Brovudine cream for treating herpes zoster and preparation method thereof

Abstract

The invention discloses a brovudine cream for treating herpes zoster and a preparation method of the brovudine cream. Specifically, the invention provides a cream which comprises the following components in percentage by mass: 0.1-5% of bromovudine, 5-45% of an organic solvent, 0.3-10% of an emulsifier, 15-55% of an oil phase matrix and water, the cream is an oil-in-water type cream; and any one of the following conditions is met: (C1) the emulsifier comprises 15-hydroxystearic acid polyethylene glycol ester; (C2) the oil phase matrix comprises glyceryl behenate. The brovudine cream provided by the invention has one or more positive progressive effects of good safety, small side reaction, good stability and good treatment effect.

Description

TECHNICAL FIELD

[0001] The present application relates to a bromofidine cream for treating herpes zoster and a preparation method thereof. BACKGROUND

[0002] Herpes zoster is an acute inflammatory skin disease caused by varicella-zoster virus, and the lesion is mainly in the epidermis, with blisters in the deep layer of the epidermis. Generally, it is infected in childhood and shows varicella-like lesion performance, and then in the adult stage, when it is weak, the immunity is low, or the inevitable immune decline occurs with age, the varicella-zoster virus will relapse, showing herpes zoster.

[0003] Common treatment drugs mainly include acyclovir, penciclovir, etc., which all have activity in treating varicella-zoster virus infection. The anti-varicella-zoster virus activity of bromofidine is more than 200 times that of acyclovir, and currently only oral tablets are available. CN1486185A discloses a stable bromofidine topical preparation containing metal oxide pigments, which can ensure the stability of bromofidine under light by adding metal oxides such as zinc oxide, titanium dioxide or aluminum oxide. However, the addition of metal oxides poses a safety risk and may cause more side effects in the cream, and the art needs more suitable additives to improve efficacy and stability. SUMMARY

[0004] The technical problem to be solved by the present application is to overcome the defects of strong irritation and poor comfort of the bromofidine preparation in the prior art, and to provide a bromofidine cream with one or more of the advantages of good safety, small side effects, good stability and good treatment effect. The cream of the present application is suitable for treating local herpes zoster on the skin, and also has a therapeutic effect on other skin diseases caused by varicella-zoster virus (VZV), such as chickenpox.

[0005] The present application solves the above technical problems by the following technical solutions:

[0006] The present application provides a cream comprising the following components by mass fraction: 0.1-5% bromofidine, 5-45% organic solvent, 0.3-10% emulsifier, 15-55% oil phase base and water; the cream is an oil-in-water cream;

[0007] It also satisfies any of the following conditions:

[0008] (C1) The emulsifier comprises 15-hydroxystearic acid polyethylene glycol ester;

[0009] (C2) The oil phase base comprises glyceryl behenate.

[0010] In some embodiments, in addition to the technical features described further below, the remaining technical features are as described in any of the above aspects (hereinafter referred to as "in some embodiments"): the emulsifier comprises 15-hydroxysteraric acid polyethylene glycol ester, and the oil phase base can or can not comprise glyceryl behenate.

[0011] In some embodiments, the oil phase base comprises glyceryl behenate, and the emulsifier can or can not comprise 15-hydroxysteraric acid polyethylene glycol ester.

[0012] In some embodiments, the oil phase base comprises glyceryl behenate, and the emulsifier comprises 15-hydroxysteraric acid polyethylene glycol ester.

[0013] In some embodiments, the oil phase base comprises glyceryl behenate, and the emulsifier is 15-hydroxysteraric acid polyethylene glycol ester.

[0014] In some embodiments, the cream is a cream for treating a skin disease caused by a viral infection.

[0015] In some embodiments, the cream is a cream for treating a skin disease caused by varicella-zoster virus.

[0016] In some embodiments, the skin disease caused by varicella-zoster virus can be chickenpox or shingles.

[0017] In some embodiments, the skin disease caused by varicella-zoster virus is shingles.

[0018] In some embodiments, the bromfenidine is the only active ingredient in the cream.

[0019] In some embodiments, the bromfenidine is .

[0020] In the present invention, the organic solvent is a conventional organic solvent for such creams in the art.

[0021] In some embodiments, the organic solvent is selected from one or more of an ester solvent, an alcohol solvent, a sulfoxide solvent, and a triglyceride solvent.

[0022] In the present invention, the ester solvent is a conventional ester solvent for such creams in the art.

[0023] In some embodiments, the ester solvent can be a carbonate solvent; for example, propylene carbonate.

[0024] In the present invention, the alcohol solvent is a conventional alcohol solvent for such a cream in the art.

[0025] In some embodiments, the alcohol solvent can be a C 2-4 alcohol; for example a C3 alcohol; for example propylene glycol.

[0026] In some embodiments, the alcohol solvent can be a C 2-4 alcohol.

[0027] In the present invention, the sulfoxide solvent is a conventional sulfoxide solvent for such a cream in the art.

[0028] In some embodiments, the sulfoxide solvent can be dimethyl sulfoxide.

[0029] In the present invention, the triglyceride solvent is a conventional triglyceride solvent for such a cream in the art.

[0030] In some embodiments, the triglyceride solvent can be a medium-chain triglyceride.

[0031] In some embodiments, the organic solvent is selected from one or both of an alcohol solvent and a carbonate solvent.

[0032] In some embodiments, the organic solvent is selected from one or more of propylene carbonate, ethyl oleate, ethyl acetate, triethyl citrate, isopropyl myristate, isopropyl palmitate, medium-chain triglyceride, dimethyl sulfoxide, ethanol, polyethylene glycol, propylene glycol, glycerol, isopropyl alcohol, and n-butanol; for example propylene glycol and / or propylene carbonate; such as propylene glycol.

[0033] In some embodiments, the emulsifier includes polyoxyl 15-hydroxystearate, the emulsifier further including an emulsifier other than polyoxyl 15-hydroxystearate, which is a conventional emulsifier for such a cream in the art; for example one or more of a polyoxyethylene nonionic surfactant, a polyether nonionic surfactant, an anionic surfactant, a phospholipid emulsifier, a natural polymer emulsifier, and a sugar ester emulsifier.

[0034] In some embodiments, the oil phase base includes glyceryl behenate, the emulsifier being an emulsifier which is a conventional emulsifier for such a cream in the art; for example one or more of a polyoxyethylene nonionic surfactant, a polyether nonionic surfactant, an anionic surfactant, a phospholipid emulsifier, a natural polymer emulsifier, and a sugar ester emulsifier.

[0035] In the present invention, the polyoxyethylene nonionic surfactant is a conventional polyoxyethylene nonionic surfactant for such a cream in the art.

[0036] In some embodiments, the polyoxyethylene nonionic surfactant is one or more of polysorbates, poloxyl 40 stearate, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (35) castor oil, lauroyl polyoxyethylene (32) glycerides, lauroyl polyoxyethylene (6) glycerides, lauroyl polyoxyethylene (8) glycerides, lauroyl polyoxyethylene (12) glycerides, oleoyl polyoxyethylene glycerides, polyoxyethylene oleate, polyoxyethylene (50) stearate, vitamin E succinate polyethylene glycol ester, and 15-hydroxystearic acid polyethylene glycol ester.

[0037] In some embodiments, the polyoxyethylene nonionic surfactant is one or more of polysorbates, poloxyl 40 stearate, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (35) castor oil, lauroyl polyoxyethylene (32) glycerides, lauroyl polyoxyethylene (6) glycerides, lauroyl polyoxyethylene (8) glycerides, lauroyl polyoxyethylene (12) glycerides, oleoyl polyoxyethylene glycerides, polyoxyethylene oleate, polyoxyethylene (50) stearate, and vitamin E succinate polyethylene glycol ester.

[0038] In the present application, the polyether nonionic surfactant is a conventional polyether nonionic surfactant for such creams in the art.

[0039] In some embodiments, the polyether nonionic surfactant is poloxamer 188 and / or poloxamer 407.

[0040] In the present application, the anionic surfactant is a conventional anionic surfactant for such creams in the art.

[0041] In some embodiments, the anionic surfactant is sodium lauryl sulfate and / or sodium deoxycholate.

[0042] In the present application, the phospholipid emulsifier is a conventional phospholipid emulsifier for such creams in the art.

[0043] In some embodiments, the phospholipid emulsifier is soy lecithin and / or egg lecithin.

[0044] In the present application, the natural high molecular emulsifier is a conventional natural high molecular emulsifier for such creams in the art.

[0045] In some embodiments, the natural high molecular emulsifier is gum arabic and / or gum tragacanth.

[0046] In the present application, the sugar ester emulsifier is a conventional sugar ester emulsifier for such creams in the art.

[0047] In some embodiments, the sugar ester emulsifier is sucrose stearate.

[0048] In some embodiments, the emulsifier is polyethylene glycol 15-hydroxystearate.

