CN112353760A

CN112353760A - Water-in-oil type compound hydroquinone emulsion and preparation method and application thereof

Info

Publication number: CN112353760A
Application number: CN202011224161.0A
Authority: CN
Inventors: 苏冠荣; 尹贝立
Original assignee: Guangdong Reekon Pharmaceutical Co ltd
Current assignee: Guangdong Reekon Pharmaceutical Co ltd
Priority date: 2020-08-14
Filing date: 2020-11-05
Publication date: 2021-02-12
Anticipated expiration: 2040-11-05
Also published as: CN112336688A; CN112353760B; CN112336688B

Abstract

The invention relates to a water-in-oil type compound hydroquinone emulsion, a preparation method and application thereof. The invention provides a water-in-oil compound hydroquinone emulsion, which comprises an active component and a pharmaceutically acceptable carrier, wherein the active component comprises 1-4% (w/w) of hydroquinone, 0.01-0.05% (w/w) of external corticosteroid or pharmaceutically acceptable salt thereof and 0.01-0.05% (w/w) of retinoid, and the pharmaceutically acceptable carrier comprises 0.5-1% (w/w) of sustained release agent. The compound hydroquinone emulsion has the advantages of good stability and the like.

Description

Water-in-oil type compound hydroquinone emulsion and preparation method and application thereof

Technical Field

The invention relates to the field of medicines, in particular to a water-in-oil type compound hydroquinone emulsion as well as a preparation method and application thereof.

Background

Hydroquinone (also called hydroquinone) is used as tyrosinase inhibitor to inhibit tyrosinase activity mainly through complexation, regulate melanocyte metabolic process, remarkably reduce the number of dopa reaction positive melanocytes in epidermis, and generate reversible skin fading. Oettel first proposed in 1936 that hydroquinone had the effect of whitening the skin. Since the 60 s of the 20 th century, hydroquinone single or compound preparations were used as whitening agents for cosmetics and external preparations for dermatological use in treating pigmentation, spot-removing, etc. in many countries. However, the amount of hydroquinone to be used is strictly controlled.

CN1738587B discloses a hydroquinone compound emulsion, each gram of which contains active components: fluocinolone 0.01% (0.1mg), hydroquinone 4% (40mg) and tretinoin 0.05% (0.5mg) and inactive ingredients: butylated hydroxytoluene, cetyl alcohol, citric acid, glycerol, glyceryl stearate, magnesium aluminum silicate, methyl glucoside decaethylene oxide (methyl gluceth10), methyl paraben, PEG-100 stearate, propyl paraben, purified water, sodium metabisulfite, stearic acid, and stearyl alcohol. The preparation has good speckle removing effect, but has adverse effects of skin irritation (such as erythema, desquamation, skin burning sensation, dryness, pruritus, etc.). The oil-in-water type hydroquinone compound cream has the defects of oxidative discoloration, demulsification and the like, and influences the appearance, clinical curative effect and medication safety of products. Therefore, the hydroquinone compound emulsion with higher stability is urgently needed in clinic to meet the treatment requirement of patients and ensure the safety and effectiveness of clinical medication.

Disclosure of Invention

The invention aims to provide a water-in-oil compound hydroquinone emulsion which comprises an active component and a pharmaceutically acceptable carrier, wherein the active component comprises 1-4% (w/w) of hydroquinone, 0.01-0.05% (w/w) of external corticosteroid or pharmaceutically acceptable salt or ester thereof and 0.01-0.05% (w/w) of retinoid or pharmaceutically acceptable salt or ester thereof, and the pharmaceutically acceptable carrier comprises 0.5-1% (w/w) of a slow release agent.

In a preferred technical scheme of the invention, the emulsion comprises 30-50% (w/w) of oil component, 1-8% (w/w) of emulsifier, active component and pharmaceutically acceptable carrier, wherein the active component comprises 1-4% (w/w) of hydroquinone, 0.01-0.05% (w/w) of external corticosteroid or pharmaceutically acceptable salt or ester thereof and 0.01-0.05% (w/w) of retinoid or pharmaceutically acceptable salt or ester thereof, and the pharmaceutically acceptable carrier contains 0.5-1% (w/w) of sustained release agent.

In a preferred embodiment of the present invention, the pharmaceutically acceptable salt is selected from any one of hydrochloride, hydrobromide, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, acetate, oxalate, malonate, valerate, glutamate, oleate, p-toluenesulfonate, methanesulfonate, isethionate, fumarate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanilliate, mandelate, succinate, gluconate, lactobionate, or a combination thereof.

In a preferred embodiment of the present invention, the pharmaceutically acceptable ester includes, but is not limited to, any one of butyrate, propionate, acetate, formate, palmitate, xinafoate, phosphate, sulfate, or a combination thereof.

In a preferred embodiment of the present invention, the content of the topical corticosteroid or a pharmaceutically acceptable salt or ester thereof is 0.02 to 0.04% (w/w).

In a preferred embodiment of the present invention, the topical corticosteroid or its pharmaceutically acceptable salt or ester is selected from one or a combination of fluocinolone acetonide, dexamethasone dipropionate and clobetasol propionate.

In a preferred embodiment of the present invention, the retinoid or a pharmaceutically acceptable salt or ester thereof is contained in an amount of 0.02 to 0.04% (w/w).

In a preferred embodiment of the present invention, the retinoid or a pharmaceutically acceptable salt or ester thereof is selected from any one of tretinoin, isotretinoin, vitamin a acetate, adapalene and tazarotene or a combination thereof.

In a preferred embodiment of the present invention, the hydroquinone content in the emulsion is 1.5-3.5% (w/w), preferably 2-3% (w/w).

In a preferred embodiment of the present invention, the purity of hydroquinone is not less than 99%, preferably not less than 99.5%, more preferably not less than 99.8%.

