Fluocinolone hydroquinone tretinoin acid cream and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to fluocinolone hydroquinone tretinoin acid emulsifiable paste and a preparation method thereof.The fluocinolone hydroquinone tretinoin acid emulsifiable paste is prepared from fluocinolone, hydroquinone, tretinoin, a matrix, a preservative, a humectant, an antioxidant, a thickener and an emulsifier; wherein the humectant is a mixed humectant of glycerol and methyl glucitol polyether-10 in a mass ratio of (1: 1.5)-(1: 3), and the quality of the cream product is favorably improved. In addition, by limiting the feeding sequence and the feeding temperature of the raw materials and the auxiliary materials in the preparation process, the fluocinolone hydroquinone tretinoin acid cream which is good in product quality and stable in release can be obtained.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a fluocinolone hydroquinone retinoic acid cream and a preparation method thereof. Background Art

[0002] Dark mottled patches or melasma, as a common pigment abnormality, are particularly troubling for women of childbearing age. Dark mottled patches refer to patches of pigmentation that appear on the skin. These patches mainly appear on the face and neck, especially on the cheeks and forehead areas. Melasma is a specific type of dark mottled patches that are often associated with hormonal activity caused by pregnancy or taking birth control pills. During pregnancy, women's hormone levels change significantly, especially the increase in estrogen and progesterone, which may cause melanocytes to become active, thus forming melasma on the face. Therefore, melasma is also called the "mask of pregnancy." Certain oral contraceptives contain hormonal ingredients, which may also stimulate melanocytes and lead to the formation of melasma. In addition, melasma can last for a long time and is prone to recurrence in subsequent pregnancies. In addition, men may also experience pigmentation on the face and neck, accounting for about 10% of all cases.

[0003] At present, the standard treatment for dark mottled patches or melasma is to depigment or bleach the affected skin area, then use sunscreen and avoid sunlight. Hydroquinone is one of the most commonly used topical depigmenting agents. Although 5%-10% hydroquinone concentration is very effective in some cases, high concentrations of hydroquinone are often accompanied by higher irritation. It usually takes some time for the use of hydroquinone to see obvious effects. Depending on individual differences and the severity of the spots, the course of treatment may be as long as 16 to 20 weeks, or even longer. Retinoic acid is a derivative of vitamin A and has a wide range of applications in dermatological treatments. It can reduce the melanin content by inhibiting the activity of tyrosinase that produces spots and inhibiting melanosome conversion, thereby improving spots. In existing compound composition preparations, such as the fluocinolone hydroquinone retinoic acid cream in patent CN1738587B, it has a good therapeutic effect on melasma, but due to the chemical properties of the active pharmaceutical ingredients involved, the stability (viscosity, impurity content, properties, etc.) of this variety is poor, and the raw and auxiliary materials are prone to interact with each other.

[0004] Therefore, how to prepare fluocinolone hydroquinone retinoic acid cream with stable properties and quality is worthy of study. Summary of the invention

[0005] In order to overcome the deficiencies in the prior art, the present invention aims to provide a fluocinolone hydroquinone retinoic acid cream and a preparation method thereof.

[0006] The fluocinolone hydroquinone retinoic acid cream provided by the present invention has the following prescription composition by mass percentage: 1-10% of active pharmaceutical ingredient, 3-30% of base, 0.01-1% of preservative, 3-30% of moisturizer, 0.01-1% of antioxidant, 0.1-10% of thickener, 0.5-10% of emulsifier, 0-1% of pH adjuster, and 40-80% of water; the active pharmaceutical ingredient is a combination of fluocinolone, hydroquinone and retinoic acid; the moisturizer is a mixed moisturizer of glycerol and methyl gluceth-10 in a mass ratio of 1:1.5-1:3; the antioxidant comprises antioxidant 1 and antioxidant 2, the antioxidant 1 comprises one or more of butylated hydroxytoluene, butylated hydroxyanisole and propyl penate, and the antioxidant 2 comprises one or more of sodium pyrosulfite, sodium sulfite and disodium edetate.

[0007] According to an embodiment of the present invention, a mixed moisturizer of glycerol and methyl gluceth-10 in a mass ratio of 1:1.5 to 1:3 is more conducive to ensuring the viscosity uniformity of the cream preparation during storage. For example, a mixed moisturizer of glycerol and methyl gluceth-10 in a mass ratio of 1:1.50, 1:1.51, 1:1.53, 1:1.55, 1:1.57, 1:1.60, 1:1.65, 1:1.71, 1:1.80, 1:1.91, 1:2.0, 1:2.1, 1:2.3, 1:2.5, 1:3.0, etc. is used, and the viscosity stability of the fluocinolone hydroquinone retinoic acid cream refrigerated at 2 to 8°C for 30 days is better.