[0049] In some embodiments, the emulsifier comprises polyethylene glycol 15-hydroxystearate, and the emulsifier further comprises sodium dodecyl sulfate, polysorbates, polyoxyethylene stearate (40), polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (35) castor oil, gum arabic, tragacanth gum, poloxamer 188, poloxamer 407, lauroyl polyoxyethylene (32) glyceryl ester, lauroyl polyoxyethylene One or more of the following: oleyl(6) glycerol, lauroyl polyoxyethylene(8) glycerol, lauroyl polyoxyethylene(12) glycerol, oleyl polyoxyethylene glycerol, polyoxyethylene oleate, polyoxyethylene(50) stearate, hydrogenated castor oil, sodium deoxycholate, polyethylene glycol succinate, sucrose stearate, soybean lecithin and egg yolk lecithin; for example, one or more of polysorbate 80 and sodium dodecyl sulfate; such as polysorbate 80.

[0050] In some embodiments, the oil phase matrix comprises glyceryl behenate, and the emulsifier is selected from sodium dodecyl sulfate, polysorbates, polyoxyethylene stearate (40), polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (35) castor oil, gum arabic, tragacanth gum, poloxamer 188, poloxamer 407, lauroyl polyoxyethylene (32) glyceryl ester, lauroyl polyoxyethylene (6) glyceryl ester, lauroyl polyoxyethylene (8) glyceryl ester, lauroyl One or more of the following: polyoxyethylene (12) glyceryl ester, oleoyl polyoxyethylene glyceryl ester, polyoxyethylene oleate, polyoxyethylene (50) stearate, hydrogenated castor oil, sodium deoxycholate, polyethylene glycol succinate, polyethylene glycol 15-hydroxystearate, sucrose stearate, soybean lecithin, and egg yolk lecithin; for example, one or more of the following: polyethylene glycol 15-hydroxystearate, polysorbate 80, and sodium dodecyl sulfate; such as polyethylene glycol 15-hydroxystearate and / or polysorbate 80.

[0051] In some embodiments, the emulsifier includes polyethylene glycol 15-hydroxystearate, and the oil phase matrix is ​​a conventional oil phase matrix for this type of cream in the art; for example, selected from one or more of higher aliphatic hydrocarbons, higher fatty alcohols, higher fatty acids, fatty acid esters, glycerides, polyethylene glycol esters, white beeswax, lanolin, menthol, and hydrogenated castor oil.

[0052] In some embodiments, the oil phase matrix includes glyceryl behenate, and the oil phase matrix also includes other oil phase matrices conventional to this type of cream in the art, such as higher aliphatic hydrocarbons, higher aliphatic alcohols, higher fatty acids, fatty acid esters, glyceryl esters, polyethylene glycol esters, white beeswax, lanolin, menthol, and hydrogenated castor oil.

[0053] In this invention, the higher aliphatic hydrocarbons are conventional higher aliphatic hydrocarbons in this type of cream in the art.

[0054] In some embodiments, the higher aliphatic hydrocarbon may be white petrolatum, yellow petrolatum, liquid paraffin, or paraffin.

[0055] In this invention, the higher fatty alcohol is a conventional higher fatty alcohol in this type of cream.

[0056] In some embodiments, the higher fatty alcohol may be hexadecyl alcohol, octadecyl alcohol, or hexadecyloctadecyl alcohol.

[0057] In this invention, the higher fatty acids are the conventional higher fatty acids found in this type of cream in the art.

[0058] In some embodiments, the higher fatty acid may be stearic acid or palmitic acid.

[0059] In some embodiments, the stearic acid is stearic acid type 50.

[0060] In this invention, the fatty acid ester is a conventional fatty acid ester of this type of cream in the art.

[0061] In some embodiments, the fatty acid ester may be ethyl oleate, isopropyl myristate, or ethyl acetate.

[0062] In this invention, the glyceride is a conventional glyceride of this type of cream in the art.

[0063] In some embodiments, the glyceride may be mono- or di-stearyl glyceride, behenicol glyceride, mixed fatty acid glyceride (stearic acid), or cocoa butter.

[0064] In this invention, the polyethylene glycol ester is a conventional polyethylene glycol ester used in this type of cream in the art.

[0065] In some embodiments, the polyethylene glycol ester may be polyoxyethylene stearate (40) ester or polyoxyethylene (50) stearate.

[0066] In some embodiments, the emulsifier comprises polyethylene glycol 15-hydroxystearate, and the oil phase matrix is ​​selected from one or more of the following: white petrolatum, yellow petrolatum, lanolin, silicone oil, ethyl oleate, white beeswax, hydrogenated castor oil, liquid paraffin, isopropyl myristate, cholesterol, stearic acid, palmitic acid, polyoxyethylene (50) stearate, mixed fatty acid glycerides (stear), behenate glycerides, mono- and di-stearates, polyoxyethylene (40) stearate, octadecyl alcohol, hexadecyl alcohol, ethyl acetate, menthol, paraffin, and cocoa butter.

[0067] In some embodiments, the emulsifier comprises polyethylene glycol 15-hydroxystearate, and the oil phase matrix is ​​selected from one or more of the following: mixed fatty acid glycerides (stear), cetyl alcohol, mono- and di-stearyl glycerides, white petrolatum, glyceryl behenate, isopropyl myristate, stearic acid, octadecyl alcohol, paraffin wax, ethyl oleate, silicone oil, polyoxyethylene (50) stearate, white beeswax, polyoxyethylene (40) stearate, liquid paraffin, palmitic acid, lanolin, yellow petrolatum, menthol, cetyl alcohol, ethyl acetate, and hydrogenated castor oil.

[0068] In some embodiments, the emulsifier comprises polyethylene glycol 15-hydroxystearate, and the oil phase matrix is ​​selected from one or more of the following: mixed fatty acid glycerides (stear), cetyl alcohol, mono- and di-stearyl glycerides, white petrolatum, glyceryl behenate, isopropyl myristate, stearic acid, octadecyl alcohol, paraffin wax, ethyl oleate, silicone oil, polyoxyethylene (50) stearate, white beeswax, polyoxyethylene (40) stearate, liquid paraffin, palmitic acid, cetyl alcohol, ethyl acetate, and hydrogenated castor oil.

[0069] In some embodiments, the emulsifier includes polyethylene glycol 15-hydroxystearate, and the oil phase matrix is ​​selected from hexadecyl alcohol, glyceryl mono- and distearates, white petrolatum, glyceryl behenate, isopropyl myristate, mixed fatty acid glycerides (stearate), and stearic acid.

[0070] In some embodiments, the oil phase matrix includes glyceryl behenate, and the oil phase matrix also includes one or more of the following: white petrolatum, yellow petrolatum, lanolin, silicone oil, ethyl oleate, white beeswax, hydrogenated castor oil, liquid paraffin, isopropyl myristate, cholesterol, stearic acid, palmitic acid, polyoxyethylene (50) stearate, mixed fatty acid glycerides (stear), glyceryl mono- and di-stearates, polyoxyethylene (40) stearate, octadecyl alcohol, hexadecyl alcohol, ethyl acetate, menthol, paraffin, and cocoa butter.

[0071] In some embodiments, the oil phase matrix comprises glyceryl behenate, and the oil phase matrix further comprises one or more of the following: mixed fatty acid glycerides (stearin), cetyl alcohol, glyceryl mono- and di-stearates, white petrolatum, isopropyl myristate, stearic acid, octadecyl alcohol, paraffin wax, ethyl oleate, silicone oil, polyoxyethylene (50) stearate, white beeswax, polyoxyethylene (40) stearate, liquid paraffin wax, palmitic acid, lanolin, yellow petrolatum, menthol, cetyl alcohol, ethyl acetate, and hydrogenated castor oil.

[0072] In some embodiments, the oil phase matrix comprises glyceryl behenate, and the oil phase matrix further comprises one or more of the following: mixed fatty acid glycerides (stearin), cetyl alcohol, mono- and di-stearyl glycerides, white petrolatum, isopropyl myristate, stearic acid, octadecyl alcohol, paraffin wax, ethyl oleate, silicone oil, polyoxyethylene (50) stearate, white beeswax, polyoxyethylene (40) stearate, liquid paraffin wax, palmitic acid, cetyl alcohol, ethyl acetate, and hydrogenated castor oil.

[0073] In some embodiments, the oil phase matrix comprises glyceryl behenate, and the oil phase matrix further comprises hexadecyl alcohol, glyceryl mono- and di-stearates, white petrolatum, isopropyl myristate, mixed fatty acid glycerides (stearate), and stearic acid.

[0074] In some embodiments, the stearic acid is stearic acid type 50.

[0075] The cream may also include excipients commonly used in creams of this type in the art, such as antibacterial agents and / or antioxidants.

[0076] In some embodiments, the cream also includes an antibacterial agent.

