A compound hydroquinone emulsion and its preparation method and application

Abstract

The present invention discloses a compound hydroquinone emulsion and its preparation method and application, belonging to the technical field of medicine. The compound hydroquinone emulsion comprises active ingredients and a pharmaceutically acceptable carrier. The active ingredients comprise the following components calculated by weight percentage of the emulsion: 2-4% of hydroquinone or its water-soluble derivative, 0.5-5% of crisaborole, 0.01-0.05% of vitamin A, 1.5-7.5% of vitamin B6, and 0.2-3% of asiaticoside. The compound hydroquinone emulsion of the present invention has a high hydroquinone content and a high transdermal absorption rate, and has the advantages of small irritation, wide application range, the production workshop is not restricted by the workshop that must permit raw materials containing hormones, and low production cost, etc.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly relates to a compound hydroquinone emulsion and its preparation method and application. Background Art

[0002] Currently, the active ingredients of existing compound hydroquinone creams generally consist of the following components: hydroquinone 1-4% (w / w), topical corticosteroid 0.01-0.05% (w / w), and tretinoin 0.01-0.05% (w / w). In the above compound hydroquinone creams, due to the instability of hydroquinone, it is susceptible to oxidation and degradation reactions under the influence of environmental factors such as light and temperature during preparation and storage, generating impurities. The oxidation degradation products will form colored complexes with hydroquinone, thereby affecting the purity, quality, stability, and appearance of hydroquinone and its products. The water-in-oil type hydroquinone emulsion has the defects of oxidation discoloration, poor stability, and low scalp absorption rate. To overcome this defect, Chinese Patent CN202011224161.0 proposed an oil-in-water type compound hydroquinone emulsion, which consists of an oil component, an aqueous phase component, and a compound active ingredient. The compound active ingredient includes components such as hydroquinone, tretinoin, and fluocinonide. However, tretinoin has a relatively high irritation to the skin, resulting in a significant reduction in the applicable population. In addition, raw materials such as fluocinonide can only be imported, leading to a significant increase in production costs. It also has limitations in terms of applicable age or scope, etc., restricting its application.

[0003] Therefore, it is highly necessary to develop a compound hydroquinone emulsion with good stability, low irritation, wide application scope, and low production cost, as well as its preparation method and application. Summary of the Invention

[0004] In order to overcome the deficiencies of the prior art, the purpose of the present invention is to provide a compound hydroquinone emulsion, which has high stability, extends the product usage period, has low irritation, wide application scope, low production cost, and is suitable for industrial production.

[0005] To solve the above problems, the technical solutions adopted by the present invention are as follows:

[0006] A compound hydroquinone emulsion, which comprises an active ingredient and a pharmaceutically acceptable carrier. The active ingredient comprises the following components calculated by weight percentage of the emulsion: hydroquinone or its water-soluble derivative 2-4%, crisaborole 0.5-5%, vitamin A 0.01-0.05%, vitamin B6 1.5-7.5%, and asiaticoside 0.2-3%.

[0007] In a preferred embodiment of the present invention, the emulsion further comprises an emulsifier, and the emulsifier accounts for 2-10% by weight of the emulsion.

[0008] More preferably, the emulsifier is any one or a combination thereof selected from polyoxyethylene (30) dimer hydroxystearate, cetyl polyethylene glycol / polypropylene glycol 10 / 1 dimethylsiloxane, bis-polyethylene glycol / polypropylene glycol-14 / 14 dimethylsiloxane, polyglycerol-4 diisostearate polyhydroxystearate sebacate, span-20, span-80, span-60, span-85, alkoxylated glycerol sorbitan fatty acid ester, polyglycerol stearate, and polyoleic acid ester.

[0009] In a preferred embodiment of the present invention, the water-soluble derivatives of hydroquinone include, but are not limited to, mono-esters or di-esters of hydroquinone, mono-ethers or di-ethers of hydroquinone, mono-glycosides or di-glycosides of hydroquinone, such as hydroquinone monoacetate, hydroquinone monolactate, 4-methoxyphenol, or arbutin. The hydroquinone or its water-soluble derivatives of the present invention are pharmaceutically acceptable safe active ingredients, with a purity of not less than 99.5% (weight ratio), high purity and low toxicity, and are suitable for application to the skin.

