Fluocinolone hydroquinone tretinoin acid cream and preparation method thereof

Abstract

The invention discloses fluocinolone hydroquinone tretinoin acid cream and a preparation method of the fluocinolone hydroquinone tretinoin acid cream. The invention provides a preparation method of fluocinonehydroquinone tretinoin emulsifiable paste, which comprises the following steps: S02, preparing an oil phase: mixing fatty glyceride, a fatty alcohol mixture, C12-C20 alkanoic acid and polyoxyethylene (35) castor oil, adding tretinoin, and then adding liquid alkane; s031, at the temperature of 60 DEG C to 80 DEG C, a pH regulator, polyhydric alcohol and the magnesium aluminum silicate gel are mixed; mixing with the oil phase in S02, stirring and emulsifying; and S032, mixing the product obtained in the step S031 with an antioxidant, fluocinonide and hydroquinone, stirring, and emulsifying. By improving the existing preparation method, the tretinoin can be effectively prevented from crystallizing, and the content uniformity of the tretinoin can be improved.

Description

Technical Field

[0001] The invention relates to fluocinolone hydroquinone retinoic acid cream and a preparation method thereof. Background Art

[0002] Melasma is a yellow-brown pigmentation spot on the face caused by a variety of factors. It is not an independent disease, but a subtype of skin melanosis. The rash often occurs on the face, neck, forearms, back of hands, etc. It usually worsens in spring and summer and eases in autumn and winter. It develops slowly and can last for many years. The disease is difficult to treat and is prone to recurrence, affecting people's appearance. In severe cases, it will affect people's mental health. It has gradually become a common skin problem that needs to be solved urgently.

[0003] At present, the main and common treatment methods are topical drugs, including 5% hydroquinone cream, 0.1% retinoic acid cream, 2% to 4% kojic acid cream, etc. Among them, the Kligman formula with more significant efficacy is called the gold standard for the treatment of chloasma. CN1738587B discloses a cream base containing the Kligman formula for the treatment of chloasma for local application and a method for preparing the cream base. The cream prepared by this method has poor stability and uniformity, and the active ingredients are easy to precipitate, and the incidence of side effects in clinical use is high. Chinese patent 20191055609.9 provides a preservative-free topical skin care composition, which is also a composition with a high amount of hydroquinone added. It focuses on the compounding of multiple antioxidants and other raw materials, so as to ensure that excellent antiseptic properties are obtained without the addition of preservatives. However, not much attention has been paid to the overall stability, impurity control and efficacy of the cream. Therefore, it is crucial to develop a method for preparing fluocinolone hydroquinone tretinoin cream with good stability, good uniformity, complete dissolution of the active ingredient, and low impurity levels. Summary of the invention

[0004] In order to solve the above problems, the present invention provides a fluocinolone hydroquinone tretinoin cream and a preparation method thereof. The preparation method of the present invention can overcome the above-mentioned shortcomings of the prior art, solve the problem of tretinoin crystallization, and further, improve phase stability and reduce impurity levels.

[0005] The present invention solves the above technical problems through the following technical solutions.

[0006] The present invention provides a method for preparing fluocinolone hydroquinone retinoic acid cream, which comprises the following steps:

[0007] Preparation of S02 oil phase: Fatty acid glyceride, fatty alcohol mixture, C 12 -C 20 Alkane acid and polyoxyethylene (35) castor oil are mixed, retinoic acid is added, and then liquid alkane is added;

[0008] S03 emulsification:

[0009] S031: Mix the pH regulator, polyol and magnesium aluminum silicate gel at 60-80°C; then mix with the oil phase in S02, stir and emulsify;

[0010] S032: Mix the product obtained in S031 with antioxidant, fluocinolone and hydroquinone, stir and emulsify.

[0011] In one embodiment, the magnesium aluminum silicate gel is prepared by S01 aqueous phase: magnesium aluminum silicate swells in water at 60-80°C.

[0012] In the present invention, there is no limit to the order of S01 and S02, for example, S01 is performed first and then S02, S02 is performed first and then S01, or S01 and S02 are performed simultaneously.

[0013] In a certain embodiment, after S032, the step S033 is further included: lowering the temperature to 35-45°C.

[0014] In a certain embodiment, the fluocinolone hydroquinone retinoic acid cream comprises the following components in parts by weight: 60-70 parts of water, 2-5 parts of magnesium aluminum silicate, 1-6 parts of liquid alkane, 2-6 parts of mixed fatty acid glyceride, 2-6 parts of fatty alcohol mixture, C 12 -C 20 1-3 parts of alkanoic acid, 5-10 parts of polyol, 0.1-1 parts of antioxidant, 0.02-0.1 parts of pH adjuster, 2-8 parts of polyoxyethylene (35) castor oil, 2-6 parts of hydroquinone, 0.03-0.1 parts of retinoic acid and 0.005-0.1 parts of fluocinolone.

[0015] In one embodiment, in the preparation of the SO2 oil phase, fatty acid glycerides, fatty alcohol mixture, C 12 -C 20 The alkanoic acid and polyoxyethylene (35) castor oil are mixed and heated and stirred.

[0016] In one embodiment, during the preparation of the SO2 oil phase, the temperature is raised to 60-80°C and retinoic acid is added; for example, the temperature is raised to 60-80°C, stirred for 10-30 minutes (for example, 20 minutes), and retinoic acid is added.

[0017] In one embodiment, during the preparation of the S02 oil phase, retinoic acid is added in the dark.

[0018] In one embodiment, during the preparation of the SO2 oil phase, after adding retinoic acid, stirring and dissolving, liquid alkane is then added; for example, stirring for 10-30 minutes, and for example, stirring for 20 minutes.

[0019] In one embodiment, during the preparation of the SO2 oil phase, after adding the liquid alkane, stirring is performed, for example, for 10-30 minutes, and for example, for 20 minutes.

[0020] In one embodiment, the preparation of SO2 oil phase comprises the following steps: mixing fatty acid glyceride, fatty alcohol mixture, C 12 -C 20 Mix the alkanoic acid and polyoxyethylene (35) castor oil, put them into an oil pan, turn on heating and stirring, raise the temperature to 60-80°C, stir for 20 minutes, add retinoic acid in a dark environment, and stir for 20 minutes; after dissolution, add liquid alkane and continue stirring for 20 minutes.

[0021] In one embodiment, the S03 emulsification is carried out under light-protected conditions.

[0022] In one embodiment, in S031, the pH adjuster and polyol are added to the magnesium aluminum silicate gel.

[0023] In one embodiment, in S031, the stirring is performed using an agitator, and the agitator is a combination of a low-speed agitator and a high-speed agitator; for example, the high-speed agitator is a high-shear jet emulsification mixer; for example, the low-speed agitator is a frame agitator equipped with a scraper agitator.

[0024] In a certain embodiment, the high shear jet emulsifying mixer has a stator and a rotor structure, the rotor rotates at a speed of more than 1000 r / min, and / or the gap between the stator and the rotor is less than 2 mm.

[0025] In a certain embodiment, the low-speed agitator has a main stirring blade in the shape of a frame, and the blades are distributed in the horizontal and vertical directions.

[0026] In one embodiment, the stirrer is Fig.18 shown.

[0027] In one embodiment, in S031, the stirring speed is a conventional speed in the art, such as 20-50 rpm, and another example is 30 rpm.

[0028] In one embodiment, in S031, the emulsification speed is a conventional speed in the art, for example, 1000-5000 rpm, and another example is 2000 rpm.

[0029] In one embodiment, in S031, the emulsification method is a conventional intermittent emulsification method in the art, for example, after stirring for 3 minutes, emulsification is started for 1 minute, and after emulsification stops, stirring is continued for 3 minutes and then emulsification is started again.

[0030] In one embodiment, in S031, the emulsification time is conventional in the art, for example, 10 minutes to 2 hours, and for example, 30 minutes.

[0031] In one solution, the vacuum pressure in the process of S031 is -0.04 to -0.06 MPa.

[0032] In one embodiment, in S032, the temperature at which hydroquinone is added is 40-50°C.

[0033] In one embodiment, in S032, the temperature for adding fluocinolone acetonide is 40-50°C.

[0034] In one embodiment, in S032, the antioxidant is added at a temperature of 40 to 50°C.

[0035] In one embodiment, in S032, an antioxidant is first added to S031, stirred, and emulsified, and then fluocinolone and hydroquinone are added; for example, the stirring, emulsification speed and emulsification method are the same as those of S031.

[0036] In a certain scheme, S032 includes the following steps: cooling the system to 40-50°C, stirring and emulsifying during the cooling process; after cooling, adding an antioxidant, keeping warm at 40-50°C, stirring, and emulsifying; after stirring and mixing evenly, adding fluocinolone to the system, and then adding hydroquinone, stirring, and emulsifying; for example, the stirring, emulsification speed and emulsification method in step S032 are the same as those in S031.

[0037] In a certain scheme, the vacuum pressure in the S032 process is -0.04 to -0.06 MPa.

[0038] In one embodiment, in S033, the temperature is lowered to 35-45°C, and stirring is performed during the cooling process. The stirring speed is conventional in the art, such as 10-50 rpm, and another example is 30 rpm.