[0077] In this invention, the antibacterial agent is a conventional antibacterial agent for this type of cream in the art.

[0078] In some embodiments, the antibacterial agent is selected from one or more of quaternary ammonium salt antibacterial agents, organic acids and their salts antibacterial agents, parabens antibacterial agents, alcohols antibacterial agents, phenols antibacterial agents, imidazoles antibacterial agents, quinoline antibacterial agents, and metabisulfite antibacterial agents.

[0079] In this invention, the quaternary ammonium salt antibacterial agent is a conventional quaternary ammonium salt antibacterial agent for this type of cream in the art.

[0080] In some embodiments, the quaternary ammonium salt antibacterial agent may be benzalkonium chloride or benzalkonium bromide.

[0081] In this invention, the organic acid and its salt antibacterial agent are conventional organic acids and their salt antibacterial agents for this type of cream in the art.

[0082] In some implementations, the organic acid and its salt antibacterial agent may be benzoic acid, sodium benzoate, sorbic acid and its potassium salt, octanoic acid and its sodium salt, propionic acid, dehydroacetic acid or boric acid.

[0083] In this invention, the paraben antibacterial agent is a conventional paraben antibacterial agent for this type of cream in the art.

[0084] In some embodiments, the paraben antibacterial agent may be methylparaben, ethylparaben, propylparaben, butylparaben, or benzylparaben and their sodium salts.

[0085] In this invention, the alcohol-based antibacterial agent is a conventional alcohol-based antibacterial agent for this type of cream in the art.

[0086] In some embodiments, the alcohol-based antibacterial agent may be ethanol, propylene glycol, benzyl alcohol, phenoxyethanol, or chlorobutanol.

[0087] In this invention, the phenolic antibacterial agent is a conventional phenolic antibacterial agent for this type of cream in the art.

[0088] In some embodiments, the phenolic antibacterial agent may be p-chlorophenol, m-cresol, or chlorocresol.

[0089] In this invention, the imidazole antibacterial agent is a conventional imidazole antibacterial agent for this type of cream in the art.

[0090] In some embodiments, the imidazole antibacterial agent may be an imidazolidinyl urea.

[0091] In this invention, the quinoline antibacterial agent is a conventional quinoline antibacterial agent for this type of cream in the art.

[0092] In some embodiments, the quinoline antibacterial agent may be hydroxyquinoline sulfate.

[0093] In this invention, the metabisulfite antibacterial agent is a conventional metabisulfite antibacterial agent for this type of cream in the art.

[0094] In some embodiments, the metabisulfite antibacterial agent may be sodium metabisulfite.

[0095] In some embodiments, the antibacterial agent is selected from one or more of benzalkonium chloride, benzalkonium bromide, benzoic acid and its sodium salt, sorbic acid and its potassium salt, octanoic acid and its sodium salt, propionic acid, ethanol, propylene glycol, benzyl alcohol, phenoxyethanol, methylparaben, ethylparaben, propylparaben, butylparaben, benzylparaben, sodium methylparaben, sodium propylparaben, sodium metabisulfite, imidazolidinyl urea, dehydroacetic acid, hydroxyquinoline sulfate, p-chlorophenol, chlorobutanol, m-cresol, chlorocresol, and boric acid; for example, one or more of ethylparaben, methylparaben, propylparaben, and potassium sorbate; such as ethylparaben.

[0096] In some embodiments, the cream also includes an antioxidant.

[0097] In this invention, the antioxidant is a conventional antioxidant for this type of cream in the art.

[0098] In some embodiments, the antioxidant is one or more of butylated hydroxytoluene, butylated hydroxyanisole, tert-butylhydroquinone, propyl gallate, and vitamin E; for example, butylated hydroxytoluene.

[0099] In some implementations, the water is purified water.

[0100] In some embodiments, the mass fraction of brovodine is 0.1-1%; such as 0.4-0.6%; for example, 0.5%.

[0101] In some embodiments, the organic solvent has a mass fraction of 10-35%; such as 18-22%; for example, 20%, 10%, 25% or 35%.

[0102] In some embodiments, when the organic solvent is a mixture of an alcohol solvent and an ester solvent, the mass fraction of the alcohol solvent may be 2-8%, for example 5%; and the mass fraction of the ester solvent may be 10-30%, for example 20%.

[0103] In some embodiments, when the organic solvent is a mixture of an alcohol solvent and an ester solvent, the mass ratio of the alcohol solvent to the ester solvent is 1:(3-5); for example, 1:4.

[0104] In some embodiments, the mass fraction of the emulsifier is 0.5-6%; such as 3.5-4.5%; for example, 0.5%, 1%, 4%, 5% or 6%.

[0105] In some embodiments, the mass fraction of the oil phase matrix is ​​21-35%; such as 26-29%; for example, 21%, 24.5%, 25%, 27%, 30%, 31.5%, 27.5% or 35%.

[0106] In some embodiments, the cream further includes an antibacterial agent; the mass fraction of the antibacterial agent is 0.05-0.5%; such as 0.18-0.22%; for example, 0.05%, 0.15%, 0.2% or 0.5%.

[0107] In some embodiments, when the antibacterial agent is a mixture of methylparaben and propylparaben; the mass fraction of methylparaben may be 0.05-0.3%, for example 0.18%; and the mass fraction of propylparaben may be 0.01-0.03%, for example 0.02%.

[0108] In some embodiments, when the antibacterial agent is a mixture of methylparaben and propylparaben, the mass ratio of methylparaben to propylparaben may be (6-12):1; for example, 9:1.

[0109] In some embodiments, the antioxidant has a mass fraction of 0.01 to 0.3%; such as 0.02 to 0.3%; such as 0.09 to 0.11%; for example, 0.02%, 0.05%, 0.1% or 0.3%.

[0110] In some implementations, the water has a mass fraction of 25-65%; for example, 44-52%.

[0111] In some embodiments, the mass ratio of the bromfudin to the organic solvent is 1:(20-70); for example, 1:(36-44); or even more specifically, 1:20, 1:40, 1:50, or 1:70.

[0112] In some embodiments, the mass ratio of bromfumide to the emulsifier is 1:(1-12); for example, 1:(7-9); and for example, 1:1, 1:2, 1:8, 1:10 or 1:12.

[0113] In some embodiments, the mass ratio of the bromfumide to the oil phase matrix is ​​1:(42-70); for example, 1:(52-58); and even more specifically, 1:42, 1:50, 1:54, 1:55, 1:60, 1:63, or 1:70.

[0114] In some embodiments, the brivudine cream further includes an antibacterial agent; the mass ratio of brivudine to the antibacterial agent may be 1:(0.1-1); for example, 1:(0.36-0.44); or for example, 1:0.1, 1:0.3, 1:0.4 or 1:1.

[0115] In some embodiments, the brivudine cream further includes an antioxidant; the mass ratio of brivudine to the antioxidant may be 1:(0.04-0.6); for example, 1:(0.18-0.22); or for example, 1:0.04, 1:0.2 or 1:0.6.

[0116] In some embodiments, the oil phase matrix includes a mixture of fatty acid glycerides (stearin), cetyl alcohol, mono- and di-stearyl glycerides, white petrolatum, behenate glycerides, isopropyl myristate, and stearic acid.

[0117] In some embodiments, the oil phase matrix is ​​composed of a mixture of fatty acid glycerides (stearin), cetyl alcohol, mono- and di-stearyl glycerides, white petrolatum, behenicol, isopropyl myristate, and stearic acid.

[0118] In some embodiments, the mixed fatty acid glycerides (stearin) constitute 2-25% of the oil phase matrix by mass; for example, 4.7-20.0%; or for example, 10.3-11.5%; or for example, 4.8%, 10.9% or 20%.

[0119] In some embodiments, the hexadecyl alcohol accounts for 1.5-40% of the mass of the oil phase matrix; for example, 2.8-38.1%; for another example, 6.9-7.7%; and for yet another example, 2.9%, 7.3% or 38.1%.

[0120] In some embodiments, the mono- and di-stearyl glycerides constitute 5-20% of the oil phase matrix by mass; for example, 7.1-17.1%; or for example, 13.7-15.3%; or for example, 7.1%, 14.5%, or 17.1%.

[0121] In some embodiments, the white petrolatum accounts for 1.5-30% of the mass of the oil phase matrix; for example, 9.5-28.6%; or for example, 24.2-26.8%; or for example, 9.5%, 25.5% or 28.6%.

[0122] In some embodiments, the behenicol glyceride accounts for 1.5-35% of the mass of the oil phase matrix; for example, 2.8-28.6%; for another example, 17.2-19.2%; and for yet another example, 2.9%, 18.2% or 28.6%.

[0123] In some embodiments, the isopropyl myristate accounts for 3-18% of the oil phase matrix by mass; for example, 4.7-14.3%; for another example, 10.3-11.5%; and for yet another example, 4.8%, 10.9% or 14.3%.