[0010] In a preferred embodiment of the present invention, the emulsion is a water-in-oil compound hydroquinone emulsion.

[0011] More preferably, the emulsion is a water-in-oil compound hydroquinone emulsion. The particle size of the emulsion is 200 - 600 nm, preferably 200 - 400 nm. The viscosity of the emulsion is 1000 - 50000 centipoise (cps), preferably 2500 - 15000 centipoise (cps).

[0012] In a preferred embodiment of the present invention, the oil phase in the emulsion accounts for 10 - 30% by weight of the emulsion.

[0013] In a preferred embodiment of the present invention, the oil in the oil phase is selected from any one or a combination thereof of liquid lipophilic emollients, natural and synthetic oils, and waxy lipophilic emollients.

[0014] More preferably, the liquid lipophilic emollients include any one or a combination thereof of silicone-based emollients, dimethylsiloxane, cetyl dimethylsiloxane, and polydimethylsiloxane.

[0015] More preferably, the natural and synthetic oils include any one or a combination thereof of dicaprylyl carbonate, shea butter, GTCC, C24, squalane, synthetic squalane, medical white oil No. 10, jojoba oil, sweet almond oil, avocado oil, medical petrolatum, medical white oil No. 20, C16 - C18 mixed alcohol, ozokerite, microcrystalline wax, beeswax, isocetane, and cetyl alcohol.

[0016] More preferably, the waxy lipophilic emollients include any one or a combination thereof of stearyl dimethylsiloxane, docosyloxy dimethylsiloxane, silicone wax, myristyl myristate, and stearyl heptanoate.

[0017] In a preferred embodiment of the present invention, the aqueous phase of the emulsion further contains a metal salt.

[0018] Further preferably, the metal salt accounts for 0.5 - 5% by weight of the emulsion.

[0019] Further preferably, the metal salt is sodium chloride and / or magnesium chloride.

[0020] In a preferred embodiment of the present invention, the emulsion further comprises a transdermal absorption enhancer, and the transdermal absorption enhancer accounts for no more than 7% by weight of the emulsion; the transdermal absorption enhancer is selected from any one or a combination of borneol, mint, azone, isopropyl myristate. Further preferably, the transdermal absorption enhancer is a composite transdermal absorption enhancer composed of borneol, mint, and azone. More preferably, the composition of the composite transdermal absorption enhancer is: 2 - 7 parts by weight of azone, 1 - 4 parts by weight of borneol, and 1 - 4 parts by weight of mint.

[0021] In a preferred embodiment of the present invention, the emulsion further comprises an antioxidant, and the antioxidant accounts for 1 - 5% by weight of the emulsion; the antioxidant is selected from any one or a combination of sodium bisulfite, tert-butyl-p-cresol, sodium metabisulfite, vitamin E, disodium ethylenediaminetetraacetate.

[0022] In a preferred embodiment of the present invention, the emulsion further comprises a preservative, and the preservative accounts for 1 - 5% by weight of the emulsion; the preservative is selected from any one or a combination of methylparaben, ethylparaben, propylparaben, butylparaben.

[0023] In a preferred embodiment of the present invention, the emulsion further comprises a humectant, and the humectant accounts for 1 - 8% by weight of the emulsion; the humectant is selected from any one or a combination of glycerol, polyol, urea, amino acid, propylene glycol, cetyl alcohol, paraffin oil, lanolin and its derivatives, fatty acid esters, silicone oil, cyclomethicone, polydimethylsilanol.

[0024] In a preferred embodiment of the present invention, the emulsion further comprises a pH regulator, and the pH regulator accounts for 1 - 5% by weight of the emulsion, and the pH regulator is selected from any one or a combination of lactic acid, citric acid, phosphoric acid, or glycolic acid.

[0025] The second object of the present invention is to provide a method for preparing the compound hydroquinone emulsion as described above, the emulsion is a water-in-oil emulsion, and the emulsion is prepared according to the following steps:

[0026] (1) Preparation of the aqueous phase: Measure purified water, glycerol or hyaluronic acid, place it in an aqueous phase tank, heat it to 60 - 90 °C until completely dissolved, then lower the temperature to 50 - 60 °C, and add hydroquinone, asiaticoside, and metal salt;

[0027] (2) Preparation of the oil phase: Measure the components of the oil phase, place them in an oil phase tank, heat and melt them, then add a transdermal absorbent, a compound emulsifier, and vitamin E, and cool down to 50 - 60 °C for standby;

[0028] (3) Homogenizing emulsification: Vacuum - suck the oil phase into an emulsification tank, and then vacuum - suck the water phase into the emulsification tank under stirring conditions. After preliminary homogenization, transfer it to a high - speed homogenizer to form a micro - emulsion, and then cool it to obtain the product.