In a preferred embodiment of the present invention, the content of p-benzoquinone in the hydroquinone is not higher than 0.1%, preferably not higher than 0.08%, further preferably not higher than 0.05%, and more preferably not higher than 0.03%.

In a preferred technical scheme of the invention, the content of any one of p-benzoquinone, aniline and nitrobenzene in the hydroquinone is not higher than 0.08%, preferably not higher than 0.05%, and further preferably not higher than 0.03%.

In a preferred embodiment of the present invention, the total content of the relevant substances other than p-benzoquinone, aniline and nitrobenzene in the hydroquinone is not higher than 0.3%, preferably not higher than 0.1%, and further preferably not higher than 0.05%.

In a preferred embodiment of the present invention, the related substance is any one or a combination of p-benzoquinone, aniline, nitrobenzene, pyrogallol, resorcinol, and catechol.

In a preferred technical scheme of the invention, the related substances are selected from any one or combination of potassium p-benzoquinone, aniline, nitrobenzene, pyrogallol, resorcinol, catechol, trimellitol, phloroglucinol, phenol and hydroquinone sulfate.

In a preferred technical scheme of the invention, the hydroquinone is a cyclodextrin inclusion compound of the hydroquinone, and the hydroquinone in the inclusion compound is preferably: the molar ratio of cyclodextrin is 1: 1-10, preferably 1: 3-5.

In a preferred embodiment of the present invention, the cyclodextrin is selected from any one of α -cyclodextrin, β -cyclodextrin, γ -cyclodextrin, hydroxyethyl- β -cyclodextrin, hydroxypropyl- β -cyclodextrin, dihydroxypropyl- β -cyclodextrin, methyl- β -cyclodextrin, glucose cyclodextrin, maltose cyclodextrin, maltotriose cyclodextrin, carboxymethyl cyclodextrin, sulfoalkyl cyclodextrin, or a combination thereof.

In the preferred technical scheme of the invention, the content of the slow release agent is 0.6-0.9% (w/w), and preferably 0.7-0.8% (w/w).

In a preferred technical scheme of the invention, the slow release agent is diglycerol.

In a preferred technical scheme of the invention, the emulsion also comprises a transdermal absorption enhancer.

In a preferred embodiment of the present invention, the content of the transdermal absorption agent in the emulsion is 0.5-5% (w/w), preferably 0.8-4% (w/w), preferably 1-2% (w/w).

In a preferred embodiment of the present invention, the transdermal absorption enhancer is selected from any one of borneol, mint and azone or a combination thereof, and preferably the azone is selected from any one of water-soluble azone and fat-soluble azone.

In a preferred technical scheme of the invention, the transdermal absorption enhancer is any one selected from the group consisting of a combination of azone and borneol, a combination of azone and mint and a combination of azone, mint and borneol.

In the preferred technical scheme of the invention, the transdermal absorption enhancer consisting of azone and borneol comprises azone: the weight ratio of borneol is 1:1-6:1, preferably 2:1-5:1, and more preferably 3:1-4: 1.

In the preferred technical scheme of the invention, the transdermal absorption enhancer consisting of azone and mint comprises azone: the weight ratio of the mint is 1:1-6:1, preferably 2:1-5:1, and more preferably 3:1-4: 1.

In the preferred technical scheme of the invention, the transdermal absorption enhancer consisting of azone, mint and borneol comprises azone: mint: the weight ratio of the borneol is 1: 1:1-6: 1:1, preferably 1.5: 1: 1-5: 1:1, more preferably 2: 1: 1-3: 1: 1.

in a preferred embodiment of the present invention, the oil component content of the emulsion is 32-45% (w/w), preferably 35-40% (w/w).

In a preferred embodiment of the present invention, the oil component in the oil phase is selected from any one of liquid paraffin, silicone oil, stearic acid, dimethicone, dioctyl carbonate, shea butter, caprylic capric glyceride, isopropyl palmitate, natural squalane, medical white oil No. 10, medical white oil No. 20, jojoba oil, sweet almond oil, avocado oil, medical vaseline, ozokerite, microcrystalline wax, beeswax, isohexadecane, cetyl alcohol, stearyl alcohol, behenyl siloxanyl dimethicone, silicone wax, coronene of phaseolute, stearyl heptanoate, or a combination thereof.

In a preferred embodiment of the present invention, the content of the emulsifier in the emulsion is 2 to 7%, more preferably 3 to 6%.

In a preferred technical scheme of the invention, the emulsifier is selected from any one of polyoxyethylene (30) dipolyhydroxystearate, polyglycerol-4 diisostearate, polyhydroxystearic acid sebacate, span-20, span-80, span-60, span-85, alkoxylated glycerol sorbitan fatty acid ester, polyglycerol stearate and polyglycerol oleate or a combination thereof.

In a preferred embodiment of the present invention, the emulsifier is selected from any one or combination of ARLACEL P135, ARLACEL 780, ABIL EM90, ABIL EM97, ISOLAN GPS, TEGO SML, TEGO SMOV, TEGO SMS, TEGO STOV, NIKKOMULESE WO, EM-12, GRANSURF 90, SILUBE J208-812CG, and DPHS P135.

In a preferred embodiment of the present invention, the emulsifier has an HLB value of 1 to 7, preferably 2 to 6, and more preferably 3 to 5.

In a preferred technical scheme of the invention, the pharmaceutically acceptable carrier further comprises any one or a combination of a metal salt, a whitening humectant, a preservative, an acid-base regulator and an antioxidant.

In the preferred technical scheme of the invention, the content of the metal salt in the emulsion is 0.5-5% (w/w), 0.8-4% (w/w), and preferably 1-2% (w/w).