[0124] In some embodiments, the stearic acid accounts for 4-20% of the mass of the oil phase matrix; for example, 7.1-14.3%; or for example, 12.0-13.4%; or for example, 7.1%, 12.7% or 14.3%.

[0125] In some embodiments, the mass ratio of the behenicol glyceride to the mixed fatty acid glyceride (stearin) is 1:(0.5-0.7); for example, 1:0.6.

[0126] In some embodiments, the mass ratio of behenicol to cetyl alcohol is 1:(0.3-0.5); for example, 1:0.4.

[0127] In some embodiments, the mass ratio of the behenicol glyceride to the mono- and di-stearate glycerides is 1:(0.9-1); for example, 1:0.8.

[0128] In some embodiments, the mass ratio of the behenicol glyceride to the white petrolatum is 1:(1.3-1.5); for example, 1:1.4.

[0129] In some embodiments, the mass ratio of the behenicol glyceride to the isopropyl myristate is 1:(0.5-0.7); for example, 1:0.6.

[0130] In some embodiments, the mass ratio of behenicol glyceride to stearic acid is 1:(0.6-0.8); for example, 1:0.7.

[0131] In some embodiments, the cream comprises the brivudine, the organic solvent, the emulsifier, the oil phase matrix, the antibacterial agent, the antioxidant, and the water.

[0132] In some embodiments, the cream comprises the brivudine, the organic solvent, the emulsifier, the oil phase matrix, the antibacterial agent, the antioxidant, and the water.

[0133] In some embodiments, the cream comprises an oil phase, the bromfudin, the organic solvent, and the water; the oil phase comprises the oil phase matrix, the emulsifier, the antibacterial agent, and the antioxidant.

[0134] In some embodiments, the cream comprises an oil phase, the bromfudin, the organic solvent, and the water; the oil phase comprises an oil phase matrix, the emulsifier, the antibacterial agent, and the antioxidant.

[0135] In some embodiments, the cream comprises the following components by mass fraction: 0.1-1% bivvudine, 10-35% organic solvent, 0.5-6% emulsifier, 21-35% oil phase matrix, 0.05-0.5% antibacterial agent, 0.02-0.3% antioxidant, and 25-65% water; the cream is an oil-in-water type cream.

[0136] In some embodiments, the cream comprises the following components by mass fraction: 0.4-0.6% bivudine, 18-22% organic solvent, 3.5-4.5% emulsifier, 26-29% oil phase matrix, 0.18-0.22% antibacterial agent, 0.09-0.11% antioxidant, and 44-52% water; the cream is an oil-in-water type cream.

[0137] In some embodiments, the cream contains propylene glycol as the organic solvent, polyethylene glycol 15-hydroxystearate as the emulsifier, and an oil phase matrix that is a mixture of mixed fatty acid glycerides (stear), cetyl alcohol, glyceryl mono- and distearates, white petrolatum, glyceryl behenate, isopropyl myristate, and stearic acid; the antibacterial agent is ethylparaben; and the antioxidant is butylated hydroxytoluene.

[0138] In some embodiments, the cream comprises the following components by mass fraction: 0.4-0.6% bivudine, 18-22% organic solvent, 3.5-4.5% emulsifier, 26-29% oil phase matrix, 0.18-0.22% antibacterial agent, 0.09-0.11% antioxidant, and 44-52% water; the cream is an oil-in-water emulsion.

[0139] In the cream, the organic solvent is propylene glycol, the emulsifier is polyethylene glycol 15-hydroxystearate, the oil phase matrix is ​​a mixture of mixed fatty acid glycerides (stear), cetyl alcohol, glyceryl mono- and distearates, white petrolatum, glyceryl behenate, isopropyl myristate, and stearic acid; the antibacterial agent is ethylparaben; and the antioxidant is butylated hydroxytoluene.

[0140] In some embodiments, the cream is any of the following formulations:

[0141] Formula 1: 0.5% brivudine, 20% propylene glycol, 4% polyethylene glycol 15-hydroxystearate, 3% mixed fatty acid glycerides (stear), 2% cetyl alcohol, 4% mono- and di-stearyl glycerides, 7% white petrolatum, 5% behenate glycerides, 3% isopropyl myristate, 3.5% stearic acid, 0.2% ethylparaben, 0.1% butylated hydroxytoluene, and the balance being purified water;

[0142] Formula 2: 0.5% brivudine, 10% propylene glycol, 6% polyethylene glycol 15-hydroxystearate, 1% mixed fatty acid glycerides (stear), 8% cetyl alcohol, 1.5% mono- and di-stearyl glycerides, 2% white petrolatum, 6% glyceryl behenate, 1% isopropyl myristate, 1.5% stearic acid, 0.05% ethylparaben, 0.02% butylated hydroxytoluene, and the balance being purified water;

[0143] Formula 3: 0.5% brivudine, 35% propylene glycol, 0.5% 15-hydroxystearic acid polyethylene glycol ester, 7% mixed fatty acid glycerides (stear), 1% cetyl alcohol, 6% mono- and di-stearic acid glycerides, 10% white petrolatum, 1% behenate glyceride, 5% isopropyl myristate, 5% stearic acid, 0.5% ethylparaben, 0.3% butylated hydroxytoluene, and the balance being purified water;

[0144] Formula 4: 0.5% bromhexine, 20% propylene glycol, 5% polysorbate 80, 1% mixed fatty acid glycerides (stearin), 5% stearyl alcohol, 2% cetyl alcohol, 2% paraffin wax, 3% behenicol, 4% ethyl oleate, 8% silicone oil, 0.18% methylparaben, 0.02% propylparaben, 0.05% butylated hydroxytoluene, and the balance being purified water;

[0145] Formula 5: 0.5% bromhexine, 20% propylene glycol, 4% 15-hydroxystearic acid polyethylene glycol ester, 2% mixed fatty acid glycerides (stearic acid), 5% octadecyl alcohol, 2% polyoxyethylene (50) stearate, 8% white beeswax, 5% polyoxyethylene (40) stearate, 3% liquid paraffin, 5% palmitic acid, 0.2% potassium sorbate, 0.1% butylated hydroxytoluene and the balance being purified water;

[0146] Formula 6: 0.5% brivudine, 20% propylene glycol, 5% polyethylene glycol 15-hydroxystearate, 1.5% mixed fatty acid glycerides (stearate), 5% lanolin, 5% mono- and di-stearates, 8% yellow petrolatum, 5% behenate glycerides, 4% liquid paraffin, 3% stearyl alcohol, 0.2% ethylparaben, 0.1% butylated hydroxytoluene, and the balance being purified water;

[0147] Formula 7: 0.5% bromhexine, 20% propylene glycol, 5% polyethylene glycol 15-hydroxystearate, 2% menthol, 6% cetearyl alcohol, 5% ethyl acetate, 5% liquid paraffin, 2% glyceryl behenate, 5% ethyl oleate, 2% hydrogenated castor oil, 0.2% ethylparaben, 0.1% butylated hydroxytoluene, and the balance being purified water;

[0148] Formula 8: 0.5% bromhexine, 20% propylene glycol, 5% polyoxyethylene oleate, 1% mixed fatty acid glycerides (stearin), 2% cetyl alcohol, 5% mono- and di-stearyl glycerides, 7% white petrolatum, 2% liquid paraffin, 4% isopropyl myristate, 3.5% stearic acid, 0.2% ethylparaben, 0.1% butylated hydroxytoluene, and the balance being purified water;

[0149] Formula Nine: 0.5% bromhexine, 20% propylene carbonate, 5% isopropanol, 1% sodium lauryl sulfate, 1% mixed fatty acid glycerides (stearin), 5% cetyl alcohol, 2% mono- and di-stearyl glycerides, 5% white petrolatum, 6% behenicol, 2% ethyl oleate, 4% stearic acid, 0.15% ethylparaben, 0.05% butylated hydroxytoluene, and the balance being purified water.

[0150] The present invention also provides a method for preparing an ointment, comprising the following steps:

[0151] The raw materials are mixed and homogenized by emulsification; the raw materials include brovodine, organic solvent, water, oil phase matrix and emulsifier;

[0152] The definitions and amounts of the bromfudin, the organic solvent, the water, the oil phase matrix, and the emulsifier are as described in any of the above schemes.

[0153] In some embodiments, the cream is an oil-in-water cream.

[0154] In some embodiments, the cream is a cream used to treat skin diseases caused by viral infections.

[0155] In some embodiments, the cream is a cream for treating skin diseases caused by the varicella-zoster virus.

[0156] In some implementations, the skin disease caused by the varicella-zoster virus may be chickenpox or shingles.

[0157] In some implementations, the skin disease caused by the varicella-zoster virus is shingles.

[0158] In some embodiments, the raw materials further include antibacterial agents and / or antioxidants; the definitions and dosages of the antibacterial agents and antioxidants are as described in any of the above embodiments.

