Preparation method of gel
By optimizing the addition method of carbomer and the stirring conditions, the problems of gel inhomogeneity and poor release performance in the preparation of adapalene gel were solved, and a uniform and stable adapalene gel was prepared, which improved the efficacy of the drug.
Patent Information
- Application Number
- CN202410911377.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-07-09
- Publication Date
- 2026-01-09
AI Technical Summary
In traditional adapalene gel preparation methods, the addition of carbomer leads to gel inhomogeneity and poor stability, resulting in poor in vitro release performance.
By adding carbomer to the disodium edetate solution in small amounts multiple times, and slowly lowering and wetting it under stirring conditions, combined with appropriate stirring speed and pH adjustment, the uniform dispersion and dissolution of carbomer are ensured, forming a uniform and stable adapalene gel.
This improved the uniformity and stability of adapalene gel, resulting in excellent in vitro release performance and enhanced drug efficacy.
Smart Images
Figure CN121287600A_ABST
Abstract
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 gel is a commonly used external drug, which has significant efficacy in treating skin diseases such as acne. However, during the preparation process, the addition method of carbomer directly affects the stability and use effect of the gel. In the traditional preparation method, carbomer is usually added at one time, which causes the carbomer to adhere to the stirring paddle and cannot be completely hydrated, thereby affecting the uniformity and stability of the gel, and the in vitro release performance of the obtained gel is poor.
[0005] Therefore, it is of great significance to develop a simple, efficient and stable preparation method of adapalene gel. SUMMARY
[0006] The present application provides an optimized adapalene gel and a preparation method thereof, which can prepare an adapalene gel with good uniformity and stability and excellent in vitro release performance through a specific preparation process and raw material ratio.
[0007] The purpose of the present application is to provide a preparation method of adapalene gel, which realizes the complete hydration of carbomer by optimizing the addition method of carbomer, thereby improving the stability and release effect of the gel.
[0008] Carbomer, as a kind of high molecular polymer, plays a key role in the gel preparation, which can provide the structure and stability of the gel. In step 2), the carbomer is scattered into the disodium edetate solution in small amounts and multiple times, which ensures the uniform dispersion of the carbomer and avoids the agglomeration phenomenon caused by the local high concentration. In addition, the inventor found that the setting of the stirring condition is crucial for the dispersion and dissolution of the carbomer. The stirring can break the interaction force between the carbomer particles, making it easier to be wetted and dispersed by the solution. At the same time, the stirring can also promote the molecular motion in the solution, accelerating the dissolution process of the carbomer. In addition, the disodium edetate solution as the dispersion medium of the carbomer not only provides a suitable pH environment, but also helps the dispersion and stability of the carbomer. As a chelating agent, disodium edetate can combine with metal ions in the solution, reducing the influence of metal ions on the stability of the carbomer. In summary, the operation details of step 2) have an important influence on the performance of the final gel. If the dispersion of the carbomer is not uniform, it will lead to uneven texture of the gel, even the particle feeling. And if the stirring condition is not properly set, it may cause incomplete dissolution of the carbomer, affecting the stability and use effect of the gel.
[0009] To solve the above technical problems, the technical scheme provided by the present application is as follows:
[0010] A preparation method of an adapalene gel, comprising:
[0011] 1) Preparation of disodium edetate solution: disodium edetate powder is added to purified water and stirred to form a uniform disodium edetate solution;
[0012] 2) Preparation of carbomer phase: a small amount of carbomer is scattered into the disodium edetate solution in multiple times,
[0013] 3) Preparation of adapalene solution: adapalene, propylene glycol and glycerol are mixed together and stirred until the adapalene is completely dissolved in the propylene glycol and glycerol to form a uniform adapalene solution;
[0014] 4) Preparation of adapalene gel: the adapalene solution and the carbomer phase are fully mixed under stirring, and the pH value of the gel is adjusted with sodium hydroxide to obtain the adapalene gel,
[0015] wherein,
[0016] The adapalene gel comprises the following raw material components by weight percentage:
[0017] Adapalene: 0.1% to 0.3%
[0018] Carbomer: 0.6 to 1.6%
[0019] Propylene glycol: 5% to 10.0%
[0020] Glycerin: 3.0%~5.0%
[0021] Sodium hydroxide: appropriate amount
[0022] Phenoxyethanol: 0.1%~1%
[0023] Hydroxybenzoate: 0.1%~1%
[0024] Disodium edetate: 0.05%~1%
[0025] Purified water: the balance.
[0026] Further, in the preparation of the 2) Carbomer phase, the Carbomer is added to the mixed solution in 3~8 times.