[0029] In a preferred embodiment of the present invention, the stirring temperature in step (3) is 50 - 60 °C, the stirring speed is 50 - 150 r / min, the stirring time is 10 - 30 min, and the homogenization speed of the preliminary homogenization is 1000 - 2000 r / min.

[0030] In a preferred embodiment of the present invention, the temperature of the emulsion at the outlet during the cooling process in step (3) is 45 °C.

[0031] The third object of the present invention is to provide the application of the compound hydroquinone emulsion as described above in the preparation of drugs or cosmetics for treating, preventing or improving skin diseases.

[0032] In a preferred embodiment of the present invention, the skin diseases may be: pigmentation, including pigment dispersion and pigmentation; actinic keratosis, solar keratosis, skin blemishes.

[0033] In a preferred embodiment of the present invention, the skin disease is a skin spot. The skin spot is caused by local pigmentation, and preferably, the skin spot is selected from any one or a combination of freckles, melasma, and post - inflammatory hyperpigmentation spots.

[0034] In a preferred embodiment of the present invention, the skin diseases may be skin diseases caused by exposure to UV radiation, photo - induced or chronic - aging skin, photo - pigmentation and keratosis, or any diseases pathologically associated with chronic aging or photo - aging, especially skin sebum - related diseases, especially acne - like hyper - seborrheic dermatitis or simple seborrhea or seborrheic dermatitis; healing disorders or pregnancy stretch marks in pregnant women, pigmentation disorders, such as pigment deposition, melasma, hypopigmentation or vitiligo.

[0035] For clearly expressing the protection scope of the present invention, the present invention defines the following terms as follows:

[0036] 1. Unless otherwise specified, when the present invention relates to the percentage between liquids, the percentage is volume / volume percentage; when the present invention relates to the percentage between a liquid and a solid, the percentage is volume / weight percentage; when the present invention relates to the percentage between a solid and a liquid, the percentage is weight / volume percentage; the rest are weight / weight percentages.

[0037] 2. The term "emulsion" refers to a colloidal dispersion of two immiscible liquids in the form of droplets. An emulsion is denoted as O / W (oil-in-water) if the continuous phase is an aqueous solution, and as W / O (water-in-oil) if the continuous phase is an oil.

[0038] 3. The "oil phase" in a water-in-oil emulsion refers to all the components in the formulation that individually exceed their solubility limits in the aqueous phase; these are materials that typically have a solubility of less than 1% in distilled water. The oil phase refers to the non-aqueous part of a water-in-oil emulsion.

[0039] 4. The "aqueous phase" or "water phase" in a water-in-oil emulsion refers to the water present and any water-soluble components, i.e., those that do not exceed their solubility limits in water.

[0040] 5. HLB value: An emulsifier is an amphiphilic molecule with a hydrophilic group and a lipophilic group. The measure of the balance of size and strength between the hydrophilic and lipophilic groups in an emulsifier molecule is defined as the hydrophilic-lipophilic balance value of the emulsifier.

[0041] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0042] 1. By adding crisaborole to the compound hydroquinone emulsion of the present invention, the skin irritation can be effectively reduced, and the applicable range of the compound hydroquinone emulsion can be extended from several months old infants to adults, with a wide applicable range; by using asiaticoside, the mildness of the emulsion can be effectively improved, greatly improving the use experience of the compound hydroquinone cream. At the same time, the problem that the raw material drug of fluocinonide needs to rely on imports is solved, so that the production plant is not restricted by the plant that must allow raw materials containing hormones, effectively reducing the production cost and being suitable for industrial production.