[0159] In some embodiments, the preparation method of the cream includes the following steps: mixing brivudine solution and cream base, homogenizing and emulsifying to obtain the product;

[0160] The brovidine solution comprises brovidine and an organic solvent; the cream base is an oil-in-water cream base, comprising an aqueous phase and an oil phase; the aqueous phase comprises water; and the oil phase comprises the oil phase base and the emulsifier.

[0161] In some embodiments, the raw materials further include antibacterial agents and / or antioxidants, and the oil phase of the cream matrix includes the antibacterial agents and / or the antioxidants.

[0162] In some embodiments, the homogenization emulsification temperature is 50~85°C; for example, 55~65°C.

[0163] In some embodiments, the pressure of the homogenization emulsification is -0.01 to -0.08 MPa; for example, -0.03 to -0.06 MPa.

[0164] In some embodiments, the temperature of the aqueous phase is 60-85°C; for example, 70-80°C.

[0165] In some embodiments, the oil phase is prepared by step S2;

[0166] S2. Preparation of oil phase: Mix the materials of the oil phase to obtain the oil phase.

[0167] In some implementations, in step S2, the mixing is a hot melt mixing; preferably a hot melt mixing at 60~85°C; for example, a hot melt mixing at 70~80°C.

[0168] In some embodiments, the cream base is prepared in step S3;

[0169] S3. Preparation of cream matrix: Mix the oil phase and the aqueous phase, homogenize and emulsify, and cool to obtain cream matrix.

[0170] In some implementations, the temperature of homogenization emulsification in step S3 is 60~85°C; for example, 70~80°C.

[0171] In some implementations, in step S3, the pressure of homogenization emulsification is -0.03 to -0.06 MPa.

[0172] In some implementations, in step S3, the cooling is to reduce the temperature to 50~70°C; for example, 55~65°C.

[0173] The present invention also provides a cream prepared according to the above-described method for preparing a cream.

[0174] In some embodiments, the cream is an oil-in-water cream.

[0175] In some embodiments, the cream is a cream used to treat skin diseases caused by viral infections.

[0176] In some embodiments, the cream is a cream for treating skin diseases caused by the varicella-zoster virus.

[0177] In some implementations, the skin disease caused by the varicella-zoster virus may be chickenpox or shingles.

[0178] In some implementations, the skin disease caused by the varicella-zoster virus is shingles.

[0179] The present invention also provides the use of the above-described cream in the preparation of a medicament for treating skin diseases caused by viral infections.

[0180] In some implementations, the skin disease caused by the viral infection is a skin disease caused by the varicella-zoster virus.

[0181] In some implementations, the skin disease caused by the varicella-zoster virus may be chickenpox or shingles; for example, shingles.

[0182] The present invention also provides a method for administering brivudine, comprising the following steps: applying the aforementioned brivudine cream topically to the skin.

[0183] In some embodiments, the dosage per unit area of ​​the administration method is 1.5-20 mg / cm². 2 For example, 2 mg / cm 2 .

[0184] The present invention also provides a method for treating skin diseases caused by viral infection in patients in need, comprising applying the above-mentioned brivudine cream to the patient.

[0185] In some implementations, the skin disease caused by the viral infection is a skin disease caused by the varicella-zoster virus.

[0186] In some implementations, the skin disease caused by the varicella-zoster virus may be chickenpox or shingles; for example, shingles.

[0187] In some embodiments, the dosage per unit area of ​​the treatment method is 1.5-20 mg / cm². 2 For example, 2 mg / cm 2 .

[0188] The present invention also provides the application of glyceryl behenate or polyethylene glycol 15-hydroxystearate in improving the photostability of brovodine.

[0189] In some embodiments, the mass ratio of behenicol glyceride to bromfumidine is (2~12):1, for example 2:1, 4:1, 6:1, 10:1 or 12:1.

[0190] In some embodiments, the mass ratio of the 15-hydroxystearic acid polyethylene glycol ester to the brovodine is (1~12):1, for example 1:1, 8:1, 10:1 or 12:1.

[0191] The present invention also provides the application of glyceryl behenate or polyethylene glycol 15-hydroxystearate in brovodiamine.

[0192] In some embodiments, the bromide agent is a cream.

[0193] In some embodiments, the behenicol glyceride plays a role in improving photostability in the bromofuc agent.

[0194] In some embodiments, the 15-hydroxystearic acid polyethylene glycol ester plays a role in improving photostability in the bromofuryl agent.

[0195] In some embodiments, the mass ratio of behenicol glyceride to bromfumidine is (2~12):1, for example 2:1, 4:1, 6:1, 10:1 or 12:1.

[0196] In some embodiments, the behenicol glyceride accounts for 0.5-10% of the mass of the bromofuran agent; such as 1-6%; for example, 1%, 5% or 6%.

[0197] In some embodiments, the mass ratio of the 15-hydroxystearic acid polyethylene glycol ester to the brovodine is (1~12):1, for example 1:1, 8:1, 10:1 or 12:1.

[0198] In some embodiments, the 15-hydroxystearic acid polyethylene glycol ester accounts for 0.1-10% by mass of the bromofut agent; such as 0.5-6%; for example 0.5%, 4% or 6%.

[0199] In some embodiments, the brofvédex agent is the brofvédex agent described in any of the foregoing embodiments.

[0200] Unless otherwise specified, the terms used in this invention have the following definitions.

[0201] The term "brovudine" refers to Or a pharmaceutically acceptable salt thereof; the brivudine may also exist as a solvate (such as a hydrate) or a prodrug.

[0202] The term "organic solvent" refers to an organic liquid or mixture of organic liquids that is miscible with water and is used to dissolve or disperse bromivudine in the cream formulation of this invention.

[0203] The term "antimicrobial agent" refers to a preservative in creams that can effectively inhibit the growth of microorganisms and meet the safety requirements for topical application, and whose concentration within the stated range should not irritate the skin.

[0204] The term "emulsifier" refers to a substance whose molecule contains both hydrophilic and lipophilic groups, which helps to form and maintain a uniform and stable emulsion dispersion system in the aqueous and oil phases of an emulsion.

[0205] The term "oil phase matrix" refers to the basic component that makes up the emulsion dispersion system (oil phase) in a cream. It is typically composed of oily substances.

[0206] The term "antioxidant" refers to a class of additives that can inhibit or delay the oxidative deterioration of easily oxidized components (such as unsaturated fatty acids) in drugs and matrices, thereby preventing the preparation from becoming rancid, discolored, off-flavored, or ineffective.

[0207] Those skilled in the art will understand that in this invention, a component is selected from one or more of the following categories. When the selection of a category itself includes multiple cases, and when limited to a specific category that includes multiple cases, "one" can be further interpreted as one or more of multiple cases. For example, the organic solvent is selected from one or more of alcohol solvents, ester solvents, and sulfoxide solvents; when the organic solvent is an alcohol solvent, the organic solvent can be a mixture of propylene glycol and isopropanol, or it can be propylene glycol alone.

[0208] The positive and progressive effects of the present invention are as follows: the brivudine cream provided by the present invention has one or more of the following positive and progressive effects: good safety, few side effects, good stability, and good therapeutic effect. Attached Figure Description

[0209] Figure 1 Images of the redness and swelling area in mice 7 days after administration of the formulation in Example 1.

[0210] Figure 2 Images of the redness and swelling area in mice 7 days after administration of the formulation in Example 2.

[0211] Figure 3 Images of the redness and swelling area in mice 7 days after administration of the formulation in Example 3.

[0212] Figure 4 Images of the redness and swelling area in mice 7 days after administration of the formulation in Example 4.

[0213] Figure 5 Images of the redness and swelling area in mice 7 days after administration of the formulation in Example 5.

[0214] Figure 6 Images of the redness and swelling area in mice 7 days after administration of the formulation in Example 6.

[0215] Figure 7 Images of the redness and swelling area in mice 7 days after administration of the formulation in Example 7.

[0216] Figure 8 Images of the redness and swelling area in mice 7 days after administration of the formulation in Example 8.

[0217] Figure 9 Images of the redness and swelling area in mice 7 days after administration of the formulation in Example 9.

[0218] Figure 10 Images of the redness and swelling area in mice 7 days after administration of the formulation in Example 1 of the comparative document.

[0219] Figure 11 Images of the redness and swelling area in mice 7 days after administration of the formulation in Example 9 of the comparative document.

[0220] Figure 12Images of the redness and swelling area in mice 7 days after administration of the formulation in Example 10 of the comparative document. Detailed Implementation

[0221] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions are performed according to conventional methods and conditions, or as selected in the product instructions.

[0222] The raw materials used in the examples comply with the Chinese Pharmacopoeia.

[0223] The following are some of the raw material types or sources:

[0224] Hexadecyl alcohol: Hunan Ercon Pharmaceutical Co., Ltd.

[0225] The raw material "stearic acid" used in the examples is stearic acid type 50.