[0039] In one solution, in S033, the vacuum pressure is maintained at -0.04 to -0.06 MPa during the cooling process.

[0040] In one embodiment, in S033, under inert gas conditions, the vacuum pressure is restored to normal pressure.

[0041] In one embodiment, in the preparation of the S01 aqueous phase, the swelling time of magnesium aluminum silicate is 5-24 hours, for example, 10 hours.

[0042] In a certain embodiment, the fluocinolone hydroquinone retinoic acid cream comprises the following components in parts by weight: 65.49 parts of water, 3.0 parts of magnesium aluminum silicate, 4.0 parts of liquid alkane, 3.5 parts of mixed fatty acid glyceride, 4 parts of fatty alcohol mixture, C 12 -C20 2 parts of alkanoic acid, 7.5 parts of polyol, 0.4 parts of antioxidant, 0.05 parts of pH adjuster, 6 parts of polyoxyethylene (35) castor oil, 4 parts of hydroquinone, 0.05 parts of retinoic acid and 0.01 parts of fluocinolone.

[0043] In one embodiment, the water is purified water.

[0044] In a certain embodiment, the liquid alkane mainly functions as a moisturizer to adjust the ointment state of the preparation, such as white vaseline and / or liquid paraffin; another example is white vaseline.

[0045] In a certain embodiment, the mixed fatty acid glyceride is C8-C 18 A mixture of mono-, di- and triesters of saturated fatty acids, for example, mixed fatty acid glyceride type 36.

[0046] In a certain embodiment, the fatty alcohol mixture is mainly used to increase the viscosity of the product, for example, one or more selected from cetyl alcohol, stearyl alcohol and cetostearyl alcohol, and another example is cetostearyl alcohol.

[0047] In one embodiment, the C 12 -C 20 The alkanoic acid is an alkanoic acid having a total carbon number of 12 to 20, such as lauric acid and / or stearic acid, and another example is stearic acid.

[0048] In a certain embodiment, the polyol is a diol and / or a triol; the diol is, for example, 1,2-propylene glycol; the triol is, for example, glycerol.

[0049] In a certain embodiment, the antioxidant is selected from one or more of butylated hydroxytoluene, sodium sulfite, sodium bisulfite and sodium metabisulfite; for example, sodium metabisulfite.

[0050] In one embodiment, the pH adjuster is lactic acid and / or citric acid, for example, lactic acid.

[0051] The present invention also provides a fluocinolone hydroquinone retinoic acid cream, which is prepared by the preparation method described in any of the above schemes.

[0052] In a certain embodiment, in the fluocinolone hydroquinone tretinoin cream, tretinoin will not crystallize.

[0053] In the present invention, polyoxyethylene (35) castor oil is a nonionic surfactant obtained by polymerization of castor oil and ethylene oxide, which means that about 35 moles of ethylene oxide are added to the castor oil molecule; polyoxyethylene (35) castor oil (for injection) is preferred, and polyoxyethylene (35) castor oil (for injection) produced by Nanjing Well Pharmaceutical Group Co., Ltd. is more preferred.

[0054] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0055] The reagents and raw materials used in the present invention are commercially available.

[0056] The positive and progressive effects of the present invention are:

[0057] The present invention can effectively prevent crystallization of retinoic acid and further improve the uniformity of retinoic acid content by improving the existing preparation method; further, it can also improve the phase stability of the cream while reducing the levels of hydroquinone and fluocinolone-related substances; the prepared cream is a shear-thinning pseudoplastic non-Newtonian fluid, has viscoelasticity, and has a suitable yield stress, so that the cream can be more convenient to produce, fill, apply and use. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1 This is a graph showing the centrifugal stability results of Examples 1 to 6 of the present invention.

[0059] Figure 2 This is a graph showing the centrifugal stability results of Examples 7 to 11 of the present invention.

[0060] Figure 3 This is a graph showing the thermal stability results of Examples 1 to 6 of the present invention.

[0061] Figure 4 This is a graph showing the thermal stability results of Examples 7 to 11 of the present invention.

[0062] Figure 5 This corresponds to the microscope image under a 40× objective lens of Example 1 of the present invention.

[0063] Figure 6 This corresponds to the microscope image under a 40× objective lens of Example 2 of the present invention.

[0064] Figure 7 This corresponds to the microscope image under a 40× objective lens of Example 3 of the present invention.

[0065] Figure 8 This corresponds to the microscope image under a 40× objective lens of Example 4 of the present invention.

[0066] Fig. 9 This corresponds to the microscope image under a 40× objective lens of Example 5 of the present invention.

[0067] Fig.10 This corresponds to the microscope image under a 40× objective lens of Example 6 of the present invention.

[0068] Fig.11 This corresponds to the microscope image under a 40× objective lens of Example 7 of the present invention.

[0069] Fig.12 This corresponds to the microscope image under a 40× objective lens of Example 8 of the present invention.

[0070] Fig.13 This corresponds to the microscope image under a 40× objective lens of Example 9 of the present invention.

[0071] Fig.14 This corresponds to the microscope image under a 40× objective lens of Example 10 of the present invention.

[0072] Fig.15 This corresponds to the microscope image under a 40× objective lens of Example 11 of the present invention.

[0073] Fig.16 This is a diagram of the ordinary stirring (frame stirring) used in Example 9 of the present invention.

[0074] Fig.17 This is a diagram of the common stirring (twisted paddle) used in Example 10 of the present invention.

[0075] Fig.18 This is a diagram of a special agitator used in the present invention. DETAILED DESCRIPTION

[0076] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0077] Example 1

[0078] The fluocinolone hydroquinone retinoic acid cream of the present embodiment comprises:

[0079] 65.49 parts of water, 3.0 parts of magnesium aluminum silicate, 4.0 parts of liquid alkane, 3.5 parts of mixed fatty acid glyceride, 4 parts of fatty alcohol mixture, C 12 -C 20 2 parts of alkanoic acid, 7.5 parts of polyol, 0.4 parts of antioxidant, 0.05 parts of pH adjuster, 6 parts of surfactant, 4 parts of hydroquinone, 0.05 parts of retinoic acid and 0.01 parts of fluocinolone.

[0080] Wherein, the liquid alkane is white vaseline.

[0081] The mixed fatty acid glyceride is type 36 mixed fatty acid glyceride.

[0082] The fatty alcohol mixture is cetostearyl alcohol.

[0083] The C 12 -C 20 The alkanoic acid is stearic acid.

[0084] The polyol is propylene glycol.

[0085] The antioxidant is sodium pyrosulfite.

[0086] The pH adjuster is citric acid.

[0087] The surfactant is polyoxyethylene (35) castor oil (for injection), produced by Nanjing Well Pharmaceutical Group Co., Ltd., batch number 20240301.

[0088] A preparation process of fluocinolone hydroquinone retinoic acid cream, comprising:

[0089] S01 water phase: weigh purified water and add it into the main pot, heat and stir. Heat the purified water to 60-80°C, add the weighed magnesium aluminum silicate, and swell for 10 hours.

[0090] S02 oil phase: Weigh the oil phase: mixed fatty acid glyceride, fatty alcohol mixture, C12-C20 alkanoic acid, put into an oil pan, turn on heating and stirring, raise the temperature to 60-80°C, stir for 20 minutes, add retinoic acid in the dark, stir for 20 minutes. After dissolution, add liquid alkane and continue stirring for 20 minutes.

[0091] S03 emulsification (protect from light):

[0092] S031 Control the temperature of the main pot at 60-80℃, add pH adjuster and polyol, and stir for 20 minutes. Pump the oil phase into the main pot and use a special stirrer. * Stir and emulsify for 10 minutes. After the initial emulsification is completed, add a surfactant (polyoxyethylene (35) castor oil) and continue stirring and emulsifying for 20 minutes. The stirring speed is 30 rpm, the emulsification speed is 2000 rpm, and the emulsification method is to stir for 3 minutes, start emulsification for 1 minute, and after the emulsification stops, stir for 3 minutes and then start emulsification again, and repeat the above operation; the vacuum pressure is maintained at -0.04 to -0.06 MPa.

[0093] S032: Lower the temperature of the main pot to 40-50℃. During the cooling process, the stirring, emulsification speed and emulsification method are the same as S031. After the cooling is completed, add the antioxidant, keep warm at 40-50℃, stir and emulsify for 30 minutes. The stirring, emulsification speed and emulsification method are the same as S031. After stirring and mixing evenly, add fluocinolone acetonide and hydroquinone, stir and emulsify for 30 minutes. The stirring, emulsification speed and emulsification method are the same as S031. The vacuum pressure is maintained at -0.04 to -0.06Mpa.

[0094] S033: Lower the temperature of the main pot to 35-45℃. During the cooling process, the stirring speed is 30rpm, and the vacuum pressure is maintained at -0.04-0.06Mpa. Use inert gas to restore the vacuum pressure of the main pot to normal pressure and then fill.

[0095] *Use special agitator: low-speed agitator combined with high-speed agitator, high-speed emulsification agitation uses high-shear jet emulsification agitator, which is divided into stator and rotor structure, the rotor rotates at a speed of more than 1000r / min, and the gap between the stator and the rotor is less than 2mm. The low-speed agitator is a frame-type agitator with scraping wall agitator. The main agitator blades are frame-shaped, and there are blades distributed in the horizontal and vertical directions, such as Fig.18 The "special agitator" mentioned in the following examples is the same as that in this example.