[0027] Further, in the preparation of the 2) Carbomer phase, the Carbomer is allowed to slowly descend under the action of gravity and is wetted by water.
[0028] Further, in the preparation of the 2) Carbomer phase, a stirring process is further included, and the stirring speed is 100 rpm~10000 rpm.
[0029] Further, in the Carbomer phase, the Carbomer: disodium edetate = 1.0:0.05, and the adapalene: propylene glycol: glycerin = 0.1:10.0:5.0, by mass percentage.
[0030] Further, the Carbomer is selected from Carbomer 980, Carbomer 940.
[0031] Further, in the preparation of the 4) adapalene gel, the pH value of the gel is adjusted to 5.5~6.5 by sodium hydroxide.
[0032] Further, in the preparation of the 4) adapalene gel, the pH value of the gel is adjusted to 5.5~6.0 by sodium hydroxide.
[0033] In addition, the present application provides an adapalene gel prepared by the above-mentioned preparation method of the adapalene gel.
[0034] Compared with the prior art, the preparation method of the adapalene gel of the present application has the following advantages:
[0035] Uniform dispersion: through a specific preparation process and raw material ratio, the prepared adapalene gel is uniform and stable, easy to be absorbed by the skin, and improves the drug efficacy;
[0036] Excellent in vitro release: by using appropriate excipients and preparation process, the adapalene gel has excellent in vitro release performance. BRIEF DESCRIPTION OF DRAWINGS
[0037] Figure 1 This diagram shows the phenomena observed during the preparation of the adapalene gel in the carbomer phase according to Example 1 of the present invention.
[0038] Figure 2 This diagram shows the phenomena observed during the preparation of the adapalene gel in the carbomer phase of Comparative Example 1 of this invention.
[0039] Figure 3 This diagram shows the phenomena observed during the preparation of the adapalene gel in the carbomer phase of Comparative Example 2 of this invention. Detailed Implementation
[0040] The technical solutions of the embodiments of this application will be clearly described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of this application. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.
[0041] The terms "first," "second," etc., used in the specification and claims of this application are used to distinguish similar objects and not to describe a specific order or sequence. It should be understood that such use of data can be interchanged where appropriate so that embodiments of this application can be implemented in orders other than those illustrated or described herein, and the objects distinguished by "first," "second," etc., are generally of the same class and the number of objects is not limited; for example, the first object can be one or more. Furthermore, in the specification and claims, "and / or" indicates at least one of the connected objects, and the character " / " generally indicates that the preceding and following objects are in an "or" relationship.
[0042] Raw material information
[0043]
[0044]
[0045] Example 1
[0046] The formula is as follows (based on total gel weight):
[0047] Adapalene: 0.1% w / w
[0048] Carbomer 940: 1.1% w / w
[0049] Propylene glycol: 10.0% w / w
[0050] Glycerin: 5.0% w / w
[0051] Sodium hydroxide (used to adjust pH): appropriate amount
[0052] Phenoxyethanol: 0.5% w / w
[0053] Methylparaben: 0.1% w / w
[0054] Disodium edetate: 0.05% w / w
[0055] Purified water: Balance
[0056] The specific preparation process is as follows:
[0057] (1) Preparation of disodium edetate solution
[0058] Slowly add the weighed disodium edetate powder to the pre-weighed purified water, turn on the stirrer to ensure that the disodium edetate is fully dissolved in the water to form a homogeneous disodium edetate solution.
[0059] (2) Preparation of the carbomer phase
[0060] Begin by adding carbomer 940 to the disodium edetate solution in small, frequent additions. To ensure complete hydration of the carbomer, add only small amounts (0.2% carbomer each time), allowing the carbomer to slowly sink and be wetted by gravity. Repeat this process until all carbomer 940 is added and fully hydrated.
[0061] The states of the paddle and carbomer solution were observed during the multiple small-batch addition of carbomer, after complete wetting, and after 5 minutes of homogenization. (The results are shown in the original text.) Figure 1 .
[0062] (3) Preparation of adapalene solution
[0063] Mix the weighed adapalene powder, propylene glycol, and glycerin together, and turn on the stirrer to stir until the adapalene is completely dissolved in the propylene glycol and glycerin to form a homogeneous adapalene solution.
[0064] (4) Gel preparation
[0065] Under stirring, slowly add the adapalene solution to the prepared carbomer phase. Continue stirring during the addition process to ensure thorough mixing of the adapalene solution and the carbomer phase.
[0066] Adjust the pH of the gel to 5.5 using an appropriate amount of sodium hydroxide solution. When adjusting the pH, the sodium hydroxide solution should be added slowly dropwise while continuously stirring the gel, and the pH change of the gel should be monitored using pH test paper.