[0226] The formula for Example 1 is as follows:

[0227]

[0228] The brovodine cream of Example 1 was prepared according to the following steps:

[0229] (1) Preparation of aqueous phase: Heat purified water to 70~80℃ to obtain aqueous phase.

[0230] (2) Preparation of oil phase mixture: Cetyl alcohol, glyceryl mono- and di-stearyl esters, white petrolatum, glyceryl behenate, isopropyl myristate, stearic acid, polyethylene glycol 15-hydroxystearic acid, mixed fatty acid glycerides (stear), ethylparaben, and dibutylhydroxytoluene are hot-melted and mixed at 70~80℃ to obtain oil phase mixture.

[0231] (3) Preparation of cream matrix: The oil phase mixture is added to the aqueous phase, the temperature is controlled at 70~80℃, and homogenized emulsified at -0.03~-0.06MPa for 15~30min. Then, the temperature is lowered to 55~65℃ to obtain cream matrix.

[0232] (4) Preparation of active ingredient solution: Add bromivudine to propylene glycol and stir to dissolve at 55~65℃ to obtain bromivudine solution.

[0233] (5) Add brombutin solution to the cream base, control the temperature at 55~65℃, homogenize and emulsify at -0.03~-0.06MPa for 30~60min, then cool down to 30~40℃, fill and obtain the sample. The inner packaging material is a polyethylene / aluminum / polyethylene composite pharmaceutical ointment tube.

[0234] The formula for Example 2 is as follows:

[0235]

[0236] The formula for Example 3 is as follows:

[0237]

[0238] The formula for Example 4 is as follows:

[0239]

[0240] The formula for Example 5 is as follows:

[0241]

[0242] The formula for Example 6 is as follows:

[0243]

[0244] The formula for Example 7 is as follows:

[0245]

[0246] The formulation for Example 8 is as follows:

[0247]

[0248] The formula for Example 9 is as follows:

[0249]

[0250] The quality of the topical drug composition obtained in the above embodiments and the cream obtained according to Examples 1, 9 and 10 of CN1486185A were evaluated.

[0251] Quality evaluation methods:

[0252] (1) Characteristics

[0253] Operating procedure: Take an appropriate amount of sample, place it in a petri dish, and visually inspect it.

[0254] (2) Centrifugal stability

[0255] Centrifugation stability test: Centrifuge at 2500 r / min for 30 min and visually observe. It should be stable with no aqueous phase precipitation and no stratification.

[0256] (3) Uniformity (content) within the container

[0257] Take the tube samples prepared in the above examples, cut them longitudinally, and accurately weigh approximately 1g from each end (sealed end, middle end, and capped end). Place them in a beaker, extract with methanol, and transfer to a 20ml volumetric flask. Dilute to the mark, let stand, centrifuge the supernatant, accurately measure 2ml of the supernatant, place it in a 10ml volumetric flask, add 2ml of methanol, dilute with water to the mark, shake well, filter, and use a high-performance liquid chromatograph (HPLC) to determine the content. A smaller content range indicates better sample homogeneity, which is beneficial to the safety, efficacy, and quality stability of the drug. (Range = Maximum content - Minimum content)

[0258] (4) Light stability test

[0259] Sample (naked sample: sample without original packaging, 0.1 g / cm³) 2 After 2 hours of exposure to ultraviolet light (24.8 Wh / m²), 2 (UVA light) Take approximately 1g of the sample after irradiation, accurately weigh it, place it in a beaker, extract with methanol and transfer it to a 20ml volumetric flask, dilute to the mark, let stand, centrifuge the supernatant, accurately measure 2ml of the supernatant, place it in a 10ml volumetric flask, add 2ml of methanol, dilute with water to the mark, shake well, filter, and take the filtrate. Use high-performance liquid chromatography (HPLC) to determine the content and impurities. The higher the brovodine content and the lower the impurity level in the sample after irradiation, the better the photostability.

[0260] The results are shown in Table 1 below:

[0261] Table 1

[0262]

[0263]

[0264] As shown in the table above, when the cream base contains polyethylene glycol 15-hydroxystearate or glyceryl behenate, it can effectively prevent the photodegradation of bromfumide in the cream, and the content can be maintained at around 95%. The protective effect is better than adding a light stabilizer to the topical formulation (Patent publication number CN1486185A, adding 20% ​​w / w titanium dioxide to the cream, after the cream is irradiated with a UV lamp for 2 hours (24.8Wh / m²)). 2 The content of UVA light can be maintained at around 85%, while the content without added light stabilizer is reduced to below 60%, which ensures the content of active ingredients in the formulation, controls the level of impurities, and ensures the effectiveness and safety of the formulation.

[0265] Irritation test

[0266] Skin irritation tests were conducted on domestic rabbits. Forty-eight healthy New Zealand rabbits were randomly divided into 12 groups, half male and half female. The creams obtained in the above examples and comparative documents Example 1, 9, and 10 were applied to intact skin of each rabbit. The test dose was 0.5g / rabbit. The treatment was carried out for 7 consecutive days. After each removal of the drug, the skin was observed for local irritation reactions such as redness, swelling, congestion, exudation, degeneration, and necrosis 1 hour (±15 minutes) and before each administration. The irritation and allergic reactions (erythema and edema) were scored according to the following criteria. The two scores were added together to obtain the irritation score for the day. The average irritation score for each animal was calculated for each day, and the intensity of skin irritation was determined based on the average score.

[0267] Erythema scoring criteria:

[0268] 0 points: No erythema; 1 point: Mild erythema (barely visible);

[0269] 2 points: Moderate erythema (clearly visible); 3 points: Severe erythema;

[0270] 4 points: purplish-red erythema with eschar formation.

[0271] Edema scoring criteria:

[0272] 0 points: No edema; 1 point: Mild edema (barely visible);

[0273] 2 points: Moderate edema (obvious swelling); 3 points: Severe edema (skin swelling 1mm with clear outline);

[0274] 4 points: Severe edema (bulging of more than 1 mm and enlarging).

[0275] Skin irritation intensity evaluation:

[0276]

[0277] Based on the above scoring criteria, the 12 groups of rabbits were scored before administration and 1 hour (±15 min) after administration. The average stimulus score for each animal per day was calculated, and the results are shown in Table 2 below:

[0278] Table 2 Results of the intact skin irritation test on New Zealand rabbits

[0279]

[0280]

[0281] At the experimental dosage, according to the "skin irritation intensity judgment" standard, the creams obtained in Examples 1-7 and Example 9 caused mild irritation to intact skin, while the creams obtained in Example 8, Comparative Document Example 1, Comparative Document Example 9, and Comparative Document Example 10 caused moderate irritation to intact skin. At the end of the administration period, erythema and edema were observed at the administration site in Examples 1-9, but no crust formation was observed; purplish-red erythema and eschar formation were observed in Comparative Document Examples 1, 9, and 10, with average daily irritation scores of 3.81, 3.85, and 3.73 per animal, respectively, indicating moderate irritation and significant lesions.

[0282] Conclusion: Examples 1-7 and Example 9 caused mild irritation to intact skin, while Example 8, Comparative Document Examples 1, 9 and 10 caused moderate irritation to intact skin, with stronger skin irritation.

[0283] Biological efficacy test

[0284] Pharmacodynamic tests were conducted on the creams prepared in Examples 1-9 and the creams obtained in the comparative documents Examples 1, 9, and 10 in mice. Ninety-six SPF-grade mice were inoculated with varicella-zoster virus on both sides of the spine on their backs to establish an animal model. Each group received one of the above-mentioned creams, applied twice a day (0.5g / mouse each time), for a total of 7 days. The area of ​​redness and swelling at the lesion site of the mice was observed (the area was calculated using Image-J software). After the treatment period, skin tissue was collected for section pathological observation and the viral load in the skin tissue was studied.

[0285] Area of ​​skin redness and swelling in mice (unit: cm) 2 The results are shown in Table 3 below:

[0286] Table 3

[0287]

[0288] The mouse skin histopathology grading scoring criteria and change results are as follows:

[0289]

[0290]

[0291] The viral load results in mouse skin tissue are as follows:

[0292]

[0293] Based on the results of the change in the area of ​​redness and swelling, it can be seen that the creams obtained in Examples 1 to 9 can promote the faster reduction of the area of ​​redness and swelling compared with the examples in the comparative document. After 7 days of administration, the area of ​​red and swollen skin in the groups of Examples 1 to 9 was significantly smaller than that of the cream formulation in the comparative document, and the difference was statistically significant. Among them, the preferred example (Example 1) had the best efficacy.

[0294] The therapeutic trend in the area of ​​redness and swelling is also reflected in the pathological changes. After 7 days of administration, the severity of skin inflammation cell infiltration in mice in Examples 1-9 was weaker than that in the cream examples of the comparative document, and the viral load was also significantly lower than that in the comparative document. The viral load of the preferred formulation (Example 1) was orders of magnitude different from that in the comparative document, indicating that the preferred formulation has a better inhibitory effect on the replication of varicella-zoster virus.

