4. Determination Method

[0065] Accurately pipette the Test Solution and the Control Solution, and inject them into the liquid chromatograph, respectively.

[0066] Record the chromatogram, and calculate the impurity content according to the chromatogram.

[0067] 5. Linear relationship investigation

[0068] Accurately weigh a certain amount of the adalaline reference substance, dilute it with the diluent solvent, and prepare a linear series of standard solutions with different concentrations. Inject the sample according to the above chromatographic conditions, record the chromatogram, and calculate the linear regression equation and the correlation coefficient.

[0069] 6. Sample determination

[0070] Take multiple batches of adalaline gel samples, process them according to the sample solution preparation method, and examine them under the determined chromatographic conditions.

[0071] Calculate the content of impurities by the principal component self-control method (summarized in Table 1 below).

[0072] Transdermal absorption test

[0073] Apply the obtained adalaline gel to the simulated skin and measure the cumulative transdermal amount of the drug in the simulated skin to evaluate its transdermal absorption performance.

[0074] Sample preparation:

[0075] Prepare the adalaline gel into a test liquid or ointment according to a certain proportion.

[0076] Transdermal cell culture:

[0077] Use cow skin, small pig skin, or other skin models to form a transparent transdermal cell model on top of the transdermal cells, simulating human skin. Perform cell culture and maintenance to ensure the stability and accuracy of the model.

[0078] Apply the drug:

[0079] Uniformly apply the adalaline gel to the transdermal cell model.

[0080] Wait for absorption:

[0081] According to the requirements of the experimental design, wait for the drug to be absorbed and metabolized in the transdermal cells within a certain period of time.

[0082] Sample analysis:

[0083] At different time nodes, collect samples from the transdermal cell model using a specific method.

[0084] Using HPLC (high performance liquid chromatography) and other analytical methods, determine the concentration of adalaline in the sample and calculate the cumulative transdermal amount.

[0085] The results are shown in Table 2 below.

[0086] Example 2

[0087] Formulation

[0088]

[0089]

[0090] The preparation method of the adapalene gel was the same as that of Example 1 described above.

[0091] The stability of the resulting adapalene gel was investigated and a transdermal absorption test was performed by the same method as that of Example 1 described above, and the results are shown in Tables 1 and 2 below, respectively.

[0092] Example 3

[0093] Formulation

[0094]

[0095] The preparation method of the adapalene gel was the same as that of Example 1 described above.

[0096] The stability of the resulting adapalene gel was investigated and a transdermal absorption test was performed by the same method as that of Example 1 described above, and the results are shown in Tables 1 and 2 below, respectively.

[0097] Example 4

[0098] Formulation

[0099]

[0100]

[0101] The preparation method of the adapalene gel was the same as that of Example 1 described above.

[0102] The stability of the resulting adapalene gel was investigated and a transdermal absorption test was performed by the same method as that of Example 1 described above, and the results are shown in Tables 1 and 2 below, respectively.

[0103] Example 5

[0104] Formulation

[0105]

[0106] The preparation method of the adapalene gel was the same as that of Example 1 described above.

[0107] The stability of the resulting adapalene gel was investigated and a transdermal absorption test was performed by the same method as that of Example 1 described above, and the results are shown in Tables 1 and 2 below, respectively.

[0108] Comparative Example 1

[0109] Formulation

[0110]

[0111]

[0112] 1) Preparation of Carbomer Phase

[0113] Sodium edetate was added to water and stirred to dissolve. Carbomer was passed through a 40 mesh sieve and allowed to soak in the solution for 24 hours with slow stirring to swell. Poloxamer 182 was added to the carbomer phase.

[0114] 2) Preparation of Adapalene Phase

[0115] Phenoxyethanol, methylparaben and propylene glycol were mixed and stirred to dissolve with heating to 50°C. Adapalene was added and dispersed evenly.

[0116] 3) Total Mixing

[0117] The prescribed amount of 0.18% sodium hydroxide was weighed and added to water and stirred to dissolve. The Adapalene phase was added while stirring, and the Carbomer phase was used to rinse, with a stirring speed of 100 rpm, a homogenization speed of 10,000 rpm, and a stirring time of 15 min. The sodium hydroxide solution was added while stirring, and the pH was adjusted to 5.25. The remaining water was used to wash, and a gel precursor was obtained, with a vacuum degree of -0.08 MPa, a stirring speed of 100 rpm, and a stirring time of 30 min. Sampling was performed to detect the content uniformity of the top, middle and bottom. The gel precursor was transferred to a vacuum stirring tank, and a vacuum pump was turned on for degassing treatment to remove bubbles. The degassed gel precursor was transferred to a filling device, and filling, sealing and other operations were performed to produce an Adapalene gel.

[0118] The stability of the obtained Adapalene gel was investigated by the same method as in Example 1 above, and a transdermal absorption test was performed, with the results shown in Tables 1 and 2 below, respectively.

[0119] Comparative Example 2

[0120] Formulation

[0121]

[0122]

[0123] The preparation method of the Adapalene gel was the same as in Comparative Example 1 above.

[0124] The stability of the obtained Adapalene gel was investigated by the same method as in Comparative Example 1 above, and a transdermal absorption test was performed, with the results shown in Tables 1 and 2 below, respectively.