[0043] 2. By screening compound emulsifiers and controlling the distribution balance of the oil phase and the water phase in the emulsification process, the preparation of a water-in-oil type hydroquinone emulsion is achieved; since hydroquinone is easily soluble in water, it is more stable in the water phase, and the emulsion is isolated from the outside by the oil phase, effectively improving the stability of the compound hydroquinone emulsion, thereby extending the product use cycle and reducing the production cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 It is a microscopic picture of the compound hydroquinone emulsion prepared in Example 1 of the present invention without high-pressure homogenization;

[0045] Figure 2 It is a microscopic picture of the compound hydroquinone emulsion prepared in Example 1 of the present invention after high-pressure homogenization;

[0046] Figure 3 It is a picture of the skin irritation animal experiment of Comparative Examples 1-2 and Examples 1-2 of the present invention;

[0047] Figure 4Comparison diagrams of the emulsion prepared in Comparative Example 1 of the present invention before and after accelerated centrifugation;

[0048] Figure 5 Comparison diagrams of the emulsion prepared in Example 1 of the present invention before and after accelerated centrifugation;

[0049] Figure 6 Comparison diagrams of the emulsion prepared in Example 2 of the present invention before and after accelerated centrifugation. Detailed implementation manners

[0050] The present invention will be further described in detail below with reference to the drawings and specific implementation manners.

[0051] Example 1

[0052] The compound hydroquinone emulsion of this example is composed of an oil phase and an aqueous phase. The composition of the oil phase components is as follows:

[0053] Caprylic / capric triglyceride 25 g, liquid paraffin 65 g, cetyl alcohol 40 g, stearyl alcohol 30 g, microcrystalline wax 20 g, dimethicone 25 g, emulsifier Arlacel P135 (polyoxyethylene (30), dimerized hydroxystearate) 30 g, propylparaben 0.2 g, vitamin B6 5 g, crisaborole 2 g;

[0054] The composition of the aqueous phase components is as follows:

[0055] 1,3 - butanediol 50 g, glycerol 40 g, hyaluronic acid 0.5 g, sodium metabisulfite 2 g, methylparaben 1.8 g, sodium chloride 8 g, deionized water 585.5 g, hydroquinone 40 g, asiaticoside 30 g.

[0056] The preparation method of the compound hydroquinone emulsion of this example includes the following steps:

[0057] (1) Preparation of the aqueous phase: Pour purified water, 1,3 - butanediol, glycerol, and hyaluronic acid into the aqueous phase pot, introduce steam into the jacket, heat to 70 ± 5 °C, then add the aqueous phase components to the aqueous phase pot, stir at a speed of 40 rp / min until completely dissolved, and finally add sodium metabisulfite, methylparaben, sodium chloride, hydroquinone, and asiaticoside to the aqueous phase pot, stir at a speed of 40 rp / min until completely dissolved, and lower the temperature to 50 - 60 °C for standby.

[0058] (2) Preparation of the oil phase: Add the oil phase components to the oil phase pot and heat and melt by introducing steam, lower the temperature to 50 - 60 °C, add crisaborole and stir evenly for standby.

[0059] (3) Homogeneous emulsification: Turn on the power switch of the emulsifying pot and the vacuum pump. When the vacuum degree reaches -80 KPa, stop vacuum pumping. Turn on the stirrer at 40 rp / min. First, suck the oil phase prepared in step (2) into the emulsifying tank, and then slowly suck the water phase prepared in step (1) into the emulsifying tank under stirring. Under the conditions of 70 ± 5 °C and a vacuum degree of -80 KPa, start the homogenizer of the emulsifying machine and carry out homogeneous emulsification for 20 minutes.

[0060] (4) After the homogeneous emulsification is completed, turn on the cooling water valve, and the cooling water pressure should not be too high. When the temperature drops to 45 °C, add the active ingredient. Under the conditions of 45 ± 5 °C and a vacuum degree of -80 KPa, start the homogenizer of the emulsifying machine and carry out homogeneous emulsification for 20 minutes. Adjust the stirring speed to 30 rp / min and cool for about 1 hour. Then lower the stirring speed to 5 rp / min until the paste temperature cools to room temperature to obtain the compound hydroquinone emulsion.

[0061] To obtain the compound hydroquinone emulsion, it can also be subjected to high-pressure homogenization

[0062] Figure 1 is the microscopic picture of the compound hydroquinone emulsion prepared in Example 1 of the present invention without high-pressure homogenization;

[0063] Figure 2 is the microscopic picture of the compound hydroquinone emulsion prepared in Example 1 of the present invention after high-pressure homogenization.