[0096] Example 2

[0097] The fluocinolone hydroquinone retinoic acid cream of the present embodiment comprises:

[0098] 65.49 parts of water, 3.0 parts of magnesium aluminum silicate, 4.0 parts of liquid alkane, 3.5 parts of mixed fatty acid glyceride, 4 parts of fatty alcohol mixture, C 12 -C 20 2 parts of alkanoic acid, 7.5 parts of polyol, 0.4 parts of antioxidant, 0.05 parts of pH adjuster, 6 parts of surfactant, 4 parts of hydroquinone, 0.05 parts of retinoic acid and 0.01 parts of fluocinolone.

[0099] Wherein, the liquid alkane is white vaseline.

[0100] The mixed fatty acid glyceride is type 36 mixed fatty acid glyceride.

[0101] The fatty alcohol mixture is cetostearyl alcohol.

[0102] The C 12 -C 20 The alkanoic acid is stearic acid.

[0103] The polyol is propylene glycol.

[0104] The antioxidant is sodium pyrosulfite.

[0105] The pH adjuster is citric acid.

[0106] The surfactant is polyoxyethylene (35) castor oil (for injection), produced by Nanjing Well Pharmaceutical Group Co., Ltd., batch number 20240301.

[0107] A preparation process of fluocinolone hydroquinone retinoic acid cream, comprising:

[0108] S01 water phase: weigh purified water and add it into the main pot, heat and stir. Heat the purified water to 60-80°C, add the weighed magnesium aluminum silicate, and swell for 10 hours.

[0109] S02 oil phase: Weigh the oil phase: mixed fatty acid glyceride, fatty alcohol mixture, C12-C20 alkanoic acid, put into an oil pan, turn on heating and stirring, raise the temperature to 60-80°C, stir for 20 minutes, add retinoic acid in the dark, stir for 20 minutes. After dissolution, add liquid alkane and continue stirring for 20 minutes.

[0110] S03 emulsification (protect from light):

[0111] S031 Control the temperature of the main pot at 60-80℃, add surfactant (polyoxyethylene (35) castor oil), pH adjuster, and polyol, and stir for 20 minutes. Pump the oil phase into the main pot, stir and emulsify for 30 minutes with a special stirrer. The stirring speed is 30rpm, the emulsification speed is 2000rpm, and the emulsification method is to stir for 3 minutes, then start emulsification for 1 minute, and after the emulsification stops, stir for 3 minutes and then start emulsification again, and repeat the above operation; the vacuum pressure is maintained at -0.04 to -0.06Mpa.

[0112] S032: Lower the temperature of the main pot to 40-50℃. During the cooling process, the stirring, emulsification speed and emulsification method are the same as S031. After the cooling is completed, add the antioxidant, keep warm at 40-50℃, stir and emulsify for 30 minutes. The stirring, emulsification speed and emulsification method are the same as S031. After stirring and mixing evenly, add fluocinolone acetonide and hydroquinone, stir and emulsify for 30 minutes. The stirring, emulsification speed and emulsification method are the same as S031. The vacuum pressure is maintained at -0.04 to -0.06Mpa.

[0113] S033: Lower the temperature of the main pot to 35-45℃. During the cooling process, the stirring speed is 30rpm, and the vacuum pressure is maintained at -0.04-0.06Mpa. Use inert gas to restore the vacuum pressure of the main pot to normal pressure and then fill.

[0114] Example 3

[0115] The fluocinolone hydroquinone retinoic acid cream of the present embodiment comprises:

[0116] 65.49 parts of water, 3.0 parts of magnesium aluminum silicate, 4.0 parts of liquid alkane, 3.5 parts of mixed fatty acid glyceride, 4 parts of fatty alcohol mixture, C 12 -C 20 2 parts of alkanoic acid, 7.5 parts of polyol, 0.4 parts of antioxidant, 0.05 parts of pH adjuster, 6 parts of surfactant, 4 parts of hydroquinone, 0.05 parts of retinoic acid and 0.01 parts of fluocinolone.

[0117] Wherein, the liquid alkane is white vaseline.

[0118] The mixed fatty acid glyceride is type 36 mixed fatty acid glyceride.

[0119] The fatty alcohol mixture is cetostearyl alcohol.

[0120] The C 12 -C 20 The alkanoic acid is stearic acid.

[0121] The polyol is propylene glycol.

[0122] The antioxidant is sodium pyrosulfite.

[0123] The pH adjuster is citric acid.

[0124] The surfactant is polyoxyethylene (35) castor oil (for injection), produced by Nanjing Well Pharmaceutical Group Co., Ltd., batch number 20240301.

[0125] A preparation process of fluocinolone hydroquinone retinoic acid cream, comprising:

[0126] S01 water phase: weigh purified water and add it into the main pot, heat and stir. Heat the purified water to 60-80°C, add the weighed magnesium aluminum silicate, and swell for 10 hours.

[0127] S02 oil phase: Weigh the oil phase: mixed fatty acid glycerides, fatty alcohol mixture, C12-C20 alkanoic acid, surfactant (polyoxyethylene (35) castor oil), liquid alkane, put into an oil pan, turn on heating and stirring, raise the temperature to 60-80°C, stir for 20 minutes, add retinoic acid in a dark place, and stir for 40 minutes.

[0128] S03 emulsification (protect from light):

[0129] S031 Control the temperature of the main pot at 60-80℃, add pH adjuster and polyol, and stir for 20 minutes. Pump the oil phase into the main pot, stir and emulsify for 30 minutes with a special stirrer. The stirring speed is 30rpm, the emulsification speed is 2000rpm, and the emulsification method is to stir for 3 minutes, then start emulsification for 1 minute, and after the emulsification stops, stir for 3 minutes and then start emulsification again, and repeat the above operation; the vacuum pressure is maintained at -0.04~-0.06Mpa.

[0130] S032: Lower the temperature of the main pot to 40-50℃. During the cooling process, the stirring, emulsification speed and emulsification method are the same as S031. After the cooling is completed, add the antioxidant, keep warm at 40-50℃, stir and emulsify for 30 minutes. The stirring, emulsification speed and emulsification method are the same as S031. After stirring and mixing evenly, add fluocinolone acetonide and hydroquinone, stir and emulsify for 30 minutes. The stirring, emulsification speed and emulsification method are the same as S031. The vacuum pressure is maintained at -0.04 to -0.06Mpa.

[0131] S033: Lower the temperature of the main pot to 35-45℃. During the cooling process, the stirring speed is 30rpm, and the vacuum pressure is maintained at -0.04-0.06Mpa. Use inert gas to restore the vacuum pressure of the main pot to normal pressure and then fill.

[0132] Example 4

[0133] The fluocinolone hydroquinone retinoic acid cream of the present embodiment comprises:

[0134] 65.49 parts of water, 3.0 parts of magnesium aluminum silicate, 4.0 parts of liquid alkane, 3.5 parts of mixed fatty acid glyceride, 4 parts of fatty alcohol mixture, C 12 -C 20 2 parts of alkanoic acid, 7.5 parts of polyol, 0.4 parts of antioxidant, 0.05 parts of pH adjuster, 6 parts of surfactant, 4 parts of hydroquinone, 0.05 parts of retinoic acid and 0.01 parts of fluocinolone.

[0135] Wherein, the liquid alkane is white vaseline.

[0136] The mixed fatty acid glyceride is type 36 mixed fatty acid glyceride.

[0137] The fatty alcohol mixture is cetostearyl alcohol.

[0138] The C 12 -C 20 The alkanoic acid is stearic acid.

[0139] The polyol is propylene glycol.

[0140] The antioxidant is sodium pyrosulfite.

[0141] The pH adjuster is citric acid.

[0142] The surfactant is 165.

[0143] A preparation process of fluocinolone hydroquinone retinoic acid cream, comprising:

[0144] S01 water phase: weigh purified water and add it into the main pot, heat and stir. Heat the purified water to 60-80°C, add the weighed magnesium aluminum silicate, and swell for 10 hours.

[0145] S02 oil phase: weigh the oil phase: mixed fatty acid glyceride, fatty alcohol mixture, C12-C20 alkanoic acid, surfactant ( 165), put into oil pan, turn on heating and stirring, raise the temperature to 60-80°C, stir for 20 minutes, add retinoic acid in dark place, stir for 20 minutes. After dissolution, add liquid alkane and continue stirring for 20 minutes.

[0146] S03 emulsification (protect from light):

[0147] S031 Control the temperature of the main pot at 60-80℃, add pH adjuster and polyol, and stir for 20 minutes. Pump the oil phase into the main pot, stir and emulsify for 30 minutes with a special stirrer. The stirring speed is 30rpm, the emulsification speed is 2000rpm, and the emulsification method is to stir for 3 minutes, then start emulsification for 1 minute, and after the emulsification stops, stir for 3 minutes and then start emulsification again, and repeat the above operation; the vacuum pressure is maintained at -0.04~-0.06Mpa.