[0295] Images of the redness and swelling area in mice 7 days after drug administration are shown below. Figures 1-12 As shown.

[0296] Local drug concentration detection

[0297] Brivudine oral tablets and topical formulations (Example 1) were used to determine the skin drug concentration in Bama miniature pigs.

[0298] Two small Bama miniature pigs were taken and administered brivudine tablets (human dosage converted, 3 mg / kg by gavage) orally and 0.5% brivudine cream (Example 1) topically to the skin, respectively. The amount of medication applied was 7.6 g / pig (8cm*8cm, 119 mg / cm²). 2 The dressing was left on the skin for 4 hours to ensure full absorption. After gavage and 4 hours after application and cleaning, the same area was anesthetized by infiltration anesthesia with lidocaine hydrochloride 2-4 mg / kg. Skin samples (including epidermis and dermis, each 1cm × 1cm in size and approximately 4 mm in thickness) were collected at 0h (before administration), 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h, and 48h after administration.

[0299] After weighing, the tissue samples were added to methanol at three times their mass volume and ground at 70 Hz for 120 s to prepare a tissue homogenate. 50.0 μL of the porcine skin homogenate sample was taken, and 150.0 μL of internal standard solution (3.00 ng / mL glibenclamide, prepared in methanol) was added. The mixture was vortexed at 2000 rpm for 5 min, centrifuged for 5 min (12000 rpm, 4℃), and 100.0 μL of the supernatant was mixed with 100.0 μL of ultrapure water and injected for analysis.

[0300] 0.5% brivudine cream (Example 1) was applied topically to the skin. The T content of brivudine in animal skin was measured. max It is 0.083h, Cmax The concentration was 44400 ng / mL, with an AUC of 1000 ng / mL. last The concentration was 819782.2 h*ng / mL.

[0301] Following oral administration of brivudine, the T concentration of brivudine in the skin of animals was... max For 1 h, C max The concentration was 962 ng / mL, with an AUC of 1000 ng / mL. last The value was 3884.0 h*ng / mL.

[0302] The results showed that brivudine cream can significantly increase the drug content of brivudine in the skin. In the treatment of herpes zoster virus, brivudine cream can exert a local inhibitory effect on viral replication through a stronger local drug concentration, accelerate the astringent crusting of the lesion site, and thus speed up healing.

Claims

1. A cream comprising the following components in the indicated mass fractions: 0.1-5% bivudine, 5-45% organic solvent, 0.3-10% emulsifier, 15-55% oil phase matrix, and water; wherein the cream is an oil-in-water emulsion. It also meets any of the following conditions: (C1) The emulsifier includes polyethylene glycol 15-hydroxystearate; (C2) The oil phase matrix includes behenicol glycerol.

2. The cream as described in claim 1, characterized in that, It meets one or more of the following conditions: (1) The cream is a cream used to treat skin diseases caused by viral infection; the skin diseases caused by viral infection are such as skin diseases caused by varicella-zoster virus; the skin diseases caused by varicella-zoster virus can be chickenpox or shingles; for example, shingles; (2) The organic solvent is selected from one or more of ester solvents, alcohol solvents, sulfoxide solvents, and triglyceride solvents; the ester solvent may be a carbonate solvent, such as propylene carbonate; the alcohol solvent may be C 2-4 Alcohols; can also be C-type compounds containing two hydroxyl groups. 2-4 Alcohols; for example, C3 alcohols; or propylene glycol; the sulfoxide solvent may be dimethyl sulfoxide; the triglyceride solvent may be a medium-chain triglyceride; For example, the organic solvent is selected from one or both of alcohol solvents and carbonate solvents; For example, the organic solvent is selected from one or more of propylene carbonate, ethyl oleate, ethyl acetate, triethyl glycerol, isopropyl myristate, isopropyl palmitate, medium-chain triglycerides, dimethyl sulfoxide, ethanol, polyethylene glycol, propylene glycol, glycerol, isopropanol, and n-butanol; for example, propylene glycol and / or propylene carbonate; such as propylene glycol; (3) The emulsifier is polyethylene glycol 15-hydroxystearic acid, or the emulsifier includes polyethylene glycol 15-hydroxystearic acid, and also includes one or more of the following emulsifiers other than polyethylene glycol 15-hydroxystearic acid: polyoxyethylene nonionic surfactant, polyether nonionic surfactant, anionic surfactant, phospholipid emulsifier, natural polymer emulsifier and sugar ester emulsifier; (4) The oil phase matrix includes glyceryl behenate, and the emulsifier is selected from one or more of polyoxyethylene nonionic surfactants, polyether nonionic surfactants, anionic surfactants, phospholipid emulsifiers, natural polymer emulsifiers and sugar ester emulsifiers; (4) The emulsifier includes polyethylene glycol 15-hydroxystearic acid, and the oil phase matrix is ​​selected from one or more of the following: higher aliphatic hydrocarbons, higher aliphatic alcohols, higher fatty acids, fatty acid esters, glycerides, polyethylene glycol esters, white beeswax, lanolin, menthol and hydrogenated castor oil; (5) The oil phase matrix includes glyceryl behenate, and the oil phase matrix also includes oil phase matrix other than glyceryl behenate: one or more of the following: higher aliphatic hydrocarbons, higher aliphatic alcohols, higher fatty acids, fatty acid esters, glyceryl esters, polyethylene glycol esters, white beeswax, lanolin, menthol and hydrogenated castor oil; (6) The cream further includes an antibacterial agent; the antibacterial agent may be selected from one or more of quaternary ammonium salt antibacterial agents, organic acids and their salts antibacterial agents, parabens, alcohols, phenols, imidazoles, quinolines, and metabisulfites; the quaternary ammonium salt antibacterial agent may be benzalkonium chloride or benzalkonium bromide; the organic acids and their salts antibacterial agents may be benzoic acid, sodium benzoate, sorbic acid and its potassium salt, octanoic acid and its sodium salt, propionic acid, etc. The antibacterial agents are: acid, dehydroacetic acid, or boric acid; the paraben antibacterial agents may be methylparaben, ethylparaben, propylparaben, butylparaben, or benzylparaben and their sodium salts; the alcohol antibacterial agents may be ethanol, propylene glycol, benzyl alcohol, phenoxyethanol, or chlorobutanol; the phenolic antibacterial agents may be p-chlorophenol, m-cresol, or chlorocresol; the imidazole antibacterial agents may be imidazolidinyl urea; the quinoline antibacterial agents may be hydroxyquinoline sulfate; and the metabisulfite antibacterial agents may be sodium metabisulfite. For example, the antibacterial agent is selected from one or more of benzalkonium chloride, benzalkonium bromide, benzoic acid and its sodium salt, sorbic acid and its potassium salt, octanoic acid and its sodium salt, propionic acid, ethanol, propylene glycol, benzyl alcohol, phenoxyethanol, methylparaben, ethylparaben, propylparaben, butylparaben, benzylparaben, sodium methylparaben, sodium propylparaben, sodium metabisulfite, imidazolidinyl urea, dehydroacetic acid, hydroxyquinoline sulfate, p-chlorophenol, chlorobutanol, m-cresol, chlorocresol, and boric acid; for example, one or more of ethylparaben, methylparaben, propylparaben, and potassium sorbate; such as ethylparaben. (7) The cream further includes an antioxidant; the antioxidant may be selected from one or more of butylated hydroxytoluene, butylated hydroxyanisole, tert-butylhydroquinone, propyl gallate and vitamin E; for example, butylated hydroxytoluene; (8) The water is purified water; (9) The cream comprises the organic solvent, the bromfudin, the emulsifier, the water, and the oil phase; the oil phase comprises the oil phase matrix, the antibacterial agent, and the antioxidant. (10) The mass fraction of the brovodine is 0.1-1%; such as 0.4-0.6%; for example, 0.5%; (11) The mass fraction of the organic solvent is 10-35%; such as 18-22%; for example, 20%, 10%, 25% or 35%; (12) The mass fraction of the emulsifier is 0.5-6%; such as 3.5-4.5%; for example, 0.5%, 1%, 4%, 5% or 6%; (13) The mass fraction of the oil phase matrix is ​​21-35%; such as 26-29%; for example, 21%, 24.5%, 25%, 27%, 27.5%, 30%, 31.5% or 35%; (14) The cream further includes an antibacterial agent; the mass fraction of the antibacterial agent is 0.05~0.5%; such as 0.18~0.22%; for example 0.05%, 0.15%, 0.2% or 0.5%; (15) The cream further includes an antioxidant; the antioxidant has a mass fraction of 0.02-0.3%; such as 0.09-0.11%; for example, 0.02%, 0.05%, 0.1% or 0.3%; (16) The mass fraction of the water is 25-65%; for example, 44-52%; (17) The brovodine is ; The brovodine described in (18) is the only active ingredient in the cream.