[0008] Based on the chemical structures of the three active pharmaceutical ingredients (API, i.e., fluocinolone acetonide, hydroquinone and tretinoin) contained in the fluocinolone hydroquinone tretinoin cream described in the present invention, these active pharmaceutical ingredients may react with each other, thereby affecting the stability of the cream. Therefore, it is necessary to pay attention to the feeding order and feeding temperature of different active pharmaceutical ingredients in the formulation process.

[0009] In an embodiment of the present invention, the feeding temperature of tretinoin during the preparation of the fluocinolone hydroquinone tretinoin cream is 50°C to 65°C, which is conducive to avoiding the precipitation of tretinoin crystals. If tretinoin is fed at a temperature of 45°C or below, the resulting cream preparation is prone to the precipitation of tretinoin crystals, which also seriously affects the in vitro release of tretinoin.

[0010] In order to further ensure that the tretinoin in the fluocinolone hydroquinone tretinoin cream has a suitable in vitro release rate, tretinoin and fluocinolone acetonide are separately added at different temperatures during the preparation of the fluocinolone hydroquinone tretinoin cream.

[0011] Because hydroquinone is easily oxidized and discolored, oxidation not only affects product quality, but also affects the user's mood in properties. Therefore, in order to resist oxidation, two types of antioxidants (antioxidant 1 and antioxidant 2) are added and used in the fluocinolone hydroquinone retinoic acid cream prescription. Wherein, the antioxidant 1 is an organic antioxidant, including one or more of butylated hydroxytoluene, butylated hydroxyanisole, and propyl ester, preferably butylated hydroxytoluene, which mainly plays a role after filling, so that it can continue to play an antioxidant role during preparation and storage, and ensure the biological activity of hydroquinone; Antioxidant 2 is a salt antioxidant, including one or more of sodium pyrosulfite, sodium sulfite, and disodium edetate, preferably sodium pyrosulfite, which mainly plays a role in the process. In addition, the feeding of antioxidant 2 is before hydroquinone, which is conducive to controlling the change of impurity content of cream preparations during storage and use.

[0012] Furthermore, the water used in the fluocinolone hydroquinone tretinoin cream is purified water that is deoxygenated by keeping it at 85-100° C. for 0.5-1.5 hours, in order to reduce the introduction of oxygen into the system and avoid subsequent oxidation of hydroquinone.

[0013] Furthermore, the thickener used in the fluocinolone hydroquinone retinoic acid cream includes one or more of magnesium aluminum silicate, xanthan gum, and carbomer, preferably magnesium aluminum silicate.

[0014] Furthermore, the matrix used in the fluocinolone hydroquinone retinoic acid cream includes one or more of cetyl alcohol (i.e., cetyl alcohol), octadecanol (i.e., stearyl alcohol), stearic acid, white vaseline, cetostearyl alcohol (i.e., cetearyl alcohol), and castor oil; the pH adjuster includes one or more of citric acid (i.e., citric acid), tartaric acid, hydrochloric acid, and acetic acid.

[0015] Creams generally have problems with oil-water distribution, so care must also be taken in the selection of preservatives.

[0016] Further, the preservative used in the fluocinolone hydroquinone retinoic acid cream includes one or more of methylparaben, propylparaben, and benzyl alcohol, preferably a combination of methylparaben and propylparaben. It is understood that although methylparaben is more water-soluble than propylparaben, its antiseptic power is not as good as propylparaben; therefore, methylparaben and propylparaben are selected for joint use, so that methylparaben can make up for the insufficient antiseptic power of propylparaben due to its poor water solubility.

[0017] Furthermore, the emulsifier used in the fluocinolone hydroquinone retinoic acid cream includes 165 and / or a combination of glyceryl stearate and polyethylene glycol (PEG)-100 stearate in a mass ratio of 1: 1. It can be understood that the choice of emulsifier is also crucial for creams. 165 is a water-in-oil emulsifier suitable for various lipophilic substances. It can also be used as a skin care stabilizer. It is a relatively mature emulsifier product on the market. This emulsifier can be used to prepare creams with good droplet morphology. In addition, a mixture of glyceryl stearate and polyethylene glycol-100 stearate in a mass ratio of 1:1 can also be selected as an emulsifier. It can also prepare creams with good droplet morphology and smaller droplets, and higher viscosity. The cost is lower than that of using 165 is also lower.