[0148] S032: Lower the temperature of the main pot to 40-50℃. During the cooling process, the stirring, emulsification speed and emulsification method are the same as S031. After the cooling is completed, add the antioxidant, keep warm at 40-50℃, stir and emulsify for 30 minutes. The stirring, emulsification speed and emulsification method are the same as S031. After stirring and mixing evenly, dissolve fluocinolone in 3.5 parts of polyol at a temperature of 40-50℃, add them to the main pot, add fluocinolone and hydroquinone, stir and emulsify for 30 minutes. The stirring, emulsification speed and emulsification method are the same as S031. The vacuum pressure is maintained at -0.04 to -0.06Mpa.

[0149] S033: Lower the temperature of the main pot to 35-45℃. During the cooling process, the stirring speed is 30rpm, and the vacuum pressure is maintained at -0.04-0.06Mpa. Use inert gas to restore the vacuum pressure of the main pot to normal pressure and then fill.

[0150] Example 5

[0151] The fluocinolone hydroquinone retinoic acid cream of the present embodiment comprises:

[0152] 65.49 parts of water, 3.0 parts of magnesium aluminum silicate, 4.0 parts of liquid alkane, 3.5 parts of mixed fatty acid glyceride, 4 parts of fatty alcohol mixture, C 12 -C 20 2 parts of alkanoic acid, 7.5 parts of polyol, 0.4 parts of antioxidant, 0.05 parts of pH adjuster, 6 parts of surfactant, 4 parts of hydroquinone, 0.05 parts of retinoic acid and 0.01 parts of fluocinolone.

[0153] Wherein, the liquid alkane is white vaseline.

[0154] The mixed fatty acid glyceride is type 36 mixed fatty acid glyceride.

[0155] The fatty alcohol mixture is cetostearyl alcohol.

[0156] The C 12 -C 20 The alkanoic acid is stearic acid.

[0157] The polyol is propylene glycol.

[0158] The antioxidant is sodium pyrosulfite.

[0159] The pH adjuster is citric acid.

[0160] The surfactant is polysorbate 80.

[0161] A preparation process of fluocinolone hydroquinone retinoic acid cream, comprising:

[0162] S01 water phase: weigh purified water and add it into the main pot, heat and stir. Heat the purified water to 60-80°C, add the weighed magnesium aluminum silicate, and swell for 10 hours.

[0163] S02 oil phase: Weigh the oil phase: mixed fatty acid glyceride, fatty alcohol mixture, C12-C20 alkanoic acid, surfactant (polysorbate 80), put into an oil pan, turn on heating and stirring, raise the temperature to 60-80°C, stir for 20 minutes, add retinoic acid in a dark place, stir for 20 minutes. After dissolution, add liquid alkane and continue stirring for 20 minutes.

[0164] S03 emulsification (protect from light):

[0165] S031 Control the temperature of the main pot at 60-80℃, add pH adjuster and polyol, and stir for 20 minutes. Pump the oil phase into the main pot, stir and emulsify for 30 minutes with a special stirrer. The stirring speed is 30rpm, the emulsification speed is 2000rpm, and the emulsification method is to stir for 3 minutes, then start emulsification for 1 minute, and after the emulsification stops, stir for 3 minutes and then start emulsification again, and repeat the above operation; the vacuum pressure is maintained at -0.04~-0.06Mpa.

[0166] S032: Lower the temperature of the main pot to 40-50℃. During the cooling process, the stirring, emulsification speed and emulsification method are the same as S031. After the cooling is completed, add the antioxidant, keep warm at 40-50℃, stir and emulsify for 30 minutes. The stirring, emulsification speed and emulsification method are the same as S031. After stirring and mixing evenly, add fluocinolone acetonide and hydroquinone, stir and emulsify for 30 minutes. The stirring, emulsification speed and emulsification method are the same as S031. The vacuum pressure is maintained at -0.04 to -0.06Mpa.

[0167] S033: Lower the temperature of the main pot to 35-45℃. During the cooling process, the stirring speed is 30rpm, and the vacuum pressure is maintained at -0.04-0.06Mpa. Use inert gas to restore the vacuum pressure of the main pot to normal pressure and then fill.

[0168] Example 6

[0169] The fluocinolone hydroquinone retinoic acid cream of the present embodiment comprises:

[0170] 65.49 parts of water, 3.0 parts of magnesium aluminum silicate, 4.0 parts of liquid alkane, 3.5 parts of mixed fatty acid glyceride, 4 parts of fatty alcohol mixture, C 12 -C 20 2 parts of alkanoic acid, 7.5 parts of polyol, 0.4 parts of antioxidant, 0.05 parts of pH adjuster, 6 parts of surfactant, 4 parts of hydroquinone, 0.05 parts of retinoic acid and 0.01 parts of fluocinolone.

[0171] Wherein, the liquid alkane is white vaseline.

[0172] The mixed fatty acid glyceride is type 36 mixed fatty acid glyceride.

[0173] The fatty alcohol mixture is cetostearyl alcohol.

[0174] The C 12 -C 20 The alkanoic acid is stearic acid.

[0175] The polyol is propylene glycol.

[0176] The antioxidant is sodium pyrosulfite.

[0177] The pH adjuster is citric acid.

[0178] The surfactant is polyoxyethylene (35) castor oil (for injection), produced by Nanjing Well Pharmaceutical Group Co., Ltd., batch number 20240301.

[0179] A preparation process of fluocinolone hydroquinone retinoic acid cream, comprising:

[0180] S01 water phase: weigh purified water and add it into the main pot, heat and stir. Heat the purified water to 60-80°C, add the weighed magnesium aluminum silicate, and swell for 10 hours.

[0181] S02 oil phase: Weigh the oil phase: mixed fatty acid glyceride, fatty alcohol mixture, C12-C20 alkanoic acid, surfactant (polyoxyethylene (35) castor oil), put into an oil pan, turn on heating and stirring, raise the temperature to 60-80°C, stir for 20 minutes, add retinoic acid in a dark place, stir for 20 minutes. After dissolution, add liquid alkane and continue stirring for 20 minutes.

[0182] S03 emulsification (protect from light):

[0183] S031 Control the temperature of the main pot at 60-80℃, add pH adjuster, polyol, antioxidant, and stir for 20 minutes. Pump the oil phase into the main pot, stir and emulsify for 30 minutes with a special stirrer. The stirring speed is 30rpm, the emulsification speed is 2000rpm, and the emulsification method is to stir for 3 minutes, then start emulsification for 1 minute, and after the emulsification stops, stir for 3 minutes and then start emulsification again, and repeat the above operation; the vacuum pressure is maintained at -0.04~-0.06Mpa.

[0184] After S032 is stirred and mixed evenly, add fluocinolone acetonide and hydroquinone, stir and emulsify for 30 minutes. The stirring, emulsification speed and emulsification method are the same as S031, and the vacuum pressure is maintained at -0.04 to -0.06Mpa.

[0185] S033: Lower the temperature of the main pot to 35-45℃. During the cooling process, the stirring speed is 30rpm, and the vacuum pressure is maintained at -0.04-0.06Mpa. Use inert gas to restore the vacuum pressure of the main pot to normal pressure and then fill.

[0186] Example 7

[0187] The fluocinolone hydroquinone retinoic acid cream of the present embodiment comprises:

[0188] 65.49 parts of water, 3.0 parts of magnesium aluminum silicate, 4.0 parts of liquid alkane, 3.5 parts of mixed fatty acid glyceride, 4 parts of fatty alcohol mixture, C 12 -C 20 2 parts of alkanoic acid, 7.5 parts of polyol, 0.4 parts of antioxidant, 0.05 parts of pH adjuster, 6 parts of surfactant, 4 parts of hydroquinone, 0.05 parts of retinoic acid and 0.01 parts of fluocinolone.

[0189] Wherein, the liquid alkane is white vaseline.

[0190] The mixed fatty acid glyceride is type 36 mixed fatty acid glyceride.

[0191] The fatty alcohol mixture is cetostearyl alcohol.

[0192] The C 12 -C 20 The alkanoic acid is stearic acid.

[0193] The polyol is propylene glycol.

[0194] The antioxidant is sodium pyrosulfite.

[0195] The pH adjuster is citric acid.

[0196] The surfactant is polyoxyethylene (35) castor oil (for injection), produced by Nanjing Well Pharmaceutical Group Co., Ltd., batch number 20240301.

[0197] A preparation process of fluocinolone hydroquinone retinoic acid cream, comprising:

[0198] S01 water phase: weigh purified water and add it into the main pot, heat and stir. Heat the purified water to 60-80°C, add the weighed magnesium aluminum silicate, and swell for 10 hours.

[0199] S02 oil phase: Weigh the oil phase: mixed fatty acid glyceride, fatty alcohol mixture, C12-C20 alkanoic acid, surfactant (polyoxyethylene (35) castor oil), put into an oil pan, turn on heating and stirring, raise the temperature to 60-80°C, stir for 20 minutes, add retinoic acid in a dark place, stir for 20 minutes. After dissolution, add liquid alkane and continue stirring for 20 minutes.