In a preferred embodiment of the present invention, the metal salt is selected from any one of sodium salt, potassium salt, and magnesium salt, or a combination thereof, and is preferably any one of sodium chloride, potassium chloride, sodium sulfate, magnesium sulfate, and potassium sulfate, or a combination thereof.

In a preferred embodiment of the present invention, the content of the whitening moisturizer in the emulsion is 1-10% (w/w), preferably 2-9% (w/w), and more preferably 5-8% (w/w).

In a preferred technical scheme of the invention, the whitening humectant is selected from any one of or a combination of hyaluronic acid, glycerol, 1, 3-butanediol, propylene glycol, cetyl alcohol, urea, amino acid, lanolin, cysteine hydrochloride, L-cysteine hydrochloride and acetylcysteine.

In a preferred embodiment of the present invention, the antioxidant is present in the emulsion in an amount of 0.1-4% (w/w), preferably 0.2-3% (w/w), more preferably 0.5-2% (w/w).

In a preferred embodiment of the present invention, the antioxidant is selected from any one of sodium bisulfite, t-butyl-p-cresol, sodium metabisulfite, vitamin E, ascorbyl glucoside, ascorbyl ethyl ether, ascorbyl palmitate, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, disodium ethylenediaminetetraacetate, or a combination thereof.

In a preferred embodiment of the present invention, the emulsion further comprises a preservative, and the content of the preservative in the emulsion is 0.1-5%, preferably 0.2-3%, and more preferably 0.5-2%.

In a preferred embodiment of the present invention, the preservative is selected from any one of phenoxyethanol, methyl paraben propyl ester, methylisothiazolinone, methylparaben, ethylparaben, propylparaben, sodium benzoate, potassium sorbate, benzoic acid or a salt thereof, sorbic acid or a salt thereof, paraben, sodium metabisulfite, chlorhexidine, sodium citrate, Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), tocopherol, ethylenediaminetetraacetic acid, propyl gallate, quaternary ammonium compounds, or a combination thereof.

In a preferred technical scheme of the invention, the emulsion also contains 0.5-3% (w/w) of an acid-base regulator, preferably 1-2.5%, and more preferably 1.5-2%.

In a preferable technical scheme of the invention, the acid-base regulator is selected from any one or combination of triethanolamine, sodium hydroxide, citric acid, sodium citrate, malic acid, sodium malate, acetic acid and sodium acetate.

In a preferred embodiment of the present invention, the emulsion has a pH of 5 to 9, preferably a pH of 6 to 7.5, and more preferably a pH of 6.5 to 7.

In the preferred technical scheme of the invention, the particle size of the emulsion is less than or equal to 600nm, preferably less than or equal to 500nm, more preferably less than or equal to 400nm, still preferably 100nm-350nm, and still more preferably 150 nm-300 nm.

In a preferable technical scheme of the invention, the emulsion comprises 1-4% (w/w) of hydroquinone, 0.01-0.05% (w/w) of fluocinolone acetonide or fluocinolone acetonide and 0.01-0.05% (w/w) of tretinoin, and the pharmaceutically acceptable carrier comprises 0.5-1% (w/w) of diglycerol.

In a preferred technical scheme of the invention, the emulsion comprises 1.5-3.5% (w/w) of hydroquinone, 0.02-0.04% (w/w) of fluocinolone acetonide or fluocinolone acetonide and 0.02-0.04% (w/w) of tretinoin, and the pharmaceutically acceptable carrier comprises 0.6-0.8% (w/w) of diglycerol.

The invention also aims to provide a water-in-oil compound hydroquinone emulsion which comprises an active component and a pharmaceutically acceptable carrier, wherein the active component comprises 1-4% (w/w) of hydroquinone, 0.01-0.05% (w/w) of external corticosteroid or pharmaceutically acceptable salt or ester thereof and 0.01-0.05% (w/w) of retinoid or pharmaceutically acceptable salt or ester thereof, and the pharmaceutically acceptable carrier comprises 0.5-1% (w/w) of irritation relieving agent.

In a preferred technical scheme of the invention, the emulsion comprises 30-50% (w/w) of oil component, 1-8% (w/w) of emulsifier, active component and pharmaceutically acceptable carrier, wherein the active component comprises 1-4% (w/w) of hydroquinone, 0.01-0.05% (w/w) of external corticosteroid or pharmaceutically acceptable salt or ester thereof and 0.01-0.05% (w/w) of retinoid or pharmaceutically acceptable salt or ester thereof, and the pharmaceutically acceptable carrier contains 0.5-1% (w/w) of irritation relieving agent.

In a preferred embodiment of the present invention, the pharmaceutically acceptable carrier comprises a sustained release agent 0.5-1% (w/w), preferably 0.6-0.9% (w/w), preferably 0.7-0.8% (w/w).

In a preferred embodiment of the present invention, the content of the irritation-relieving agent is 0.6-0.9% (w/w), preferably 0.7-0.8% (w/w).

In a preferred embodiment of the present invention, the irritation-relieving agent is any one selected from vitamin B6, asiaticoside, or a combination thereof.

In a preferred technical scheme of the invention, the pharmaceutically acceptable carrier further comprises any one or a combination of a metal salt, a transdermal absorbent, a whitening humectant, a preservative, an acid-base regulator and an antioxidant.

In a preferred embodiment of the present invention, the content of the percutaneous absorption agent in the emulsion is 0.5-5% (w/w), preferably 0.8-4% (w/w), preferably 1-2% (w/w).

In a preferred embodiment of the present invention, the content of the preservative in the emulsion is 0.1 to 5%, preferably 0.2 to 3%, more preferably 0.5 to 2%.

In a preferred embodiment of the present invention, the acid-base regulator in the emulsion is 0.5-3% (w/w), preferably 1-2.5%, and more preferably 1.5-2%.