[0067] Add the weighed phenoxyethanol and methylparaben as preservatives, and continue stirring for 5 minutes to ensure that all components are fully mixed to obtain adapalene gel.
[0068] The appearance, color, texture and transparency of the adapalene gel obtained in Example 1 were observed to be uniform, with no obvious layering or precipitation.
[0069] Example 2
[0070] The formula is as follows (based on total gel weight):
[0071] Adapalene: 0.1% w / w
[0072] Carbomer 940: 0.6% w / w
[0073] Propylene glycol: 10.0% w / w
[0074] Glycerin: 5.0% w / w
[0075] Sodium hydroxide (used to adjust pH): appropriate amount
[0076] Phenoxyethanol: 0.5% w / w
[0077] Methylparaben: 0.1% w / w
[0078] Disodium edetate: 0.05% w / w
[0079] Purified water: Balance
[0080] The specific preparation process is as follows:
[0081] In (2) the preparation of the carbomer phase, 0.1% carbomer was added each time. Other than that, the preparation conditions were the same as in Example 1, and adapalene gel was obtained.
[0082] The appearance of the adapalene gel obtained in Example 2 was observed. Its physical properties, such as color, texture, and transparency, were uniform and consistent, with no obvious layering or precipitation.
[0083] Example 3
[0084] The formula is as follows (based on total gel weight):
[0085] Adapalene: 0.1% w / w
[0086] Carbomer 940: 1.6% w / w
[0087] Propylene glycol: 10.0% w / w
[0088] Glycerin: 5.0% w / w
[0089] Sodium hydroxide (used to adjust pH): appropriate amount
[0090] Phenoxyethanol: 0.5% w / w
[0091] Methylparaben: 0.1% w / w
[0092] Disodium edetate: 0.05% w / w
[0093] Purified water: Balance
[0094] The specific preparation process is as follows:
[0095] In (2) the preparation of the carbomer phase, 0.4% carbomer was added each time. Other than that, the preparation conditions were the same as in Example 1, and adapalene gel was obtained.
[0096] The appearance of the adapalene gel obtained in Example 3 was observed. Its physical properties, such as color, texture, and transparency, were uniform and consistent, with no obvious layering or precipitation.
[0097] Example 4
[0098] The formula is as follows (based on total gel weight):
[0099] Adapalene: 0.1% w / w
[0100] Carbomer 980: 1.6% w / w
[0101] Propylene glycol: 10.0% w / w
[0102] Glycerin: 5.0% w / w
[0103] Sodium hydroxide (used to adjust pH): appropriate amount
[0104] Phenoxyethanol: 0.5% w / w
[0105] Methylparaben: 0.1% w / w
[0106] Disodium edetate: 0.05% w / w
[0107] Purified water: Balance
[0108] The specific preparation process is as follows:
[0109] In (2) the preparation of the carbomer phase, 0.2% carbomer was added each time. Other than that, the preparation conditions were the same as in Example 1, and adapalene gel was obtained.
[0110] The appearance of the adapalene gel obtained in Example 4 was observed. Its physical properties, such as color, texture, and transparency, were uniform and consistent, with no obvious layering or precipitation.
[0111] Comparative Example 1
[0112] The formula is as follows (based on total gel weight):
[0113] Adapalene: 0.1% w / w
[0114] Carbomer 940: 1.0% w / w
[0115] Propylene glycol: 10.0% w / w
[0116] Glycerin: 5.0% w / w
[0117] Sodium hydroxide (used to adjust pH): appropriate amount
[0118] Phenoxyethanol: 0.5% w / w
[0119] Methylparaben: 0.1% w / w
[0120] Disodium edetate: 0.05% w / w
[0121] Purified water: Balance
[0122] The specific preparation process is as follows:
[0123] In the preparation of the carbomer phase (2), all of carbomer 940 was weighed and added to the emulsifier at once. The mixture was stirred at 200 rpm, and the swelling of the carbomer 940 was observed at 20 min, 40 min, and 60 min. The state of the impeller and the carbomer solution was observed at 20 min, 40 min, and 60 min of stirring, as shown in the figure. Figure 2 .
[0124] Apart from this, the other preparation conditions were the same as in Example 1, and adapalene gel was obtained.
[0125] The appearance, texture, and transparency of the adapalene gel obtained in Comparative Example 1 were observed to be uneven or inconsistent, with obvious layering or precipitation.