[0200] S03 emulsification (protect from light):

[0201] S031 Control the temperature of the main pot at 60-80℃, add pH adjuster and polyol, and stir for 20 minutes. Pump the oil phase into the main pot, stir and emulsify for 30 minutes with a special stirrer. The stirring speed is 30rpm, the emulsification speed is 2000rpm, and the emulsification method is to stir for 3 minutes, then start emulsification for 1 minute, and after the emulsification stops, stir for 3 minutes and then start emulsification again, and repeat the above operation; the vacuum pressure is maintained at -0.04~-0.06Mpa.

[0202] S032: Lower the temperature of the main pot to 40-50℃. During the cooling process, the stirring, emulsification speed and emulsification method are the same as S031. After the cooling is completed, add antioxidant, fluocinolone acetonide and hydroquinone, keep warm at 40-50℃, stir and emulsify for 30 minutes, the stirring, emulsification speed and emulsification method are the same as S031, and the vacuum pressure is maintained at -0.04--0.06Mpa.

[0203] S033: Lower the temperature of the main pot to 35-45℃. During the cooling process, the stirring speed is 30rpm, and the vacuum pressure is maintained at -0.04-0.06Mpa. Use inert gas to restore the vacuum pressure of the main pot to normal pressure and then fill.

[0204] Example 8

[0205] The fluocinolone hydroquinone retinoic acid cream of the present embodiment comprises:

[0206] 65.49 parts of water, 3.0 parts of magnesium aluminum silicate, 4.0 parts of liquid alkane, 3.5 parts of mixed fatty acid glyceride, 4 parts of fatty alcohol mixture, C 12 -C 20 2 parts of alkanoic acid, 7.5 parts of polyol, 0.4 parts of antioxidant, 0.05 parts of pH adjuster, 6 parts of surfactant, 4 parts of hydroquinone, 0.05 parts of retinoic acid and 0.01 parts of fluocinolone.

[0207] Wherein, the liquid alkane is white vaseline.

[0208] The mixed fatty acid glyceride is type 36 mixed fatty acid glyceride.

[0209] The fatty alcohol mixture is cetostearyl alcohol.

[0210] The C 12 -C 20 The alkanoic acid is stearic acid.

[0211] The polyol is propylene glycol.

[0212] The antioxidant is sodium pyrosulfite.

[0213] The pH adjuster is citric acid.

[0214] The surfactant is polyoxyethylene (35) castor oil (for injection), produced by Nanjing Well Pharmaceutical Group Co., Ltd., batch number 20240301.

[0215] A preparation process of fluocinolone hydroquinone retinoic acid cream, comprising:

[0216] S01 water phase: weigh purified water and add it into the main pot, heat and stir. Heat the purified water to 60-80°C, add the weighed magnesium aluminum silicate, and swell for 10 hours.

[0217] S02 oil phase: Weigh the oil phase: mixed fatty acid glyceride, fatty alcohol mixture, C12-C20 alkanoic acid, surfactant (polyoxyethylene (35) castor oil), put into an oil pan, turn on heating and stirring, raise the temperature to 60-80°C, stir for 20 minutes, add retinoic acid in a dark place, stir for 20 minutes. After dissolution, add liquid alkane and continue stirring for 20 minutes.

[0218] S03 emulsification (protect from light):

[0219] S031 Control the temperature of the main pot at 60-80℃, add pH adjuster and polyol, and stir for 20 minutes. Pump the oil phase into the main pot, stir and emulsify for 30 minutes with a special stirrer. The stirring speed is 30rpm, the emulsification speed is 2000rpm, and the emulsification method is to stir for 3 minutes, then start emulsification for 1 minute, and after the emulsification stops, stir for 3 minutes and then start emulsification again, and repeat the above operation; the vacuum pressure is maintained at -0.04~-0.06Mpa.

[0220] S032: Lower the temperature of the main pot to 40-50℃. During the cooling process, the stirring, emulsification speed and emulsification method are the same as S031. After the cooling is completed, add the antioxidant, keep warm at 40-50℃, stir and emulsify for 30 minutes. The stirring, emulsification speed and emulsification method are the same as S031. After stirring and mixing evenly, add fluocinolone acetonide and hydroquinone, stir and emulsify for 30 minutes. The stirring, emulsification speed and emulsification method are the same as S031. The vacuum pressure is maintained at -0.04 to -0.06Mpa.

[0221] S033: Lower the temperature of the main pot to 35-45℃. During the cooling process, the stirring speed is 30rpm and the vacuum pressure is maintained at -0.04-0.06Mpa. Introduce air to restore the vacuum pressure of the main pot to normal pressure and then fill.

[0222] Example 9

[0223] The fluocinolone hydroquinone retinoic acid cream of the present embodiment comprises:

[0224] 65.49 parts of water, 3.0 parts of magnesium aluminum silicate, 4.0 parts of liquid alkane, 3.5 parts of mixed fatty acid glyceride, 4 parts of fatty alcohol mixture, C 12 -C 20 2 parts of alkanoic acid, 7.5 parts of polyol, 0.4 parts of antioxidant, 0.05 parts of pH adjuster, 6 parts of surfactant, 4 parts of hydroquinone, 0.05 parts of retinoic acid and 0.01 parts of fluocinolone.

[0225] Wherein, the liquid alkane is white vaseline.

[0226] The mixed fatty acid glyceride is type 36 mixed fatty acid glyceride.

[0227] The fatty alcohol mixture is cetostearyl alcohol.

[0228] The C 12 -C 20 The alkanoic acid is stearic acid.

[0229] The polyol is propylene glycol.

[0230] The antioxidant is sodium pyrosulfite.

[0231] The pH adjuster is citric acid.

[0232] The surfactant is polyoxyethylene (35) castor oil (for injection), produced by Nanjing Well Pharmaceutical Group Co., Ltd., batch number 20240301.

[0233] A preparation process of fluocinolone hydroquinone retinoic acid cream, comprising:

[0234] S01 water phase: weigh purified water and add it into the main pot, heat and stir. Heat the purified water to 60-80°C, add the weighed magnesium aluminum silicate, and swell for 10 hours.

[0235] S02 oil phase: Weigh the oil phase: mixed fatty acid glyceride, fatty alcohol mixture, C12-C20 alkanoic acid, surfactant (polyoxyethylene (35) castor oil), put into an oil pan, turn on heating and stirring, raise the temperature to 60-80°C, stir for 20 minutes, add retinoic acid in a dark place, stir for 20 minutes. After dissolution, add liquid alkane and continue stirring for 20 minutes.

[0236] S03 emulsification (protect from light):

[0237] S031 Control the temperature of the main pot at 60-80℃, add pH adjuster and polyol, and stir for 20 minutes. Pump the oil phase into the main pot, stir and emulsify for 30 minutes with a twist paddle. The stirring speed is 30rpm, the emulsification speed is 2000rpm, and the emulsification method is to stir for 3 minutes, then start emulsification for 1 minute, and after the emulsification stops, stir for 3 minutes and then start emulsification again, and repeat the above operation; the vacuum pressure is maintained at -0.04~-0.06Mpa.

[0238] S032: Lower the temperature of the main pot to 40-50℃. During the cooling process, the stirring, emulsification speed and emulsification method are the same as S031. After the cooling is completed, add the antioxidant, keep warm at 40-50℃, stir and emulsify for 30 minutes. The stirring, emulsification speed and emulsification method are the same as S031. After stirring and mixing evenly, add fluocinolone acetonide and hydroquinone, stir and emulsify for 30 minutes. The stirring, emulsification speed and emulsification method are the same as S031. The vacuum pressure is maintained at -0.04 to -0.06Mpa.

[0239] S033: Lower the temperature of the main pot to 35-45℃. During the cooling process, the stirring speed is 30rpm, and the vacuum pressure is maintained at -0.04-0.06Mpa. Use inert gas to restore the vacuum pressure of the main pot to normal pressure and then fill.

[0240] Example 10

[0241] The fluocinolone hydroquinone retinoic acid cream of the present embodiment comprises:

[0242] 65.49 parts of water, 3.0 parts of magnesium aluminum silicate, 4.0 parts of liquid alkane, 3.5 parts of mixed fatty acid glyceride, 4 parts of fatty alcohol mixture, C 12 -C 20 2 parts of alkanoic acid, 7.5 parts of polyol, 0.4 parts of antioxidant, 0.05 parts of pH adjuster, 6 parts of surfactant, 4 parts of hydroquinone, 0.05 parts of retinoic acid and 0.01 parts of fluocinolone.

[0243] Wherein, the liquid alkane is white vaseline.

[0244] The mixed fatty acid glyceride is type 36 mixed fatty acid glyceride.

[0245] The fatty alcohol mixture is cetostearyl alcohol.

[0246] The C 12 -C 20 The alkanoic acid is stearic acid.

[0247] The polyol is propylene glycol.

[0248] The antioxidant is sodium pyrosulfite.

[0249] The pH adjuster is citric acid.

[0250] The surfactant is polyoxyethylene (35) castor oil (for injection), produced by Nanjing Well Pharmaceutical Group Co., Ltd., batch number 20240301.

[0251] A preparation process of fluocinolone hydroquinone retinoic acid cream, comprising:

[0252] S01 water phase: weigh purified water and add it into the main pot, heat and stir. Heat the purified water to 60-80°C, add the weighed magnesium aluminum silicate, and swell for 10 hours.