In the preferable technical scheme of the invention, the emulsion comprises 1-4% (w/w) of hydroquinone, 0.01-0.05% (w/w) of fluocinolone acetonide or fluocinolone acetonide and 0.01-0.05% (w/w) of tretinoin, and the pharmaceutically acceptable carrier comprises 0.5-1% (w/w) of vitamin B6.

In the preferable technical scheme of the invention, the emulsion comprises 1.5-3.5% (w/w) of hydroquinone, 0.02-0.04% (w/w) of fluocinolone acetonide or fluocinolone acetonide and 0.02-0.04% (w/w) of tretinoin, and the pharmaceutically acceptable carrier comprises 0.6-0.8% (w/w) of vitamin B6.

Another object of the present invention is to provide a method for preparing a water-in-oil type compound hydroquinone emulsion, which comprises an active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient comprises hydroquinone 1-4% (w/w), topical corticosteroid or its pharmaceutically acceptable salt or its ester 0.01-0.05% (w/w), and retinoid or its pharmaceutically acceptable salt or its ester 0.01-0.05% (w/w), and the pharmaceutically acceptable carrier comprises sustained release agent 0.5-1% (w/w), the method comprises the following steps:

1) preparing a water phase;

2) preparing an oil phase;

3) adding the water phase prepared in the step 1) into the oil phase prepared in the step 2), and homogenizing and emulsifying for the first time;

4) after the active component is added, carrying out secondary homogenization and emulsification to prepare the water-in-oil emulsion.

In the preferable technical scheme of the invention, a transdermal absorption enhancer is added into the active component.

In a preferred technical scheme of the invention, the active component is added with a stimulation relieving agent.

In a preferred technical scheme of the invention, the water phase preparation steps are as follows: adding water of required amount into a water phase pot, heating to 60-90 deg.C, stirring to dissolve completely, adding metal salt, stirring to dissolve completely, and keeping at 50-60 deg.C.

In the preferable technical scheme of the invention, in the step of preparing the water phase, the heating temperature is 65-85 ℃, and more preferably 70-80 ℃.

In a preferred technical scheme of the invention, any one or a combination of a transdermal absorption enhancer, a preservative, a whitening humectant, a sustained-release agent, an antioxidant and an emulsifier can be added in the water phase preparation step.

In a preferred technical scheme of the invention, the oil phase preparation steps are as follows: adding oil into oil phase pan, introducing steam, heating for melting, and keeping at 60-90 deg.C.

In a preferred embodiment of the present invention, in the step of preparing the oil phase, the temperature of the oil phase is maintained at 65 to 85 ℃, more preferably 70 to 80 ℃.

In a preferred technical scheme of the invention, any one or a combination of an antioxidant, a transdermal absorption enhancer, a preservative and an emulsifier can be added in the oil phase preparation step.

In the preferred technical scheme of the invention, the primary homogenizing and emulsifying step comprises the following steps: firstly, the oil phase prepared in the step (2) is sucked into an emulsification tank in vacuum, and is quickly stirred, then the water phase prepared in the step (1) is slowly sucked into the emulsification tank in vacuum, is vacuumized, and is homogenized for 15-60min at the temperature of 50-90 ℃.

In the preferred technical scheme of the invention, in the homogenizing and emulsifying step, the homogenizing temperature is 60-80 ℃, and more preferably 65-75 ℃.

In the preferred technical scheme of the invention, the stirring speed is 30-150r/min, preferably 40-100r/min, and more preferably 50-80 r/min.

In the preferred technical scheme of the invention, the secondary homogenizing and emulsifying step comprises the following steps: adding active ingredient into the primary homogenized emulsion, homogenizing and emulsifying again at 25-70 deg.C for 15-60min to obtain emulsifier.

In the preferred technical scheme of the invention, the secondary homogenization temperature is 35-65 ℃, and more preferably 40-55 ℃.

In a preferred embodiment of the present invention, the homogenization is selected from any one of ultrasonic homogenization and high-pressure homogenization, or a combination thereof.

In the preferred technical scheme of the invention, the homogenization time is 20-50min, and more preferably 30-40 min.

In the preferred technical scheme of the invention, the homogenization speed is 1500-3000r/min, preferably 2000-2800r/min, and more preferably 2200-2500 r/min.

In the preferred technical scheme of the invention, the homogeneous pressure is 600-1500bar, preferably 700-1200bar, and more preferably 800-1000 bar.

The invention also aims to provide the application of the compound hydroquinone emulsion in preparing medicaments or cosmetics for removing freckles and whitening.

The invention also aims to provide the application of the compound hydroquinone emulsion in preparing medicines or cosmetics for preventing and treating skin diseases, color spots and pigmentation.

In a preferred technical scheme of the invention, the color spot is selected from any one of black spots, freckles, chloasma, senile plaques, liver spots, dark eye circles, severe acne marks, post-inflammatory pigmentation spots and color spots caused by local pigmentation or complications thereof.

The 'oxygen-free condition' is the reaction condition of isolating oxygen or other oxidants, and is selected from any one or combination of inert gas protection or reducing agent addition.

The composite efficacy component comprises an active component and any one or the combination of a stimulation and relief agent, a slow release agent and a transdermal absorption enhancer.

Unless otherwise indicated, when the present invention relates to percentages between liquids, said percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentages between solid and liquid, said percentages being weight/volume percentages; the balance being weight/weight percent.

In the present invention, "part" means part by weight and "%" means percent by weight unless otherwise specified.

Compared with the prior art, the invention has the following beneficial technical effects:

1. the invention scientifically screens the components and the proportion of the compound hydroquinone emulsion, optimizes the emulsification process parameters and prepares the water-in-oil compound hydroquinone emulsion with good stability.