[0018] Furthermore, as a specific experimental scheme, the fluocinolone hydroquinone retinoic acid cream of the present invention has the following prescription composition by mass percentage:

[0019]

[0020] Furthermore, the present invention provides a method for preparing fluocinolone hydroquinone retinoic acid cream, comprising:

[0021] Preparing a non-aqueous phase: preparing a non-aqueous phase at a temperature of 75 to 80° C., wherein the non-aqueous phase is made of a matrix and a preservative, and further comprises a mixed moisturizer of glycerol and methyl gluceth-10 in a mass ratio of 1:1.5 to 1:3, and maintaining the temperature of the non-aqueous phase at 75 to 80° C. for standby use;

[0022] Preparing an aqueous phase: preparing an aqueous phase at a temperature of 75 to 80° C., wherein the aqueous phase is made of water, antioxidant 1 and a thickener, and the temperature of the aqueous phase is maintained at 75 to 80° C. for standby use;

[0023] Emulsification: Add the non-aqueous phase to the aqueous phase and mix to obtain a two-phase mixed liquid, and cool it; when the two-phase mixed liquid is cooled to 68°C to 70°C, add an emulsifier and fluocinolone acetonide and mix; when the two-phase mixed liquid is cooled to 50°C to 65°C, add retinoic acid and a pH adjuster and mix; when the two-phase mixed liquid is cooled to 45 to 50°C, first add antioxidant 2 and mix, then add hydroquinone and mix, and mix homogeneously; stir and cool to room temperature to obtain the fluocinolone acetonide hydroquinone retinoic acid cream; nitrogen replacement protection is performed before and after the above feeding steps.

[0024] Furthermore, the emulsifier and fluocinolone are added and mixed in the emulsification process as follows: the emulsifier is first melted at 75-80°C, fluocinolone is added to the melted emulsifier to dissolve to obtain a fluocinolone-emulsifier solution, and then the fluocinolone-emulsifier solution is added to the two-phase mixed solution cooled to 68-70°C for mixing. This operation is more conducive to the uniform dispersion of fluocinolone.

[0025] Furthermore, in the preparation method, when the two-phase mixed liquid is cooled to 45-50° C., antioxidant 2 is first added and mixed, and then hydroquinone is added and mixed, and the mixture is homogenized for 5-20 minutes, and the operating temperature is maintained at 45-50° C. during the process.

[0026] The fluocinolone hydroquinone retinoic acid cream provided by the present invention has stable viscosity, impurity content and properties, high product quality, can achieve good in vitro release, and is conducive to ensuring drug safety. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is a microscopic bright field image of emulsion droplets of fluocinolone hydroquinone retinoic acid cream on day 0 of Example 1;

[0028] Figure 2 This is a polarized microscopic image of emulsion droplets of fluocinolone hydroquinone retinoic acid cream on day 0 of Example 1;

[0029] Figure 3 This is a microscopic bright field image of emulsion droplets of fluocinolone hydroquinone retinoic acid cream on day 0 of Example 2;

[0030] Figure 4 This is a polarized microscopic image of emulsion droplets of fluocinolone hydroquinone retinoic acid cream on day 0 of Example 2;

[0031] Figure 5 This is a microscopic bright field image of emulsion droplets of fluocinolone hydroquinone retinoic acid cream on day 0 of Example 8;

[0032] Figure 6 This is a polarized microscopic image of emulsion droplets of fluocinolone hydroquinone retinoic acid cream on day 0 of Example 8;

[0033] Figure 7 This is a microscopic observation of emulsion droplets of the fluocinolone hydroquinone retinoic acid cream in Example 8 after refrigeration for about 100 days. DETAILED DESCRIPTION

[0034] The present invention is further described in detail in conjunction with the following specific examples and drawings, and the protection content of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, changes and advantages that can be thought of by those skilled in the art are included in the present invention, and the attached claims are the scope of protection. The process, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are all common knowledge and common common sense in the art, and the present invention does not specifically limit the content.