[0253] S02 oil phase: Weigh the oil phase: mixed fatty acid glyceride, fatty alcohol mixture, C12-C20 alkanoic acid, surfactant (polyoxyethylene (35) castor oil), put into an oil pan, turn on heating and stirring, raise the temperature to 60-80°C, stir for 20 minutes, add retinoic acid in a dark place, stir for 20 minutes. After dissolution, add liquid alkane and continue stirring for 20 minutes.

[0254] S03 emulsification (protect from light):

[0255] S031 Control the temperature of the main pot at 60-80℃, add pH adjuster and polyol, and stir for 20 minutes. Pump the oil phase into the main pot, stir and emulsify for 30 minutes with ordinary frame stirring. The stirring speed is 30rpm, the emulsification speed is 2000rpm, and the emulsification method is to stir for 3 minutes, then start emulsification for 1 minute, and after the emulsification stops, stir for 3 minutes and then start emulsification again, and repeat the above operation; the vacuum pressure is maintained at -0.04~-0.06Mpa.

[0256] S032: Lower the temperature of the main pot to 40-50℃. During the cooling process, the stirring, emulsification speed and emulsification method are the same as S031. After the cooling is completed, add the antioxidant, keep warm at 40-50℃, stir and emulsify for 30 minutes. The stirring, emulsification speed and emulsification method are the same as S031. After stirring and mixing evenly, add fluocinolone acetonide and hydroquinone, stir and emulsify for 30 minutes. The stirring, emulsification speed and emulsification method are the same as S031. The vacuum pressure is maintained at -0.04 to -0.06Mpa.

[0257] S033: Lower the temperature of the main pot to 35-45℃. During the cooling process, the stirring speed is 30rpm, and the vacuum pressure is maintained at -0.04-0.06Mpa. Use inert gas to restore the vacuum pressure of the main pot to normal pressure and then fill.

[0258] Embodiment 11

[0259] The fluocinolone hydroquinone retinoic acid cream of the present embodiment comprises:

[0260] 65.49 parts of water, 3.0 parts of magnesium aluminum silicate, 4.0 parts of liquid alkane, 3.5 parts of mixed fatty acid glyceride, 4 parts of fatty alcohol mixture, C 12 -C 20 2 parts of alkanoic acid, 7.5 parts of polyol, 0.4 parts of antioxidant, 0.05 parts of pH adjuster, 6 parts of surfactant, 4 parts of hydroquinone, 0.05 parts of retinoic acid and 0.01 parts of fluocinolone.

[0261] Wherein, the liquid alkane is white vaseline.

[0262] The mixed fatty acid glyceride is type 36 mixed fatty acid glyceride.

[0263] The fatty alcohol mixture is cetostearyl alcohol.

[0264] The C 12 -C 20 The alkanoic acid is stearic acid.

[0265] The polyol is propylene glycol.

[0266] The antioxidant is sodium pyrosulfite.

[0267] The pH adjuster is citric acid.

[0268] The surfactant is polyoxyethylene (35) castor oil (for injection), produced by Nanjing Well Pharmaceutical Group Co., Ltd., batch number 20240301.

[0269] A preparation process of fluocinolone hydroquinone retinoic acid cream, comprising:

[0270] S01 water phase: weigh purified water and add it into the main pot, heat and stir. Heat the purified water to 60-80°C, add the weighed magnesium aluminum silicate, and swell for 10 hours.

[0271] S02 oil phase: Weigh the oil phase: mixed fatty acid glyceride, fatty alcohol mixture, C12-C20 alkanoic acid, surfactant (polyoxyethylene (35) castor oil), put into an oil pan, turn on heating and stirring, raise the temperature to 60-80°C, stir for 20 minutes, add retinoic acid in a dark place, stir for 20 minutes. After dissolution, add liquid alkane and continue stirring for 20 minutes.

[0272] S03 emulsification (protect from light):

[0273] S031 Control the temperature of the main pot at 60-80℃, add pH adjuster and polyol, and stir for 20 minutes. Pump the oil phase into the main pot, stir and emulsify for 30 minutes with a special stirrer. The stirring speed is 30rpm, the emulsification speed is 2000rpm, and the emulsification method is to stir for 3 minutes, then start emulsification for 1 minute, and after the emulsification stops, stir for 3 minutes and then start emulsification again, and repeat the above operation; the vacuum pressure is maintained at -0.04~-0.06Mpa.

[0274] S032: Lower the temperature of the main pot to 40-50℃. During the cooling process, the stirring, emulsification speed and emulsification method are the same as S031. After the cooling is completed, add the antioxidant, keep warm at 40-50℃, stir and emulsify for 30 minutes. The stirring, emulsification speed and emulsification method are the same as S031. After stirring and mixing evenly, add fluocinolone acetonide and hydroquinone, stir and emulsify for 30 minutes. The stirring, emulsification speed and emulsification method are the same as S031. The vacuum pressure is maintained at -0.04 to -0.06Mpa.

[0275] S033: Lower the temperature of the main pot to 35-45℃. During the cooling process, the stirring speed is 30rpm, and the vacuum pressure is maintained at -0.04-0.06Mpa. Use inert gas to restore the vacuum pressure of the main pot to normal pressure and then fill.

[0276] Examples 1-5 and Examples 6-11 are summarized in Tables 1 and 2 below:

[0277] Table 1

[0278]

[0279] Table 2

[0280]

[0281]

[0282] Effect test example:

[0283] The phase stability, crystallization and impurity level of the products obtained in the above embodiments were tested. The testing method is as follows:

[0284] 1. Inspection methods for each item:

[0285] 1. Centrifugal stability test method: Centrifugal conditions are speed 10000r / min, time 10min, temperature 25℃, centrifuge, check whether there is phase separation (oil-water stratification). The experimental results are as follows Figure 1-2 shown by Figure 1 , Figure 2 It can be seen that: the creams in centrifuge tubes No. 1, 2, 3, 7, 8, and 11 in the figure have a uniform texture without stratification; the cream in centrifuge tube No. 4 is divided into three layers (a transparent liquid layer is visible in the middle); the creams in centrifuge tubes No. 5, 6, 9, and 10 are divided into two layers (a transparent liquid layer is visible on the top).

[0286] 2. Thermal stability test method: Place the prepared cream in a glass test tube and place it in a 55°C water bath for 2 hours to observe whether the cream has phase separation (oil-water stratification). Figure 3-4 shown.

[0287] 3. Method for checking crystallization: Take a small amount of cream sample and place it on a glass slide, cover it lightly with a cover slip to avoid bubbles. Place the glass slide on the stage of an optical microscope, find the sample area under a 40× objective lens, and observe. The experimental results are as follows: Figure 5-15 shown.

[0288] 4. Methods for inspection of related substances:

[0289] 2. Retinoic acid related substances were determined according to the high performance liquid chromatography method (General Rule 0512). Operation was performed in a dark environment.

[0290] Take about 5 g of the product (equivalent to 2.5 mg of retinoic acid) and add 5 ml of isopropanol. Heat and stir in a 60°C water bath to disperse evenly. Transfer to a 50 ml volumetric flask with methanol, cool, dilute to the mark with methanol, shake well, filter, and take the filtrate.

[0291] Control solution: Accurately measure 1 ml of the test solution, place it in a 100 ml volumetric flask, dilute to the scale with methanol-isopropanol (90:10), shake well, filter, and take the filtrate.

[0292] Chromatographic conditions: octadecylsilane bonded silica gel was used as filler; methanol-2% glacial acetic acid (81:19) was used as mobile phase; detection wavelength was 350 nm; injection volume was 20 μl.

[0293] Determination method: Accurately measure the control solution and the test solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0294] 3. Related substances of fluocinolone are determined according to high performance liquid chromatography (General Rule 0512).

[0295] Test solution: Take about 4 g of the product (equivalent to about 0.4 mg of fluocinolone acetonide), weigh accurately, add 10 ml of methanol-trifluoroacetic acid (100:0.06), heat and stir in a 55°C water bath to disperse evenly, rinse with 7.5 ml of methanol-trifluoroacetic acid (100:0.06) into a 25 ml volumetric flask, cool, dilute to the scale with water, shake well, ice bath for 10 minutes, centrifuge, filter, and take the filtrate.

[0296] Blank solution: Take about 4 g of blank cream without fluocinolone acetonide, weigh accurately, add 10 ml of methanol-trifluoroacetic acid (100:0.06), heat and stir in a 55°C water bath to make it evenly dispersed, rinse with 7.5 ml of methanol-trifluoroacetic acid (100:0.06) into a 25 ml volumetric flask, cool, dilute to the scale with water, shake well, ice bath for 10 minutes, centrifuge, filter, and take the filtrate.

[0297] Reference solution Take an appropriate amount of fluocinolone reference, weigh accurately, dissolve and dilute with methanol-water-trifluoroacetic acid (700:300:0.42) to make a solution containing about 0.8 μg per 1 ml.

[0298] System suitability solution Take appropriate amounts of impurity D, impurity N and fluocinolone acetonide reference substance, dissolve and dilute with methanol-water-trifluoroacetic acid (700:300:0.42) to make a solution containing approximately 0.16 μg of impurity D, 1.2 μg of impurity N and 16 μg of fluocinolone acetonide per 1 ml.