2. The hydroquinone bulk drug adopted in the compound hydroquinone emulsion does not contain the toxic substances of genes such as p-benzoquinone, aniline, nitrobenzene and the like, and has good safety.

3. The preparation method is simple and convenient to operate, remarkably shortens the production period, further remarkably reduces the production cost, and is suitable for large-scale industrial production.

Drawings

FIG. 1 the separation and detection results of the substances in hydroquinone obtained in example 1 under the condition of 0.1% glacial acetic acid aqueous solution-acetonitrile (97: 3);

FIG. 2 the separation and detection results of the substances in hydroquinone obtained in example 2 under the condition of 0.1% glacial acetic acid aqueous solution-acetonitrile (97: 3);

FIG. 3 separation and detection results of related substances in hydroquinone obtained in example 3 under the condition of 0.1% glacial acetic acid aqueous solution-acetonitrile (97: 3);

FIG. 4a separation and detection results of the substances in hydroquinone in the purified product of hydroquinone obtained in example 4 under the conditions of pH3.85 potassium dihydrogen phosphate buffer-acetonitrile (75: 25);

FIG. 4b Nitrobenzene localization in pH3.85 potassium dihydrogen phosphate buffer-acetonitrile (75:25) conditions;

FIG. 5 the separation and detection results of the substances in hydroquinone obtained in example 4 under the conditions of pH3.0 potassium dihydrogen phosphate buffer-acetonitrile (95: 5);

FIG. 6 the separation and detection results of the substances in hydroquinone obtained in example 5 under the conditions of pH3.0 potassium dihydrogen phosphate buffer-acetonitrile (95: 5);

FIG. 7 separation and detection of related substances in hydroquinone in the condition of pH3.0 potassium dihydrogen phosphate buffer-acetonitrile (95:5) of hydroquinone obtained in example 6.

Detailed Description

The present invention is described below with reference to examples. The invention is not limited to the examples.

Example 1Preparation of Hydroquinone according to the invention

The preparation method of hydroquinone comprises the following steps:

1) MnO of₂280g, 430g of 98 percent sulfuric acid and 2.0L of water are added into a reaction bottle, 100g of aniline is slowly dropped into the reaction bottle at the temperature of 5-10 ℃, the mixture is stirred, and the temperature is gradually increased to about 25 ℃ until the reaction is completed. Carrying out steam distillation on the reaction liquid at 60-90 ℃, and introducing the collected p-benzoquinone condensate into another reaction bottle;

2) under the conditions of shading and nitrogen protection, adding 42g of iron powder into the collected p-benzoquinone condensate, stirring and reacting for 3-4 hours at the temperature of 90-100 ℃ until the reaction is complete, filtering, and concentrating the collected filtrate under reduced pressure until the content of hydroquinone in the concentrated solution is 35%;

3) adding 550mg of sodium pyrosulfite, 2.2g of active carbon and 330mg of zinc powder into the concentrated solution, heating to 95 ℃, carrying out hot filtration, collecting filtrate, cooling to 5 ℃, stirring for crystallization, centrifuging, collecting wet product, and carrying out vacuum drying at 60 ℃ to obtain 100.86g of hydroquinone.

Example 2Preparation of Hydroquinone according to the invention

The preparation method of hydroquinone comprises the following steps:

1) MnO of₂350g, 500g of 98 percent sulfuric acid and 2.0L of water are added into a reaction bottle, 100g of aniline is slowly dripped under the condition of 5-8 ℃, stirred and gradually heated to about 25 ℃ until the reaction is completed. Steam distilling the reaction liquid at 60-90 deg.c and introducing the collected p-benzoquinone condensate into the other reaction bottle;

2) under the conditions of shading and nitrogen protection, 60g of iron powder is added into the collected p-benzoquinone condensate, the mixture is stirred and reacted for 2 to 3 hours at the temperature of between 90 and 100 ℃ until the reaction is completed, the mixture is filtered, and the filtrate is collected and concentrated under reduced pressure until the content of hydroquinone in the concentrated solution is 25 percent;

3) adding 750mg of sodium pyrosulfite, 3.1g of active carbon and 500mg of iron powder into the concentrated solution, heating to 90 ℃, filtering, cooling the filtrate to 8 ℃, stirring for crystallization, centrifuging, collecting wet products, and drying in vacuum at 65 ℃ to obtain 96.20g of hydroquinone.

Example 3Preparation of Hydroquinone according to the invention

The preparation method of hydroquinone comprises the following steps:

1) MnO of₂250g, 370g of 98 percent sulfuric acid and 2.5L of water are added into a reaction bottle, 100g of aniline is slowly dropped into the reaction bottle at the temperature of between 6 and 10 ℃, the mixture is stirred, and the temperature is gradually increased to about 25 ℃ until the reaction is completed. Distilling the reaction solution at 70-95 deg.C with steam, and introducing the collected p-benzoquinone condensate into another reaction bottle;

2) under the conditions of shading and nitrogen protection, 31g of iron powder is added into the collected p-benzoquinone condensate, the mixture is stirred and reacted for 2 to 3 hours at the temperature of between 90 and 100 ℃ until the reaction is completed, the mixture is filtered, and the filtrate is collected and concentrated under reduced pressure until the content of hydroquinone in the concentrated solution is 30 percent;

3) adding 550mg of sodium pyrosulfite, 2.20g of active carbon and 350mg of zinc powder into the concentrated solution, heating to 90 ℃, filtering, cooling the filtrate to 10 ℃, stirring for crystallization, centrifuging, collecting wet products, and drying in vacuum at 65 ℃ to obtain 98.43g of hydroquinone.