[0125] Comparative Example 3

[0126] Formulation

[0127]

[0128] The preparation method of the gel of adapalene was the same as that of the above-mentioned Comparative Example 1.

[0129] The stability of the obtained gel of adapalene was investigated and a transdermal absorption test was performed by the same method as that of the above-mentioned Example 1, and the results are shown in Tables 1 and 2 below, respectively.

[0130] Comparative Example 4

[0131] Formulation

[0132]

[0133]

[0134] After the dispersion of adapalene and poloxamer 188 in ethanol, the solid content was 0.01-1%, and spray drying was performed with a heating temperature of 110°C, a gas flow rate of 400 L / h, and a liquid spray flow rate of 15 ml / min. Then, propylene glycol was weighed according to the prescription, and the dispersion of adapalene was added to the propylene glycol and stirred until uniform. Next, a suitable amount of water was taken in a dispersion kettle, and edetate disodium, methylparaben, and phenoxyethanol were added, followed by the addition of carbomer 941, heating, and stirring at 60±5°C until complete dispersion. The temperature was lowered to 5°C, and the mixture was transferred to a main kettle, and 5% sodium hydroxide solution was added to adjust the pH to 4.0-4.3. Finally, the above-mentioned active phase was added to the main kettle and stirred until complete dispersion. 5% sodium hydroxide solution was added to adjust the pH to 4.7-5.3, water was added to the prescription amount, and the mixture was stirred for 20 min and filled into aluminum tubes.

[0135] The stability of the obtained gel of adapalene was investigated and a transdermal absorption test was performed by the same method as that of the above-mentioned Example 1, and the results are shown in Tables 1 and 2 below, respectively.

[0136] Table 1

[0137]

[0138]

[0139] Table 2

[0140]

[0141] As can be seen from the above Table 1 and Table 2, the present application is characterized in that propylene glycol, hydroxybenzoate and phenoxyethanol are mixed with carbomer to obtain a specific carbomer phase solution, and then mixed with adapalene, so that the resulting adapalene gel has excellent stability and good skin absorption performance as detected by a transdermal absorption test. As can be seen from Comparative Examples 1 to 3 and Comparative Example 4, the carbomer phase of Comparative Examples 1 to 3 is different from that of the present application, and Comparative Example 4 is different from the present application in that the adapalene phase is first spray-dried and then dispersed in propylene glycol. As shown by the results, the present application has not only excellent stability but also good skin absorption performance as compared with Comparative Examples 1 to 4.

[0142] The present application is not limited to the above-described specific embodiments, and the above-described specific embodiments are merely illustrative, not restrictive, and those of ordinary skill in the art can make many forms under the inspiration of the present application without departing from the scope of the present application and the scope protected by the claims.

Claims

1. A method for preparing an adapalene gel, characterized in that, It comprises: 1) Preparation of Carbomer Phase: mixing the first solution and the second solution to obtain a mixed solution, and then adding Carbomer into the mixed solution, wherein the first solution is obtained by mixing disodium edetate and water, and the second solution is obtained by mixing phenoxyethanol, hydroxybenzoate and propylene glycol; 2) Preparation of Adapalene Phase: adding water to poloxamer to obtain a solution, and then adding adapalene into the solution; 3) Total Mixing: mixing the Adapalene Phase and the Carbomer Phase while stirring to obtain a gel precursor, and then degassing the gel precursor, filling and sealing, wherein, the adapalene gel comprises the following raw material components by weight percentage: Adapalene 0.1% to 0.3% Poloxamer 0.1% to 0.5% Propylene glycol 1% to 5% Phenoxyethanol 0.1% to 1% Hydroxybenzoate 0.1% to 1% Disodium edetate 0.05% to 0.5% Carbomer 0.5% to 3% Neutralizing agent in proper amount Purified water added to 100%.

2. The method of preparing the Adapalene gel according to claim 1, wherein, The Carbomer: disodium edetate: propylene glycol: hydroxybenzoate: phenoxyethanol in the Carbomer Phase = 1.1:0.1:4:0.1:0.25 by mass percentage, and the poloxamer: adapalene in the Adapalene Phase = 0.2:0.1 by mass percentage.

3. The method of preparing the Adapalene gel according to claim 1, wherein, The Carbomer is selected from Carbomer 980 and Carbomer 940.

4. The method of preparing the Adapalene gel according to claim 1, wherein, The Adapalene D90 is ≤6 μm.

5. The method of preparing the Adapalene gel according to claim 4, wherein, The Adapalene D90 is 4.81 to 5.

56.

6. The method of preparing the Adapalene gel according to claim 1, wherein, The Carbomer is passed through a 40-mesh sieve and then added into the mixed solution.

7. The method of preparing the Adapalene gel according to claim 1, wherein, In the 3) Total Mixing process, the stirring conditions are as follows: the stirring speed is 50 to 200 rpm, the homogenization speed is 8000 to 12000 rpm, and the stirring time is 10 to 20 min.

8. The method of preparing the Adapalene gel according to claim 1, wherein, In the 3) Total Mixing process, the sodium hydroxide solution is added while stirring to adjust the pH value to 4.5 to 5.

0.

9. An adapalene gel prepared by the preparation method of the adapalene gel according to any one of claims 1 to 8.

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