[0035] Example 1 Preparation of Fluocinolone Hydroquinone Retinoic Acid Cream

[0036] According to the prescription table in Table 1, weigh the raw materials and excipients to prepare fluocinolone hydroquinone retinoic acid cream, including:

[0037] (1) Preparation of non-aqueous phase

[0038] At a temperature of 75-80° C., stir and mix the prescribed amounts of cetyl alcohol, stearyl alcohol, stearic acid, methyl gluceth-10, glycerin, methylparaben and propylparaben to obtain a non-aqueous phase, and maintain the temperature of the non-aqueous phase at 75-80° C. for standby use.

[0039] (2) Preparation of aqueous phase

[0040] The purified water is kept at 85-100°C for 0.5-1.5h for deoxygenation. After cooling, at a temperature of 75-80°C, the prescribed amount of butylated hydroxytoluene and magnesium aluminum silicate are added, and the mixture is stirred to swell completely to obtain a water phase, and the temperature of the water phase is maintained at 75-80°C for standby use.

[0041] (3) Emulsification

[0042] Add the non-aqueous phase (75-80°C) to the aqueous phase (75-80°C) and stir to obtain a two-phase mixed solution, and cool it down; when the two-phase mixed solution cools to 68°C-70°C, add the emulsifiers in sequence. 165 and fluocinolone, stir and mix; when the two-phase mixed solution is cooled to 50-60°C, retinoic acid and citric acid are added and stirred and mixed; when the two-phase mixed solution is cooled to 45-50°C, sodium metabisulfite is first added and stirred and mixed, and then hydroquinone is added and stirred and mixed, and homogenized at 5000rpm for 5-20min, and the operating temperature is maintained at 45-50°C during the process; stop homogenizing, stir and cool to room temperature to obtain fluocinolone hydroquinone retinoic acid cream; nitrogen replacement protection is carried out before and after the above feeding steps.

[0043] Table 1 Prescription table

[0044]

[0045] Example 2 Preparation of Fluocinolone Hydroquinone Retinoic Acid Cream

[0046] The prescription of this example only contains the emulsifier in Example 1. 165 was replaced with a mixture of glyceryl stearate and PEG-100 stearate prepared in a mass ratio of 1:1 (i.e., a combination of glyceryl stearate and polyethylene glycol-100 stearate in a mass ratio of 1:1). The preparation method of fluocinolone hydroquinone retinoic acid cream was the same as that in Example 1.

[0047] Example 3-5 Preparation of Fluocinolone Hydroquinone Retinoic Acid Cream

[0048] The raw and auxiliary materials were weighed according to the prescription table in Table 1 respectively, and the preparation method of fluocinolone hydroquinone retinoic acid cream of Examples 3-5 was the same as that of Example 1.

[0049] Example 6 Preparation of Fluocinolone Hydroquinone Retinoic Acid Cream

[0050] The prescription of this embodiment is the same as that of Example 1, except that the method for preparing the fluocinolone hydroquinone retinoic acid cream is to add an emulsifier and mix them in the following manner: first, the emulsifier is melted at 75-80°C, and then fluocinolone is added to the melted emulsifier to dissolve to obtain a fluocinolone-emulsifier solution, and then the fluocinolone-emulsifier solution is added to the two-phase mixed liquid cooled to 68°C-70°C and mixed.

[0051] Example 7 Preparation of Fluocinolone Hydroquinone Retinoic Acid Cream

[0052] The prescription of this embodiment is the same as that of embodiment 1, except that in the preparation method of fluocinolone hydroquinone retinoic acid cream, retinoic acid is added together with the emulsifier and fluocinolone acetonide when the two-phase mixed liquid is cooled to 68°C to 70°C.

[0053] Example 8 Preparation of Fluocinolone Hydroquinone Retinoic Acid Cream

[0054] The prescription of this embodiment is the same as that of embodiment 1, except that in the preparation method of fluocinolone hydroquinone retinoic acid cream, retinoic acid is added and mixed after homogenization when the two-phase mixed solution is cooled to 45°C.

[0055] Example 9 Preparation of Fluocinolone Hydroquinone Retinoic Acid Cream

[0056] The prescription of this embodiment is the same as that of Example 5, except that in the preparation method of fluocinolone hydroquinone retinoic acid cream: when the two-phase mixed solution is cooled to 68°C to 70°C, emulsifier, fluocinolone acetonide and retinoic acid are added and stirred; when the two-phase mixed solution is cooled to 60°C, citric acid is added and mixed; when the two-phase mixed solution is cooled to 55°C, hydroquinone is added and stirred; when the two-phase mixed solution is cooled to 50°C, homogenized and mixed at 5000rpm for 5 to 20min; when the two-phase mixed solution is cooled to 45°C, sodium metabisulfite is added and stirred, and stirred and cooled to room temperature to obtain fluocinolone hydroquinone retinoic acid cream; nitrogen replacement protection is carried out before and after the above feeding steps.