Example 4Purification of Hydroquinone according to the invention

A process for the purification of hydroquinone comprising the steps of:

dissolving 25g of hydroquinone to be refined in 100ml of 95 ℃ water, adding 140mg of sodium metabisulfite, 600mg of activated carbon and 100mg of zinc powder, stirring for 40min, filtering while hot, collecting filtrate, cooling to 8 ℃, standing for crystallization for 11h, filtering, washing with water, collecting crystals, placing the crystals at 70 ℃ for vacuum drying, internally packaging 22.8g of hydroquinone in a brown glass bottle, externally packaging the hydroquinone in a black bag, and filling nitrogen in the bottle.

Example 5Purification of Hydroquinone according to the invention

A process for the purification of hydroquinone comprising the steps of:

dissolving 40g of hydroquinone to be refined in 120ml of 92 ℃ water, adding 100mg of sodium metabisulfite, 400mg of activated carbon and 60mg of iron powder, stirring for 35min, filtering while hot, collecting filtrate, cooling to 5 ℃, standing for crystallization for 12h, filtering, washing with water, collecting crystals, placing the crystals at 65 ℃ for vacuum drying, wrapping the obtained 36.8g of hydroquinone in a brown glass bottle, wrapping the hydroquinone in a black bag, and filling nitrogen in the bottle.

Example 6Purification of Hydroquinone according to the invention

A process for the purification of hydroquinone comprising the steps of:

dissolving 50g of hydroquinone to be refined in 140ml of 100 ℃ water, adding 175mg of zinc powder, stirring for 30min, adding 1.10g of activated carbon and 275mg of sodium metabisulfite, stirring for 10min, filtering while hot, collecting filtrate, cooling to 10 ℃ under the protection of nitrogen, standing for crystallization for 12h, filtering while hot, washing with water, collecting crystals, placing the crystals at 65 ℃ for vacuum drying, internally packaging 45g of hydroquinone in a brown glass bottle, externally packaging the hydroquinone in a black bag, and filling nitrogen in the bottle.

Examples 7 to 9Hydroquinone purity detection of the present invention

1. Chromatographic conditions

2. Preparation of the solution

Detecting a sample: examples 1-3 Hydroquinone was produced.

Blank solvent: 0.1% aqueous glacial acetic acid-acetonitrile (97: 3).

Impurity localization solution: precisely weighing a proper amount of the p-benzoquinone, adding water to dissolve and dilute the p-benzoquinone into a solution containing 10 mu g of the benzoquinone per 1ml, and shaking up to obtain the benzoquinone.

Test solution: precisely weighing an appropriate amount of hydroquinone, adding a diluting solvent to dissolve and dilute the hydroquinone into a solution containing about 1mg per 1ml, and shaking up to obtain the product.

Control solution: precisely measuring 1ml of the test solution, placing the test solution in a 100ml measuring flask, diluting with water to scale, and shaking up to obtain the final product.

And (3) taking 10 mu l of each of the blank solvent, the impurity positioning solution, the test solution and the reference solution, injecting the blank solvent, the impurity positioning solution, the test solution and the reference solution into a liquid chromatograph, recording a chromatogram, and testing the content of the product. The results are shown in FIGS. 1-3.

The hydroquinone obtained in examples 1-3 had a purity of 99.95%, 99.93% and 99.96%, respectively.

Example 10Hydroquinone purity detection of the present invention

1. Chromatographic conditions

2. Preparation of the solution

Detecting a sample: the purified hydroquinone obtained in example 4.

Blank solvent: potassium dihydrogen phosphate buffer-acetonitrile (75:25) ph 3.85.

Test solution: precisely weighing appropriate amount of hydroquinone refined product, adding diluting solvent to dissolve and dilute into solution containing 1mg per 1ml, and shaking.

Nitrobenzene positioning solution: precisely weighing appropriate amount of nitrobenzene, adding a diluting solvent to dissolve and dilute the nitrobenzene into a solution containing about 1mg of nitrobenzene per 1ml, and shaking up to obtain the product.

Taking the blank solvent, the test solution, the control solution and the nitrobenzene positioning solution 10 μ l each, injecting the mixture into a liquid chromatograph, and recording the chromatogram, wherein the results are shown in figures 4a-4 b.

Example 4 hydroquinone purity was 100%.

Examples 11 to 13Hydroquinone purity detection of the present invention

1. Chromatographic conditions

2. Preparation of the solution

Detecting a sample: hydroquinones from examples 4-6.

Blank solvent: pH3.0 Potassium dihydrogen phosphate buffer acetonitrile (95: 5).

And (3) taking 10 mu l of each of the blank solvent, the test solution and the reference solution, injecting the blank solvent, the test solution and the reference solution into a liquid chromatograph, recording a chromatogram, and testing the content of the product, wherein the results are shown in figures 5-7.

The purity of hydroquinone obtained in examples 4 to 6 was 100%, 100% and 100%, respectively.

Example 14Preparation of compound hydroquinone emulsion

The compound hydroquinone emulsion comprises the following components:

oil phase component

Aqueous phase component

Composite functional component

The preparation method of the compound hydroquinone emulsion comprises the following steps:

(1) preparation of an aqueous phase: pouring purified water into a water phase pot, 1.3-butanediol, glycerol and hyaluronic acid, introducing steam into an interlayer, heating to 70 +/-5 ℃, then adding water phase components into the water phase pot, stirring at 40rp/min until the components are completely dissolved, finally adding tert-butyl-p-cresol, methyl paraben and sodium chloride into the water phase pot, stirring at 40rp/min until the components are completely dissolved, and reducing the temperature to 50-60 ℃ for later use.

(2) Preparing an oil phase: adding the oil phase components into an oil phase pot, introducing steam, heating to melt, and cooling to 50-60 deg.C for use.