[0126] Comparative Example 2
[0127] The formula is as follows (based on total gel weight):
[0128] Adapalene: 0.1% w / w
[0129] Carbomer 940: 1.0% w / w
[0130] Propylene glycol: 10.0% w / w
[0131] Glycerin: 5.0% w / w
[0132] Sodium hydroxide (used to adjust pH): appropriate amount
[0133] Phenoxyethanol: 0.5% w / w
[0134] Methylparaben: 0.1% w / w
[0135] Disodium edetate: 0.05% w / w
[0136] Purified water: Balance
[0137] The specific preparation process is as follows:
[0138] In the preparation of the carbomer phase (2), all of Carbomer 940 was weighed and added to the emulsifier at once. The homogenizer was started at 10,000 rpm, and the swelling of the carbomer was observed at 20 min, 40 min, and 60 min. The state of the slurry and carbomer solution was observed at 20 min, 40 min, and 60 min of homogenization, as shown in the figure. Figure 3 .
[0139] Apart from this, the other preparation conditions were the same as in Example 1, and adapalene gel was obtained.
[0140] The appearance, texture, and transparency of the adapalene gel obtained in Comparative Example 2 were observed to be uneven or inconsistent, with obvious layering or precipitation.
[0141] Comparative Example 3
[0142] The formula is as follows (based on total gel weight):
[0143] Adapalene: 0.1% w / w
[0144] Carbomer 980: 1.0% w / w
[0145] Propylene glycol: 10.0% w / w
[0146] Glycerin: 5.0% w / w
[0147] Sodium hydroxide (used to adjust pH): appropriate amount
[0148] Phenoxyethanol: 0.5% w / w
[0149] Methylparaben: 0.1% w / w
[0150] Disodium edetate: 0.05% w / w
[0151] Purified water: Balance
[0152] The specific preparation process is as follows:
[0153] In the preparation of the carbomer phase (2), all of the carbomer 940 was weighed and added to the emulsifier at one time. The homogenizer was turned on at 10,000 rpm, and the swelling of the carbomer was observed at 20 min, 40 min, and 60 min.
[0154] Apart from this, the other preparation conditions were the same as in Example 1, and adapalene gel was obtained.
[0155] The appearance, texture, and transparency of the adapalene gel obtained in Comparative Example 3 were observed to be uneven or inconsistent, with obvious layering or precipitation.
[0156] Furthermore, the in vitro release of the gels from Examples 1 and 2 was examined, as follows:
[0157] In vitro release experiment determination
[0158] Method: Franze diffusion cell method
[0159] Instrument: Transdermal diffusion device
[0160] Artificial membrane: polyvinylidene fluoride, 25 mm in diameter, 0.45 μm in pore size.
[0161] Receiving medium: 0.9% sodium chloride aqueous solution + 75% ethanol
[0162] Temperature: 32℃±1℃
[0163] Revolutions per minute: 600 revolutions per minute
[0164] Receiving liquid volume: 12ml
[0165] Sample size: 80mg
[0166] Sampling times: 1, 2, 4, 6 and 8 hours
[0167] Sampling method: Sampling all
[0168] Result determination: The amount of drug released per unit area (μg / cm²) 2 Plotting the square root of the relative time should produce a straight line. The slope (regression) of the line represents the release rate of the formulation, and the correlation coefficient R of the regression equation should be no less than 0.90. Calculate the slope ratio T / R for each test formulation and reference formulation (license holder: Galderma International), sort them from lowest to highest, determine the 8th and 29th T / R ratios, and convert them to percentages (multiplied by 100). These values represent the 90% confidence interval (between 75% and 133.33%) for the ratio of the test formulation release rate to the reference formulation release rate.
[0169] Six portions each of the reference formulation and the self-made sample were tested using the above method, and the data are as follows:
[0170] The results of the in vitro release experiment are shown in Tables 1 and 2 below:
[0171] Table 1: In vitro release data of Example 1
[0172]
[0173] Table 2: In vitro release data of Example 2
[0174]
[0175] Table 3: In vitro release data of Example 3
[0176]
[0177]
[0178] As can be seen from Tables 1 to 3 above, the 90% confidence intervals for the in vitro release of Examples 1 to 3 meet the requirements.