[0057] Example 10 Preparation of Fluocinolone Hydroquinone Retinoic Acid Cream

[0058] The prescription of this example is the same as that of Example 1, except that in the preparation method of fluocinolone hydroquinone retinoic acid cream, the water in the aqueous phase is not deoxygenated, and nitrogen replacement protection is not performed before and after the feeding step during the emulsification process.

[0059] Experimental Example 1 Stability Study of Fluocinolone Hydroquinone Retinoic Acid Cream in Each Example

[0060] The fluocinolone hydroquinone retinoic acid cream samples obtained in Examples 1-10 were subjected to pH testing, impurity content testing, viscosity testing, and appearance property observation at 0 day, 2-8°C refrigeration for 3 days, and 2-8°C refrigeration for 30 days. The results are shown in Table 2. It was found that the viscosity of the cream increased with the increase of refrigeration time. However, when a mixed moisturizer of glycerol and methyl glucitol polyether-10 with a mass ratio of 1:1.5 to 1:3 was added, the relative deviation (RSD) of the viscosity of the fluocinolone hydroquinone retinoic acid cream was relatively small, the viscosity change was small, and the properties were more stable, which was conducive to ensuring that the cream was better absorbed. And by microscopic observation of the specific state of the droplets in the fluocinolone hydroquinone retinoic acid cream, the droplet particle size of the samples of Examples 1-4 and Example 6 on day 0 was 8-20μm, and the droplet morphology was clear, the distribution was uniform, and the properties were stable (see Figure 1-4 ), while the sample of Example 8 had the phenomenon that retinoic acid was not dissolved or retinoic acid crystals were precipitated (see Figure 5-7 ), affecting the quality of the cream preparation. Furthermore, the impurity content of the fluocinolone hydroquinone retinoic acid cream obtained by the preparation method of the present invention is more stable and does not exceed the impurity limit (limit: total impurities less than 1.5%), thereby ensuring product quality.

[0061] Table 2 Stability test results

[0062]

[0063] Test Example 2 In vitro release test

[0064] In accordance with the "Technical Guidelines for In Vitro Release (IVRT) and In Vitro Transdermal (IVPT) Research of Topically Acting Chemical Generic Drugs (Draft for Comments)", an in vitro release method for fluocinolone hydroquinone tretinoin cream was developed. After verification, the commercially available product fluocinolone hydroquinone tretinoin cream (source: Reference Preparation Catalog 24-98, licensee Galderma Laboratories, LP) and the fluocinolone hydroquinone tretinoin cream obtained in Examples 1, 6, 7, and 8 were used for in vitro release tests.

[0065] The final in vitro release results show that compared with the commercially available products, the release rates of retinoic acid in the fluocinolone hydroquinone retinoic acid cream obtained in Example 1 and Example 6 are comparable and meet the acceptable standard (acceptance standard: the 90% confidence interval of the median in vitro release rate ratio should be within the range of 75.00% to 133.33%). However, the release rate of retinoic acid in Example 7 is too fast (the 90% confidence interval of the median in vitro release rate ratio is 153.37 to 168.06%), and the release rate of retinoic acid in Example 8 is significantly reduced (the 90% confidence interval of the median in vitro release rate ratio is 19.20 to 21.25%), which are not conducive to ensuring the efficacy of the drug.

[0066] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. It should be pointed out that a person skilled in the art can make several improvements and modifications without departing from the technical principles of the present invention, and these improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A fluocinolone hydroquinone retinoic acid cream, characterized in that: The fluocinolone hydroquinone retinoic acid cream has the following prescription composition by mass percentage: 1-10% active pharmaceutical ingredient, 3-30% matrix, 0.01-1% preservative, 3-30% moisturizer, 0.01-1% antioxidant, 0.1-10% thickener, 0.5-10% emulsifier, 0-1% pH adjuster, and 40-80% water; the active pharmaceutical ingredient is a combination of fluocinolone, hydroquinone and retinoic acid; the moisturizer is a mixed moisturizer of glycerol and methyl gluceth-10 in a mass ratio of 1:1.5 to 1:3; the antioxidant includes antioxidant 1 and antioxidant 2, the antioxidant 1 includes one or more of butylated hydroxytoluene, butylated hydroxyanisole, and propyl penate, and the antioxidant 2 includes one or more of sodium pyrosulfite, sodium sulfite, and disodium edetate.