(3) Homogenizing and emulsifying: starting a power switch of an emulsifying pot, starting a vacuum pump, stopping vacuumizing when the vacuum degree is-80 KPa, starting stirring to 40rp/min, sucking the oil phase prepared in the step (2) into an emulsifying tank, slowly sucking the water phase prepared in the step (1) into the emulsifying tank under stirring, starting an emulsifying machine homogenizer at 70 +/-5 ℃ and under the vacuum degree of-80 KPa, and homogenizing and emulsifying for 20 minutes.

(4) After homogenizing and emulsifying, opening a cooling water valve, and keeping the pressure of cooling water not too high, when the temperature is reduced to 45 ℃, adding the functional components, starting an emulsifying machine homogenizer under the conditions of 45 +/-5 ℃ and vacuum degree of-80 KPa, homogenizing and emulsifying for 20 minutes, adjusting the stirring speed to 30rp/min, cooling for about 1 hour, adjusting the stirring speed to 5rp/min, and cooling the paste to room temperature.

Example 15Preparation of compound hydroquinone emulsion

The compound hydroquinone emulsion comprises the following components:

oil phase component

Aqueous phase component

Composite functional component

(1) preparation of an aqueous phase: pouring purified water, 1.3-butanediol, glycerol and hyaluronic acid into a water phase pot, introducing steam into an interlayer, heating to 70 +/-5 ℃, then adding the water phase component into the water phase pot, stirring at 40rp/min until the components are completely dissolved, finally adding sodium metabisulfite, methyl paraben and sodium chloride into the water phase pot, stirring at 40rp/min until the components are completely dissolved, and reducing the temperature to 50-60 ℃ for later use.

Example 16Preparation of compound hydroquinone emulsion

The compound hydroquinone emulsion comprises the following components:

oil phase component

Aqueous phase component

Composite functional component

(1) preparation of an aqueous phase: pouring purified water, 1.3-butanediol, glycerol and hyaluronic acid into a water phase pot, introducing steam into an interlayer, heating to 70 +/-5 ℃, then adding the water phase component into the water phase pot, stirring at 40rp/min until the components are completely dissolved, finally adding sodium metabisulfite, sodium chloride and methyl paraben into the water phase pot, stirring at 40rp/min until the components are completely dissolved, and reducing the temperature to 50-60 ℃ for later use.

Example 17Preparation of compound hydroquinone emulsion

The compound hydroquinone emulsion comprises the following components:

oil phase component

Aqueous phase component

Composite functional component

Example 18Preparation of compound hydroquinone emulsion

The compound hydroquinone emulsion comprises the following components:

oil phase component

Aqueous phase component

Composite active component

Comparative example 1

1. 344.8 kg of water, 15.0 kg of magnesium aluminum silicate and 0.2 kg of butylated hydroxytoluene were combined and mixed at 75-80 ℃ to form an aqueous phase. Mixing can be carried out with side-scraping stirring at a fixed rate to produce an aqueous suspension.

2. 20.0kg of cetyl alcohol, 15.0 kg of stearic acid, 20.0kg of stearyl alcohol, 25.0 kg of the methylglucoside decaethylene oxide (methylgluceth-10), 0.9 kg of methyl paraben, 0.1 kg of propyl paraben and 20.0kg of glycerol are mixed together at a moderate speed at about 75-80 ℃ to form a non-aqueous phase. Mix at moderate speed in a mixer. The resulting non-aqueous phase is a suspension. The second step may be performed before, after or simultaneously with the first step.

3. The non-aqueous phase was added to the aqueous phase and the combined two phase mixture was cooled to a temperature in the range of 68 ℃ to 72 ℃, or to about 70 ℃, followed by the addition of about 17.5kg of 165, 0.25kg of tretinoin and 0.050kg of fluocinolone acetonide and stirring during cooling. When the mixture reached 60 ℃, 0.25kg of citric acid was added with mixing and cooling.

When the temperature reached 55 ℃, 20.0kg of hydroquinone was added with mixing and cooling. When the temperature reached about 50 ℃, the mixture was homogenized with a homogenizer with continued cooling. When the mixture reached 45 ℃, 1.0kg of sodium metabisulfite was added with stirring and cooling. Typically, sodium metabisulfite is added about 30 minutes after the addition of hydroquinone. Mixing can be carried out in a side-scraping mixer at a fixed rate. The resulting composition of matter is an emulsion, i.e., a cream.

Test example 1

Comparative example 1 and examples 14-18 were compared to investigate cold, heat, centrifuge and conductivity with reference to the requirements associated with the national standard for skin lotions, GB 11431-89.

1. Heat resistance

Adjusting the temperature of an electric heating constant temperature incubator to 48 +/-1 ℃, putting the completely packaged emulsion 1 bottle into the electric heating constant temperature incubator, keeping for 24h, taking out, and returning to room temperature for observation.

2. Cold-resistant

Adjusting the temperature of a refrigerator to a specified temperature, adjusting the temperature to-18 +/-1 ℃, putting the heat-resistant emulsion in the refrigerator, keeping for 24 hours, taking out, and returning to room temperature for observation.

3. Centrifugation

And (3) pouring 7ml of the emulsion subjected to the cold resistance experiment into a centrifuge tube, plugging the centrifuge tube with a cork, then placing the centrifuge tube into an electrothermal constant-temperature incubator pre-adjusted to 38 +/-1 ℃, keeping the incubator for 1 hour, transferring the centrifuge tube into a centrifuge, adjusting the centrifuge to a specified centrifugation speed, rotating the centrifuge tube for 30min, and taking out and observing the centrifuge tube.

4. Conductivity test

The conductivity of the emulsion was measured with a HONEYTEK mountain trauma Meter A830L conductivity meter.