[0179] Furthermore, the inventors photographed the phenomena observed during the carbomer phase preparation process of the adapalene gels of Example 1, Comparative Example 1, and Comparative Example 2, respectively, and these are shown in [the figures]. Figures 1-3 . Figure 1 The diagram shows the phenomena observed during the preparation of the adapalene gel in the carbomer phase according to Example 1 of the present invention. In Example 1, 0.2% carbomer was added each time, and then a period of time was allowed for the carbomer to slowly descend under gravity and be wetted by water. The results showed that... Figure 1 (Leftmost) is a diagram showing the phenomenon observed when carbomer is applied in small amounts multiple times. Figure 1 (Second from left) This image shows the phenomenon observed after the area is fully wetted. Figure 1 (Rightmost and second from the right) are the phenomena observed after stirring and homogenizing for 5 minutes. From these pictures, it can be seen that the obtained carbomer solution has no foam or carbomer lumps, and there is no carbomer adhering to the paddle and scraper, which confirms that this method is feasible. Figure 2 The diagram shows the phenomena observed during the preparation of the adapalene gel in Comparative Example 1 of this invention, specifically during the carbomer phase formulation process. All of the carbomer 940 in Comparative Example 1 was added to the emulsifier at once, and the mixture was stirred at 200 rpm. The results show... Figure 2 (Leftmost) is a diagram showing the phenomenon observed after stirring for 20 minutes. Figure 2 (Second from left) This image shows the phenomenon observed after stirring for 40 minutes. Figure 2 (Rightmost and second from the right) are the phenomena observed after stirring for 60 minutes. From these pictures, it can be seen that there are a large number of carbomer lumps on the solution and the paddle, and the bottom scraper is severely stuck together. This method is not feasible. Figure 3 The diagram shows the phenomena observed during the preparation of the adapalene gel in Comparative Example 2 of this invention, using the carbomer phase. All of the carbomer 940 in Comparative Example 2 was added to the emulsifier at once, and the homogenizer was set to 10,000 rpm. The results show... Figure 3 (Leftmost) This image shows the phenomenon observed after 20 minutes of homogenization. Figure 3 (Second from left) This image shows the phenomenon observed after homogenization for 40 minutes. Figure 3(Rightmost and second from the right) are the phenomena observed after homogenization for 60 minutes. From these images, it can be seen that there are a large number of carbomer lumps on the paddle, the bottom scraper is severely adhered, and there is a lot of foam in the solution, so this method is not feasible.
[0180] This application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit and scope of the claims, and all of these forms are within the protection scope of this application.
Claims
1. A method for preparing adapalene gel, characterized in that, include: 1) Preparation of disodium edetate solution: Disodium edetate powder is added to purified water and stirred to form a homogeneous disodium edetate solution; 2) Preparation of the carbomer phase: Add carbomer to the disodium edetate solution in small amounts several times; 3) Preparation of adapalene solution: Mix adapalene, propylene glycol and glycerin together and stir until adapalene is completely dissolved in propylene glycol and glycerin to form a homogeneous adapalene solution; 4) Preparation of adapalene gel: Under stirring conditions, the adapalene solution and carbomer phase were thoroughly mixed, and the pH of the gel was adjusted with sodium hydroxide to obtain adapalene gel. in, Adapalene gel comprises the following raw material components by weight percentage: Adapalene: 0.1%–0.3% Carbomer: 0.6–1.6% Propylene glycol: 5%–10.0% Glycerin: 3.0%–5.0% Sodium hydroxide: appropriate amount Phenoxyethanol: 0.1%–1% Methylparaben: 0.1%–1% Disodium edetate: 0.05%–1% Purified water: Balance.
2. The method for preparing adapalene gel according to claim 1, wherein, In the preparation of the carbomer phase in step 2), the carbomer is added to the mixture in 3 to 8 portions.
3. The method for preparing adapalene gel according to claim 2, wherein, In the preparation of the carbomer phase in 2), the carbomer is allowed to slowly descend under the influence of gravity and be wetted by water.
4. The method for preparing adapalene gel according to claim 2, wherein, In the preparation of the carbomer phase in step 2), a stirring step is also included, with a stirring speed of 100 rpm to 10000 rpm.
5. The method for preparing adapalene gel according to claim 1, wherein, By mass percentage, the ratio of carbomer:disodium edetate in the carbomer phase is 1.0:0.05, and the ratio of adapalene:propylene glycol:glycerol is 0.1:10.0:5.
0.
6. The method for preparing adapalene gel according to claim 1, wherein, The carbomer is selected from carbomer 980 and carbomer 940.
7. The method for preparing adapalene gel according to claim 1, wherein, In the preparation of adapalene gel (4), the pH of the gel was adjusted to 5.5–6.5 using sodium hydroxide.
8. The method for preparing adapalene gel according to claim 1, wherein, In the preparation of adapalene gel (4), the pH of the gel was adjusted to 5.5–6.0 using sodium hydroxide.
9. An adapalene gel, which is prepared by the method for preparing adapalene gel according to any one of claims 1 to 8.