[0299] System suitability requires that in the chromatogram of the reference solution, the number of theoretical plates calculated based on the main peak should not be less than 3000.

[0300] Chromatographic conditions: octadecylsilane bonded silica gel was used as filler; water-tetrahydrofuran-trifluoroacetic acid (980:20:0.7) was used as mobile phase A, acetonitrile-tetrahydrofuran (980:20) was used as mobile phase B, and gradient elution was performed according to Table 3; the detection wavelength was 238 nm; the flow rate was 0.8 ml per minute; and the injection volume was 50 μl.

[0301] Table 3

[0302]

[0303] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0304] 4. Hydroquinone-related substances shall be determined according to the high performance liquid chromatography method (General Rule 0512).

[0305] Test solution Take about 2.5g of this product (equivalent to 100mg of hydroquinone), add an appropriate amount of methanol, stir to disperse evenly, transfer to a 25ml volumetric flask, dilute to the mark with methanol, and shake well. Accurately measure 1ml, place in a 25ml volumetric flask, dilute to the mark with mobile phase, shake well, filter, and take the filtrate. Prepare fresh before use.

[0306] Reference solution: Take appropriate amount of calcium hydroxybenzenesulfonate and p-benzoquinone reference, place in a 20ml volumetric flask, weigh accurately, add methanol to dissolve and dilute to the scale, shake well, accurately transfer an appropriate amount, add mobile phase to quantitatively dilute to make a solution containing approximately 2.7μg calcium hydroxybenzenesulfonate and 0.8μg p-benzoquinone per 1ml.

[0307] The chromatographic conditions used octadecylsilane bonded silica gel as the filler; potassium dihydrogen phosphate solution (take 1.36 g of potassium dihydrogen phosphate, add 1 L of water to dissolve, and adjust the pH to 3.0 with phosphoric acid)-methanol (90:10) as the mobile phase; the detection wavelengths were 246 nm and 291 nm; the injection volume was 20 μl.

[0308] System suitability requires that in the chromatogram of the reference solution, the theoretical plate number calculated based on the hydroxybenzenesulfonic acid peak and the p-benzoquinone peak should not be less than 3000.

[0309] Determination method: Accurately measure the reference solution and the test solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0310] 5. Method for checking uniformity in containers

[0311] Take the cream after filling, cut it open, and observe visually. There should be no phase separation phenomenon and no obvious difference in appearance. Take appropriate amount of cream from the tail end, middle end and cap end respectively, weigh accurately, prepare the test solution according to the following method, and determine it according to the method under the content determination item. The content of each end should meet the requirements, and the extreme difference shall not exceed 10.0%.

[0312] Take about 1g of this product (equivalent to about 0.5mg of retinoic acid), weigh accurately, add 5ml of isopropanol, heat in a 60℃ water bath and stir to disperse evenly, transfer to a 50ml volumetric flask, cool, dilute to the scale with methanol, shake well, filter, and take the filtrate as the retinoic acid test solution.

[0313] Take about 0.8g of this product (equivalent to about 0.08mg of fluocinolone), weigh accurately, add 4ml of acetonitrile-tetrahydrofuran-trifluoroacetic acid (500:100:4), heat and stir in a 60℃ water bath to make it evenly dispersed, transfer 2ml of acetonitrile-tetrahydrofuran-trifluoroacetic acid (500:100:4) to a 10ml volumetric flask, cool, add water to the scale, shake well, centrifuge, filter, and take the filtrate as the fluocinolone test solution.

[0314] Take about 1g of this product (equivalent to 40mg of hydroquinone), weigh accurately, add an appropriate amount of methanol, stir to disperse evenly, transfer to a 10ml volumetric flask, dilute to scale with methanol, and shake well. Accurately measure 1ml, place in a 25ml volumetric flask, dilute to scale with mobile phase, shake well, centrifuge, filter, and take the filtrate as the hydroquinone test solution.

[0315] VI. Content determination method

[0316] Retinoic acid was determined by high performance liquid chromatography (General Rule 0512). Operation was performed in a dark environment.

[0317] Test solution: Take about 2 g of the product (equivalent to 1 mg of retinoic acid), weigh accurately, add 10 ml of isopropanol, heat in a 60°C water bath and stir to disperse evenly, transfer to a 100 ml volumetric flask, cool, dilute to the scale with methanol, shake well, filter, and take the filtrate.

[0318] Reference solution: Take an appropriate amount of retinoic acid reference substance, weigh accurately, and dilute with isopropanol-methanol (10:90) to make a solution containing approximately 10 μg per 1 ml.

[0319] Chromatographic conditions: octadecylsilane bonded silica gel was used as filler; methanol-2% glacial acetic acid aqueous solution (81:19) was used as mobile phase; detection wavelength was 350 nm; injection volume was 20 μl.

[0320] System suitability requires that in the chromatogram of the reference solution, the theoretical plate number calculated based on the retinoic acid peak should be no less than 3000.

[0321] Determination method: Accurately measure the reference solution and the test solution, inject them into the liquid chromatograph respectively, record the chromatogram, and calculate by peak area according to the external standard method.

[0322] Fluocinolone was determined by high performance liquid chromatography (General Rule 0512).

[0323] Test solution: Take about 4 g of the product (equivalent to about 0.4 mg of fluocinolone acetonide), weigh accurately, add 20 ml of acetonitrile-tetrahydrofuran-trifluoroacetic acid (500:100:4), heat and stir in a 60°C water bath to make it evenly dispersed, rinse with 10 ml of acetonitrile-tetrahydrofuran-trifluoroacetic acid (500:100:4) into a 50 ml volumetric flask, cool, dilute to the scale with water, shake well, centrifuge, filter, and take the filtrate.

[0324] Reference solution Take an appropriate amount of fluocinolone reference, weigh accurately, dissolve and dilute with acetonitrile-tetrahydrofuran-trifluoroacetic acid-water (500:100:4:400) to make a solution containing about 8 μg per 1 ml.

[0325] Chromatographic conditions: octadecylsilane bonded silica gel was used as filler; water-tetrahydrofuran-trifluoroacetic acid (980:20:0.7) was used as mobile phase A, acetonitrile-tetrahydrofuran (980:20) was used as mobile phase B, and gradient elution was performed according to Table 4; the flow rate was 0.8 ml per minute; the detection wavelength was 238 nm; and the injection volume was 20 μl.

[0326] Table 4

[0327]

[0328]

[0329] System suitability requires that in the chromatogram of the reference solution, the theoretical plate number calculated based on the fluocinolone peak should be no less than 3000.

[0330] Determination method: Accurately measure the reference solution and the test solution, inject them into the liquid chromatograph respectively, record the chromatogram, and calculate by peak area according to the external standard method.

[0331] Hydroquinone was determined by high performance liquid chromatography (General Rule 0512).

[0332] Test solution Take about 2.5g of this product (equivalent to 100mg of hydroquinone), weigh accurately, add methanol and stir to disperse evenly, transfer to a 25ml volumetric flask, dilute to scale with methanol, and shake well. Accurately measure 1ml, place in a 25ml volumetric flask, dilute to scale with mobile phase, shake well, filter, and take the filtrate.

[0333] Reference solution: Take an appropriate amount of hydroquinone reference, weigh accurately, add mobile phase to dissolve and quantitatively dilute to make a solution containing about 160 μg per 1 ml.

[0334] Chromatographic conditions: octadecylsilane bonded silica gel was used as filler; potassium dihydrogen phosphate solution (1.36 g of potassium dihydrogen phosphate was taken, 1 L of water was added to dissolve it, and the pH was adjusted to 3.0 with phosphoric acid)-methanol (90:10) was used as mobile phase; the detection wavelength was 291 nm; and the injection volume was 20 μl.

[0335] System suitability requires that in the chromatogram of the reference solution, the theoretical plate number calculated based on the hydroquinone peak should be no less than 3000.

[0336] Determination method: Accurately measure the reference solution and the test solution, inject them into the liquid chromatograph respectively, record the chromatogram, and calculate by peak area according to the external standard method.

[0337] 7. Rheological properties

[0338] The rheological properties of the product were measured using a DHR-1 rheometer (TA Company, USA).

[0339] (1) Product fluid characteristics evaluation method:

[0340] Take about 2g of this product and place it on the flat mold of the rheometer. The measuring temperature is 25℃. Select the flow mode flow sweep. The shear rate range is 0.01~100 1 / s. Draw a flow curve with shear stress versus shear rate to evaluate the fluid properties of the product.

[0341] (2) Product viscoelasticity evaluation method:

[0342] Take about 2g of this product and place it on the flat mold of the rheometer, measure the temperature at 25℃, select the oscillation mode Oscillation Amplitude, the scanning frequency at 10Hz, the strain range at 0.01~100%, perform strain scanning, record the change curves of elastic modulus, viscous modulus, stress and strain, and evaluate the viscoelasticity and yield stress of the product.