The compound hydroquinone emulsion of comparative example 1 showed delamination and the conductivity was not 0 after cold and heat resistant centrifugation experiments. Examples 14 to 18 underwent cold and heat resistant centrifugation test, and were found to have no delamination and a conductivity of 0 and high stability.

Test example 2Long-term stability study of Compound Hydroquinone emulsion

10g of each of the samples prepared in examples 14 to 18 and comparative example 1 was taken, and the sample was placed in a test tube without sealing and left to stand at room temperature. And performing character examination on 0 day, 10 days, 30 days, 2 months, 3 months, 4 months, 6 months and 8 months. The results are shown in Table 1.

TABLE 1 Room temperature storage stability test results

Test example 3Light stability study of compound hydroquinone emulsion

The samples prepared in examples 14 to 18 and comparative example 1 were removed of the outer package, placed under a fluorescent lamp at a light intensity of 3500LX for 10 days, periodically sampled for 1 day, 3 days, 5 days, and 10 days, respectively, and observed for shape and uniformity. The results are shown in Table 2.

TABLE 2 light stability test results

Test example 4High-temperature and low-temperature stability research of compound hydroquinone emulsion

The samples prepared in examples 14 to 18 and comparative example 1 were removed of the outer package, and they were placed at 40 ℃, 60 ℃, 80 ℃ and low temperature (-20 ℃) for 10 days, respectively, and sampled periodically for 1 day, 3 days, 5 days and 10 days, respectively, to observe the shape and uniformity thereof. The results are shown in Table 3.

TABLE 3 high and Low temperature stability test results

Temperature of

Comparative example 1

Example 14

Example 15

Example 16

Example 17

Example 18

40℃

Snow white

60℃

Snow white

80℃

Light yellow

Snow white

-20℃

Tan color

Snow white

Test example 5Study on high humidity stability of Compound Hydroquinone emulsion

The samples prepared in examples 14 to 18 and comparative example 1 were taken out of the outer package, and they were left at 40 ℃ and 75% RH for 3 months, respectively, and were sampled periodically for 1 month, 2 months, and 3 months, respectively, to observe the shape and uniformity thereof. The results are shown in Table 4.

Table 4 high humidity stability test results

Time of day

Comparative example 1

Example 14

Example 15

Example 16

Example 17

Example 18

0 month

Snow white

1 month

Snow white

2 months old

Light yellow

Snow white

3 months old

Tan color

Snow white

The above description of the specific embodiments of the present invention is not intended to limit the present invention, and those skilled in the art may make various changes and modifications according to the present invention without departing from the spirit of the present invention, which is defined in the appended claims.

Claims

1. The water-in-oil compound hydroquinone emulsion is characterized by comprising an active component and a pharmaceutically acceptable carrier, wherein the active component comprises 1-4% (w/w) of hydroquinone, 0.01-0.05% (w/w) of topical corticosteroid or pharmaceutically acceptable salt or ester thereof and 0.01-0.05% (w/w) of retinoid or pharmaceutically acceptable salt or ester thereof, and the pharmaceutically acceptable carrier comprises 0.5-1% (w/w) of sustained release agent.

2. The compound hydroquinone emulsion of claim 1, wherein the emulsion comprises oil component 30-50% (w/w), emulsifier 1-8% (w/w), active ingredient and pharmaceutically acceptable carrier, wherein the active ingredient comprises hydroquinone 1-4% (w/w), topical corticosteroid or its pharmaceutically acceptable salt or ester 0.01-0.05% (w/w) and retinoid or its pharmaceutically acceptable salt or ester 0.01-0.05% (w/w), and the pharmaceutically acceptable carrier comprises sustained release agent 0.5-1% (w/w).

3. Compound hydroquinone emulsion according to anyone of claims 1-2, wherein the content of the slow release agent is 0.6-0.9% (w/w), preferably 0.7-0.8% (w/w).

4. The compound hydroquinone emulsion of any one of claims 1 to 3, wherein the slow release agent is diglycerol.

5. The compound hydroquinone emulsion of any one of claims 1 to 4, further comprising a transdermal absorption enhancer.

6. Compound hydroquinone emulsion according to anyone of claims 1 to 5, wherein the content of the transdermal absorber in the emulsion is 0.5-5% (w/w), preferably 0.8-4% (w/w), preferably 1-2% (w/w).

7. The compound hydroquinone emulsion according to any one of claims 1 to 6, wherein the transdermal absorption enhancer is selected from any one of borneol, mint and azone or a combination thereof, preferably the azone is selected from any one of water-soluble azone and fat-soluble azone.

8. The water-in-oil compound hydroquinone emulsion is characterized by comprising an active component and a pharmaceutically acceptable carrier, wherein the active component comprises 1-4% (w/w) of hydroquinone, 0.01-0.05% (w/w) of external corticosteroid or pharmaceutically acceptable salt or ester thereof and 0.01-0.05% (w/w) of retinoid or pharmaceutically acceptable salt or ester thereof, and the pharmaceutically acceptable carrier comprises 0.5-1% (w/w) of irritation relieving agent.

9. A preparation method of a water-in-oil compound hydroquinone emulsion is characterized in that the emulsion contains an active component and a pharmaceutically acceptable carrier, wherein the active component comprises 1-4% (w/w) of hydroquinone, 0.01-0.05% (w/w) of topical corticosteroid or pharmaceutically acceptable salt or ester thereof and 0.01-0.05% (w/w) of retinoid or pharmaceutically acceptable salt or ester thereof, and the pharmaceutically acceptable carrier contains 0.5-1% (w/w) of sustained release agent, and the method comprises the following steps:

1) preparing a water phase;

2) preparing an oil phase;

10. The compound hydroquinone emulsion is used for preparing medicaments or cosmetics for removing freckles and whitening.