2. The fluocinolone hydroquinone retinoic acid cream according to claim 1, characterized in that In the preparation method of the fluocinolone hydroquinone tretinoin cream, the feeding temperature of tretinoin is 50°C to 65°C.

3. The fluocinolone hydroquinone retinoic acid cream according to claim 1, characterized in that In the preparation method of the fluocinolone hydroquinone retinoic acid cream, retinoic acid and fluocinolone are added separately at different temperatures.

4. The fluocinolone hydroquinone retinoic acid cream according to claim 1, characterized in that In the preparation method of the fluocinolone hydroquinone retinoic acid cream, the antioxidant 2 is added before the hydroquinone.

5. The fluocinolone hydroquinone retinoic acid cream according to claim 1, characterized in that The water is purified water obtained by deoxygenation at 85-100° C. for 0.5-1.5 hours.

6. The fluocinolone hydroquinone retinoic acid cream according to claim 1, characterized in that The thickener includes one or more of magnesium aluminum silicate, xanthan gum, and carbomer; the matrix includes one or more of cetyl alcohol, stearyl alcohol, stearic acid, white vaseline, cetostearyl alcohol, and castor oil; the pH adjuster includes one or more of citric acid, tartaric acid, hydrochloric acid, and acetic acid; the preservative includes one or more of methylparaben, propylparaben, and benzyl alcohol; the emulsifier includes 165 and / or a combination of glyceryl stearate and polyethylene glycol-100 stearate in a mass ratio of 1:

1.

7. The fluocinolone hydroquinone retinoic acid cream according to claim 1, characterized in that The fluocinolone hydroquinone retinoic acid cream has the following prescription composition by mass percentage: ， The emulsifier is 165 and / or a combination of glyceryl stearate and polyethylene glycol-100 stearate in a mass ratio of 1:

1.

8. A method for preparing the fluocinolone hydroquinone retinoic acid cream according to any one of claims 1 to 7, characterized in that: The preparation method comprises: Preparing a non-aqueous phase: preparing a non-aqueous phase at a temperature of 75 to 80° C., wherein the non-aqueous phase is made of a matrix and a preservative, and further comprises a mixed moisturizer of glycerol and methyl gluceth-10 in a mass ratio of 1:1.5 to 1:3, and maintaining the temperature of the non-aqueous phase at 75 to 80° C. for standby use; Preparing an aqueous phase: preparing an aqueous phase at a temperature of 75 to 80° C., wherein the aqueous phase is made of water, antioxidant 1 and a thickener, and the temperature of the aqueous phase is maintained at 75 to 80° C. for standby use; Emulsification: Add the non-aqueous phase to the aqueous phase and mix to obtain a two-phase mixed liquid, and cool it; when the two-phase mixed liquid is cooled to 68°C to 70°C, add an emulsifier and fluocinolone acetonide and mix; when the two-phase mixed liquid is cooled to 50°C to 65°C, add retinoic acid and a pH adjuster and mix; when the two-phase mixed liquid is cooled to 45 to 50°C, first add antioxidant 2 and mix, then add hydroquinone and mix, and mix homogeneously; stir and cool to room temperature to obtain the fluocinolone acetonide hydroquinone retinoic acid cream; nitrogen replacement protection is performed before and after the above feeding steps.

9. The preparation method according to claim 8, characterized in that: The method of adding the emulsifier and fluocinolone acetonide to the emulsification is as follows: firstly, the emulsifier is melted at 75-80°C, and then fluocinolone acetonide is added to the melted emulsifier to dissolve to obtain a fluocinolone acetonide-emulsifier solution, and then the fluocinolone acetonide-emulsifier solution is added to the two-phase mixed liquid cooled to 68-70°C and mixed.

10. The preparation method according to claim 8, characterized in that: In the preparation method, when the two-phase mixed liquid is cooled to 45-50° C., antioxidant 2 is first added and mixed, and then hydroquinone is added and mixed, and the mixture is homogenized for 5-20 minutes, and the operating temperature is maintained at 45-50° C. during the process.

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