[0064] From Figure 1 and Figure 2 it can be seen by comparison that after the compound hydroquinone emulsion of the present invention is subjected to high-pressure homogenization, the particle size of the emulsion in the emulsion can be further reduced, thereby effectively improving the transdermal absorption of the emulsion.

[0065] Example 2

[0066] The compound hydroquinone emulsion of this example is composed of an oil phase and a water phase. The composition of the oil phase components is as follows:

[0067] Caprylic / capric triglyceride 25 g, liquid paraffin 65 g, cetyl alcohol 40 g, stearyl alcohol 30 g, microcrystalline wax 20 g, dimethicone 25 g, Arlacel 780 (alkoxylated glycerol sorbitan fatty acid ester) 30 g, propylparaben 0.2 g, vitamin B6 5 g, crisaborole 3 g;

[0068] The composition of the water phase components is as follows:

[0069] 1,3-Butanediol 50 g, glycerol 40 g, hyaluronic acid 0.5 g, sodium metabisulfite 2 g, methylparaben 1.8 g, sodium chloride 5 g, deionized water 584.5 g, hydroquinone 40 g, asiaticoside 30 g.

[0070] The preparation method of the compound hydroquinone emulsion in this embodiment includes the following steps:

[0071] (1) Preparation of the aqueous phase: Pour purified water, 1,3-butanediol, glycerol, and hyaluronic acid into the aqueous phase pot, introduce steam into the jacket, heat to 70 ± 5 °C, then add the aqueous phase components to the aqueous phase pot, stir at a speed of 40 rp / min until completely dissolved, and finally add sodium metabisulfite, sodium chloride, and methylparaben to the aqueous phase pot, stir at a speed of 40 rp / min until completely dissolved, and cool to 50 - 60 °C for standby.

[0072] (2) Preparation of the oil phase: Add the oil phase components to the oil phase pot and heat and melt them by introducing steam, and cool to 50 - 60 °C for standby.

[0073] (3) Homogeneous emulsification: Turn on the power switch of the emulsification pot, turn on the vacuum pump, stop evacuating when the vacuum degree is -80 KPa, turn on the stirring at 40 rp / min, first suck the oil phase prepared in step (2) into the emulsification tank, and then slowly suck the aqueous phase prepared in step (1) into the emulsification tank under stirring. Under the conditions of 70 ± 5 °C and a vacuum degree of -80 KPa, start the homogenizer of the emulsifier and homogenize and emulsify for 20 minutes.

[0074] (4) After the homogeneous emulsification is completed, turn on the cooling water valve, and the cooling water pressure should not be too high. When the temperature drops to 45 °C, add the active component. Under the conditions of 45 ± 5 °C and a vacuum degree of -80 KPa, start the homogenizer of the emulsifier and homogenize and emulsify for 20 minutes. Adjust the stirring speed to 30 rp / min, cool for about 1 hour, and then lower the stirring speed to 5 rp / min until the paste temperature cools to room temperature to obtain the compound hydroquinone emulsion.

[0075] Comparative Example 1

[0076] In this comparative example, the hydroquinone emulsion was prepared according to the composition and preparation method of hydroquinone cream recorded in the "Fujian Provincial Hospital Preparation Specification". The specific composition is as follows:

[0077] Hydroquinone 40 g, sodium lauryl sulfate 9 g, cetyl alcohol 81 g, liquid paraffin 60 g, white vaseline 150 g, NaHSO 3 3 g, tert-butyl-p-cresol 1 g, glycerol 50 g, distilled water 1000 g.

[0078] Its preparation method includes the preparation of the oil phase, the preparation of the aqueous phase, and emulsification:

[0079] ① Preparation method of the oil phase: Take cetyl alcohol, liquid paraffin, and vaseline, heat and melt them. When the temperature reaches about 70 °C, add tert-butyl-p-cresol and hydroquinone in sequence and dissolve them;

[0080] ② The preparation method of the aqueous phase is as follows: Mix glycerol with an appropriate amount of distilled water, heat to about 70 °C, add sodium bisulfite and sodium dodecyl sulfate, and dissolve.

[0081] ③ Emulsification: Under stirring conditions, slowly add the oil phase to the aqueous phase until the full amount, emulsify, and stir until coagulated to obtain the product.