[0343] The results of Examples 1-5 that do not fall within the protection scope of this application are shown in Table 5 below:

[0344] Table 5

[0345]

[0346]

[0347]

[0348] The results of Examples 6-11 falling within the protection scope of the present application are shown in Table 6 below:

[0349] Table 6

[0350]

[0351]

[0352] The description of the relevant substances mentioned in the above text is shown in Table 7 below:

[0353] Table 7

[0354]

[0355]

[0356] Examples 1-5 do not fall within the scope of this application, while Examples 6-11 fall within the scope of this application. It was found that in Examples 1-5, retinoic acid crystallized, while in Examples 6-11, there was no crystallization, and the content was uniform. In addition, the embodiments of the present invention improve the phase stability of the cream while reducing the levels of hydroquinone and fluocinolone-related substances; the prepared cream is a shear-thinning pseudoplastic non-Newtonian fluid, has viscoelasticity, and has a suitable yield stress, which can make the cream production, filling, and application more convenient.

Claims

1. A method for preparing fluocinolone hydroquinone retinoic acid cream, characterized in that: It includes the following steps: Preparation of S02 oil phase: Fatty acid glyceride, fatty alcohol mixture, C 12 -C 20 Alkane acid and polyoxyethylene (35) castor oil are mixed, retinoic acid is added, and then liquid alkane is added; S03 emulsification: S031: Mix the pH regulator, polyol and magnesium aluminum silicate gel at 60-80°C; then mix with the oil phase in S02, stir and emulsify; S032: Mix the product obtained in S031 with antioxidant, fluocinolone and hydroquinone, stir and emulsify.

2. The method for preparing the fluocinolone hydroquinone retinoic acid cream according to claim 1, wherein: The fluocinolone hydroquinone retinoic acid cream comprises the following components in parts by weight: 60-70 parts of water, 2-5 parts of magnesium aluminum silicate, 1-6 parts of liquid alkane, 2-6 parts of mixed fatty acid glyceride, 2-6 parts of fatty alcohol mixture, C 12 -C 20 1-3 parts of alkanoic acid, 5-10 parts of polyol, 0.1-1 parts of antioxidant, 0.02-0.1 parts of pH adjuster, 2-8 parts of polyoxyethylene (35) castor oil, 2-6 parts of hydroquinone, 0.03-0.1 parts of retinoic acid and 0.005-0.1 parts of fluocinolone.

3. The preparation method of fluocinolone hydroquinone retinoic acid cream as claimed in claim 1, characterized in that, It meets one or more of the following conditions: (1) In the preparation of SO2 oil phase, fatty acid glyceride, fatty alcohol mixture, C 12 -C 20 After mixing the alkanoic acid and polyoxyethylene (35) castor oil, heating and stirring; (2) During the preparation of the SO2 oil phase, the temperature is raised to 60-80°C, and retinoic acid is added; for example, the temperature is raised to 60-80°C, stirred for 10-30 minutes (for example, 20 minutes), and retinoic acid is added; (3) During the preparation of the SO2 oil phase, add retinoic acid in a dark place; (4) In the preparation of the SO2 oil phase, after adding retinoic acid, stirring and dissolving, and then adding liquid alkane; for example, stirring for 10-30 minutes, and for example, stirring for 20 minutes; (5) In the preparation of SO2 oil phase, after adding liquid alkane, stirring is performed, for example, stirring for 10-30 minutes, and for example, stirring for 20 minutes; (6) The magnesium aluminum silicate gel is prepared by S01 aqueous phase: magnesium aluminum silicate swells in water at 60-80°C; (7) After S032, the method further includes S033: reducing the temperature to 35-45°C.

4. The preparation method of fluocinolone hydroquinone retinoic acid cream according to claim 1, characterized in that, The preparation of S02 oil phase comprises the following steps: mixing fatty acid glyceride, fatty alcohol mixture, C 12 -C 20 Mix the alkanoic acid and polyoxyethylene (35) castor oil, put them into an oil pan, turn on heating and stirring, raise the temperature to 60-80°C, stir for 20 minutes, add retinoic acid in a dark environment, and stir for 20 minutes; after dissolution, add liquid alkane and continue stirring for 20 minutes.

5. The method for preparing the fluocinolone hydroquinone retinoic acid cream according to claim 1, characterized in that: It meets one or more of the following conditions: (1) S03 emulsification was carried out under light-proof conditions; (2) In S031, the pH regulator and polyol are added to the magnesium aluminum silicate gel; (3) In S031, the stirring is performed using a stirrer, and the stirrer is a combination of a low-speed stirrer and a high-speed stirrer; for example, the high-speed stirrer is a high-shear jet emulsifying stirrer; for example, the low-speed stirrer is a frame stirrer equipped with a scraper stirrer; For another example, the high shear jet emulsifying mixer has a stator and a rotor structure, the rotor rotates at a speed of more than 1000 r / min, and / or the gap between the stator and the rotor is less than 2 mm; For another example, the low-speed agitator has a main stirring blade in a frame shape, with blades distributed in the horizontal and vertical directions; For another example, the stirrer is shown in FIG18 ; (4) In S031, the stirring speed is 20-50 rpm, for example, 30 rpm; (5) In S031, the emulsification speed is 1000-5000 rpm, for example, 2000 rpm; (6) In S031, the emulsification method is an intermittent emulsification method, for example, after stirring for 3 minutes, the emulsification is started for 1 minute, and after the emulsification stops, the emulsification is started again after stirring for 3 minutes; (7) In S031, the emulsification time is 10 minutes to 2 hours, for example, 30 minutes; (8) The vacuum pressure during the process of S031 is -0.04 to -0.06 MPa.

6. The method for preparing the fluocinolone hydroquinone retinoic acid cream according to claim 1, characterized in that: It meets one or more of the following conditions: (1) In S032, the addition temperature of hydroquinone is 40-50°C; (2) In S032, the addition temperature of fluocinolone is 40-50°C; (3) In S032, the antioxidant is added at a temperature of 40 to 50°C; (4) In S032, first add an antioxidant to S031, stir, emulsify, and then add fluocinolone and hydroquinone; for example, the stirring, emulsification speed and emulsification method are the same as those of S031; (5) The vacuum pressure during the S032 process is -0.04 to -0.06 MPa.

7. The method for preparing the fluocinolone hydroquinone retinoic acid cream according to claim 6, characterized in that: S032 includes the following steps: cooling the system to 40-50°C, stirring and emulsifying during the cooling process; after cooling, adding an antioxidant, keeping warm at 40-50°C, stirring, and emulsifying; after stirring and mixing evenly, adding fluocinolone to the system, and then adding hydroquinone, stirring, and emulsifying; for example, the stirring, emulsification speed and emulsification method in step S032 are the same as those in S031.

8. The method for preparing the fluocinolone hydroquinone retinoic acid cream according to claim 3, characterized in that: It meets one or more of the following conditions: (1) In S033, the temperature is lowered to 35-45° C., and the mixture is stirred during the cooling process. The stirring speed is conventional in the art, for example, 10-50 rpm, and for example, 30 rpm; (2) In S033, the vacuum pressure is maintained at -0.04 to -0.06 MPa during the cooling process; (3) In S033, under inert gas conditions, the vacuum pressure is restored to normal pressure; (4) In the preparation of the S01 aqueous phase, the swelling time of magnesium aluminum silicate is 5-24 hours, for example, 10 hours.

9. The method for preparing the fluocinolone hydroquinone retinoic acid cream according to claim 1 or 2, characterized in that: It meets one or more of the following conditions: (1) The fluocinolone hydroquinone retinoic acid cream contains the following components in parts by weight: 65.49 parts of water, 3.0 parts of magnesium aluminum silicate, 4.0 parts of liquid alkane, 3.5 parts of mixed fatty acid glyceride, 4 parts of fatty alcohol mixture, C 12 -C 20 2 parts of alkanoic acid, 7.5 parts of polyol, 0.4 parts of antioxidant, 0.05 parts of pH adjuster, 6 parts of polyoxyethylene (35) castor oil, 4 parts of hydroquinone, 0.05 parts of retinoic acid and 0.01 parts of fluocinolone (2) The water is purified water; (3) The liquid alkane mainly acts as a moisturizer to adjust the ointment state of the preparation, such as white vaseline and / or liquid paraffin; another example is white vaseline; (4) The mixed fatty acid glyceride is C8-C 18 Mixtures of mono-, di- and triesters of saturated fatty acids, for example, mixed fatty acid glycerides type 36; (5) The fatty alcohol mixture is mainly used to increase the viscosity of the product, for example, one or more selected from cetyl alcohol, stearyl alcohol and cetostearyl alcohol, and another example is cetostearyl alcohol; (6) C 12 -C 20 The alkanoic acid is an alkanoic acid having a total carbon number of 12 to 20, such as lauric acid and / or stearic acid, and another example is stearic acid; (7) The polyol is a diol and / or a triol; the diol is, for example, 1,2-propylene glycol; the triol is, for example, glycerol; (8) The antioxidant is selected from one or more of butylated hydroxytoluene, sodium sulfite, sodium bisulfite and sodium pyrosulfite; for example, sodium pyrosulfite; (9) The pH adjuster is lactic acid and / or citric acid, for example, lactic acid.

10. A fluocinolone hydroquinone retinoic acid cream, prepared by the preparation method according to any one of claims 1 to 9, for example, in the fluocinolone hydroquinone retinoic acid cream, retinoic acid does not crystallize.

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