[0082] Comparative Example 2

[0083] Take a compound hydroquinone emulsion with excellent freckle removal effect disclosed in Patent CN1738587B as Comparative Example 2. This emulsion contains active components and inactive components. Among them, the active components are fluocinolone acetonide 0.01% (0.1 mg), hydroquinone 4% (40 mg), and tretinoin 0.05% (0.5 mg), and the inactive components are butylated hydroxytoluene 0.04%, cetyl alcohol 4%, citric acid 0.05%, glycerol 4%, glyceryl stearate 3%, magnesium aluminum silicate 3%, methyl gluceth10 5%, methylparaben, PEG - 100 stearate 3.5%, propylparaben 0.02%, purified water 68.95%, sodium metabisulfite 0.2%, stearic acid 3%, and stearyl alcohol 4%.

[0084] The test sample of this comparative example is a commercially available product of the US Galderma's CN1738587B patent.

[0085] I. Determination of emulsion particle size

[0086] Use a German NANOPHOX (NX0158) particle size distribution measuring instrument to measure the compound hydroquinone emulsions prepared in Examples 1 - 2 and Comparative Examples 1 - 2. The results are as Figure 3 shown in Table 1.

[0087] Table 1 Emulsion particle sizes of Examples 1 - 2 and Comparative Examples 1 - 2

[0088] Emulsion Particle size (nm) Comparative Example 1 800-2000 Comparative Example 2 500-1500 Example 1 30-300 Example 2 50-400

[0089] The results in Table 1 show that the average particle sizes of Example 1 and Example 2 of the present invention are 165 nm and 225 nm respectively, while the average particle sizes of Comparative Example 1 and Comparative Example 2 are 1400 nm and 1000 nm respectively. This shows that the particle size of the emulsion prepared by the present invention is reduced by about 1 / 7 to 1 / 5 compared with Comparative Example 1 and Comparative Example 2. The reduction of particle size is beneficial to the transdermal absorption of active ingredients, improves the bioavailability of drugs, and the reduction of drug usage can reduce the irritation to the skin.

[0090] II. Animal experiment on skin irritation

[0091] The emulsion of Examples 1-2 and Comparative Examples 1-2 was evaluated by a skin irritation animal experiment. The specific steps are as follows: White guinea pigs were divided into 5 groups, with 20 in each group. The hair on the back of the guinea pigs was shaved off, and the skin was administered the drug 3 times a day, evenly applied to the ultraviolet irradiation site. The dose of ultraviolet light irradiation each time was: UVA 5.67 / cm 2 , UVB and UVA were continuously irradiated for 2 weeks. The appearance of the skin of the experimental animals is shown in Figure 3 , and the proportion of animals with erythema is shown in Table 2.

[0092] Table 2 Skin irritation animal experiment results of the emulsions prepared in Examples 1-2 and Comparative Examples 1-2

[0093] Emulsion Percentage of animals with erythema % Comparative Example 1 100％ Comparative Example 2 80％ Example 1 0％ Example 2 0％

[0094] From Figure 3 and the results in Table 2, it can be seen that compared with Comparative Examples 1-2, there was no erythema caused by irritation on the skin of the guinea pigs using the emulsions prepared in Examples 1-2 of the present invention, indicating that the emulsions prepared in Examples 1-2 had very low irritation to the skin, while Comparative Examples 1-2 all had erythema caused by irritation to varying degrees.

[0095] III. Heat stability test of the emulsion

[0096] The heat stability of the emulsions prepared in Examples 1-2 and Comparative Examples 1-2 was tested under heat load (heating test). The specific operation is as follows: 1 g of the emulsion was placed in a glass sample tube, then sealed and placed in a constant temperature tank at 60 °C. The appearance of the emulsion was observed over time to check whether the oil phase and water phase were separated. The results are shown in Table 3.

[0097] Table 3 Heat experiment results of the emulsions prepared in Examples 1-2 and Comparative Examples 1-2

[0098] Investigation time Comparative Example 1 Comparative Example 2 Example 1 Example 2 0 hour Not separated Not separated Not separated Not separated 10 days Not separated Not separated Not separated Not separated 20 days Separated Not separated Not separated Not separated 30 days Separated Not separated Not separated Not separated

[0099] It can be seen from Table 3 that Examples 1-2 of the present invention all had good heat stability, and Comparative Example 1 had the worst heat resistance and did not meet the product requirements.

[0100] IV. Accelerated stability test

[0101] The emulsions prepared in Comparative Example 1, Example 1, and Example 2 were simultaneously placed in a constant temperature room at -18 °C for 48 hours, then the samples were taken out and placed at room temperature to return to room temperature, and then placed in a constant temperature oven at 50 °C for 48 hours. The samples were taken out and placed at room temperature to return to room temperature, and a centrifugal separation experiment was carried out on the samples. Centrifugation was carried out at 2500 r / min for 30 min, and the layering situation of the product was observed. The results are as Figures 4 to 6 shown.

[0102] From Figure 4It can be seen that the emulsion of Comparative Example 1 was significantly demulsified and delaminated after acceleration and centrifugation, indicating that the emulsion of Comparative Example 1 had insufficient stability. From Figure 5 and Figure 6 it can be seen that the emulsion samples of Example 1 and Example 2 did not show delamination before and after accelerated centrifugation, indicating that the emulsion samples of Example 1 and Example 2 both had excellent stability.

[0103] The above embodiments are only the preferred embodiments of the present invention and cannot be used to limit the scope of protection of the present invention. Any non-substantive changes and substitutions made by those skilled in the art on the basis of the present invention fall within the scope of protection required by the present invention.

Claims

1. A water-in-oil type compound hydroquinone emulsion, characterized in that: the emulsion comprises active ingredients and a pharmaceutically acceptable carrier, and the active ingredients are composed of the following components calculated by weight percentage of the emulsion: 2-4% of hydroquinone, 0.5-5% of crisaborole, 0.01-0.05% of vitamin A, 1.5-7.5% of vitamin B6, 0.2-3% of asiaticoside; the emulsion comprises an emulsifier, and the weight percentage of the emulsifier in the emulsion is 2-10%; the emulsifier is any one or a combination of polyoxyethylene (30) dimer hydroxystearate, cetyl polyglycol / polypropylene glycol 10 / 1 dimethylsiloxane, bis-polyethylene glycol / polypropylene glycol-14 / 14 dimethylsiloxane, polyglycerol-4 bisisostearate polyhydroxystearate sebacate, span-20, span-80, span-60, span-85, alkoxylated glycerol sorbitan fatty acid ester, polyglycerol stearate and polyoleic acid ester.

2. The compound hydroquinone emulsion according to claim 1, characterized in that: the oil phase in the emulsion accounts for 10-30% of the weight of the emulsion.

3. The compound hydroquinone emulsion according to claim 1, characterized in that: the aqueous phase of the emulsion contains a metal salt, and the weight percentage of the metal salt in the emulsion is 0.5-5%; the metal salt is sodium chloride and / or magnesium chloride.

4. The compound hydroquinone emulsion according to claim 1, characterized in that: the emulsion further comprises the following components calculated by weight percentage of the emulsion: 1-7% of a transdermal absorbent, 1-5% of an antioxidant, 1-5% of a preservative, 1-8% of a moisturizer, 1-5% of a pH regulator.

5. A preparation method of the compound hydroquinone emulsion according to any one of claims 1-4, characterized in that: the emulsion is a water-in-oil type emulsion, and the emulsion is prepared according to the following steps: (1) Preparation of the aqueous phase: Measure purified water, glycerol or hyaluronic acid, place it in an aqueous phase tank, heat it to 60-90 °C until completely dissolved, then lower the temperature to 50-60 °C, and add hydroquinone, asiaticoside and metal inorganic salts; (2) Preparation of the oil phase: Measure the oil phase components, place them in an oil phase tank, heat and melt them, then add a transdermal absorbent, a compound emulsifier, and vitamin E, and cool down to 50-60 °C for standby; (3) Homogeneous emulsification: Vacuum suck the oil phase into an emulsification tank, and then vacuum suck the aqueous phase into the emulsification tank under stirring conditions. After preliminary homogenization, transfer it to a high-speed homogenizer to form a microemulsion, and cool it to obtain the product.

6. The preparation method of the compound hydroquinone emulsion according to claim 5, characterized in that: the stirring temperature in step (3) is 50-60 °C, the stirring speed is 50-150 r / min, the stirring time is 10-30 min, and the homogenization speed of the preliminary homogenization is 1000-2000 r / min.

7. An application of the compound hydroquinone emulsion according to any one of claims 1-4 in the preparation of a drug or cosmetic for treating, preventing or improving skin diseases; the skin disease is pigmentation.

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