3. The cream as described in claim 2, characterized in that, It meets one or more of the following conditions: (1) The polyoxyethylene nonionic surfactant is one or more of the following: polysorbates, polyoxyethylene stearate (40), polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (35) castor oil, lauroyl polyoxyethylene (32) glycerol, lauroyl polyoxyethylene (6) glycerol, lauroyl polyoxyethylene (8) glycerol, lauroyl polyoxyethylene (12) glycerol, oleyl polyoxyethylene glycerol, polyoxyethylene oleate, polyoxyethylene (50) stearate, polyethylene glycol succinate, and 15-hydroxystearate. (2) The polyether-type nonionic surfactant is poloxamer 188 and / or poloxamer 407; (3) The anionic surfactant is sodium dodecyl sulfate and / or sodium deoxycholate; (4) The phospholipid emulsifier is soybean lecithin and / or egg yolk lecithin; (5) The natural polymer emulsifier is gum arabic and / or tragacanth gum; (6) The higher aliphatic hydrocarbon is white petrolatum, yellow petrolatum, liquid paraffin or paraffin; (7) The higher fatty alcohol is hexadecyl alcohol, octadecyl alcohol, or hexadecyloctadecyl alcohol; (8) The higher fatty acid is stearic acid or palmitic acid; (9) The fatty acid ester is ethyl oleate, isopropyl myristate, or ethyl acetate; (10) The glycerides are mono- and di-stearyl glycerides, behenicol glycerides, mixed fatty acid glycerides (stearin) or cocoa butter; (11) The polyethylene glycol ester is stearic acid polyoxyethylene (40) ester or polyoxyethylene (50) stearic acid ester; The sugar ester emulsifier mentioned in (12) is sucrose stearate.

4. The cream as described in claim 2, characterized in that, It meets one or more of the following conditions: (1) The emulsifier includes polyethylene glycol 15-hydroxystearate, and the emulsifier further includes sodium dodecyl sulfate, polysorbates, polyoxyethylene stearate (40), polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (35) castor oil, gum arabic, tragacanth gum, poloxamer 188, poloxamer 407, lauroyl polyoxyethylene (32) glyceryl ester, lauroyl polyoxyethylene (6) One or more of the following: glyceryl esters, lauroyl polyoxyethylene (8) glyceryl esters, lauroyl polyoxyethylene (12) glyceryl esters, oleyl polyoxyethylene glyceryl esters, polyoxyethylene oleate, polyoxyethylene (50) stearate, hydrogenated castor oil, sodium deoxycholate, polyethylene glycol succinate, sucrose stearate, soybean lecithin, and egg yolk lecithin; for example, one or more of polysorbate 80 and sodium lauryl sulfate; such as polysorbate 80; (2) The oil phase matrix includes glyceryl behenate, and the emulsifier is selected from sodium dodecyl sulfate, polysorbates, polyoxyethylene stearate (40), polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (35) castor oil, gum arabic, tragacanth gum, poloxamer 188, poloxamer 407, lauroyl polyoxyethylene (32) glyceryl ester, lauroyl polyoxyethylene (6) glyceryl ester, lauroyl polyoxyethylene (8) glyceryl ester ... One or more of the following: ethylene (12) glyceride, oleoyl polyoxyethylene glyceride, polyoxyethylene oleate, polyoxyethylene (50) stearate, hydrogenated castor oil, sodium deoxycholate, polyethylene glycol succinate, polyethylene glycol 15-hydroxystearate, sucrose stearate, soybean lecithin, and egg yolk lecithin; for example, one or more of the following: polyethylene glycol 15-hydroxystearate, polysorbate 80, and sodium lauryl sulfate; such as polyethylene glycol 15-hydroxystearate or polysorbate 80. (3) The emulsifier includes polyethylene glycol 15-hydroxystearate, and the oil phase matrix is ​​selected from one or more of the following: white petrolatum, yellow petrolatum, lanolin, silicone oil, ethyl oleate, white beeswax, hydrogenated castor oil, liquid paraffin, isopropyl myristate, cholesterol, stearic acid, palmitic acid, polyoxyethylene (50) stearate, mixed fatty acid glycerides (stear), behenate glycerides, mono- and di-stearates, polyoxyethylene (40) stearate, stearyl alcohol, cetyl alcohol, cetyl octadecyl alcohol, ethyl acetate, menthol, paraffin, and cocoa butter; For example, the oil phase matrix is ​​selected from one or more of the following: mixed fatty acid glycerides (stearin), cetyl alcohol, mono- and di-stearyl glycerides, white petrolatum, behenicol, isopropyl myristate, stearic acid, octadecanol, paraffin, ethyl oleate, silicone oil, polyoxyethylene (50) stearate, white beeswax, polyoxyethylene (40) stearate, liquid paraffin, palmitic acid, lanolin, yellow petrolatum, menthol, cetyl alcohol, ethyl acetate, and hydrogenated castor oil; For example, the oil phase matrix is ​​selected from one or more of the following: mixed fatty acid glycerides (stearin), cetyl alcohol, mono- and di-stearyl glycerides, white petrolatum, behenicol, isopropyl myristate, stearic acid, octadecanol, paraffin, ethyl oleate, silicone oil, polyoxyethylene (50) stearate, white beeswax, polyoxyethylene (40) stearate, liquid paraffin, palmitic acid, cetyl alcohol, ethyl acetate, and hydrogenated castor oil; For example, the oil phase matrix is ​​selected from cetyl alcohol, glyceryl mono- and di-stearyl esters, white petrolatum, glyceryl behenate, isopropyl myristate, mixed fatty acid glycerides (stear), and stearic acid; the stearic acid may be stearic acid type 50; (4) The oil phase matrix includes glyceryl behenate, and the oil phase matrix also includes one or more of the following: white petrolatum, yellow petrolatum, lanolin, silicone oil, ethyl oleate, white beeswax, hydrogenated castor oil, liquid paraffin, isopropyl myristate, cholesterol, stearic acid, palmitic acid, polyoxyethylene (50) stearate, mixed fatty acid glycerides (stear), mono- and di-stearic acid glycerides, polyoxyethylene (40) stearate, stearyl alcohol, cetyl alcohol, cetyl octadecyl alcohol, ethyl acetate, menthol, paraffin and cocoa butter; For example, the oil phase matrix also includes one or more of the following: mixed fatty acid glycerides (stearin), cetyl alcohol, mono- and di-stearyl glycerides, white petrolatum, isopropyl myristate, stearic acid, octadecanol, paraffin, ethyl oleate, silicone oil, polyoxyethylene (50) stearate, white beeswax, polyoxyethylene (40) stearate, liquid paraffin, palmitic acid, lanolin, yellow petrolatum, menthol, cetyl alcohol, ethyl acetate, and hydrogenated castor oil; For example, the oil phase matrix also includes one or more of the following: mixed fatty acid glycerides (stearin), cetyl alcohol, mono- and di-stearyl glycerides, white petrolatum, isopropyl myristate, stearic acid, octadecanol, paraffin, ethyl oleate, silicone oil, polyoxyethylene (50) stearate, white beeswax, polyoxyethylene (40) stearate, liquid paraffin, palmitic acid, cetyl alcohol, ethyl acetate, and hydrogenated castor oil; For example, the oil phase matrix also includes cetyl alcohol, glyceryl mono- and di-stearyl esters, white petrolatum, isopropyl myristate, mixed fatty acid glycerides (stearic acid), and stearic acid; the stearic acid may be stearic acid type 50.

5. The cream as described in claim 1, characterized in that, It meets one or more of the following conditions: (1) The mass ratio of the brovodine to the organic solvent is 1:(20-70); for example, 1:(36-44); or for example, 1:20, 1:40, 1:50 or 1:70; (2) The mass ratio of the bromfumide to the emulsifier is 1:(1-12); for example, 1:(7-9); or for example, 1:1, 1:2, 1:8, 1:10 or 1:12; (3) The mass ratio of the bromfudin to the oil phase matrix is ​​1:(42-70); for example, 1:(52-58); or for example, 1:42, 1:50, 1:54, 1:55, 1:60, 1:63 or 1:70; (4) The cream also includes an antibacterial agent; the mass ratio of bromfumide to the antibacterial agent may be 1:(0.1-1); for example, 1:(0.36-0.44); or for example, 1:0.1, 1:0.3, 1:0.4 or 1:1; (5) The cream further includes an antioxidant; the mass ratio of the bromfudin to the antioxidant may be 1:(0.04-0.6); for example, 1:(0.18-0.22); or for example, 1:0.04, 1:0.1, 1:0.2 or 1:0.6; and (6) In the cream, the emulsifier includes polyethylene glycol 15-hydroxystearate; and the oil phase matrix includes glyceryl behenate.

6. The cream as described in claim 1, characterized in that, The oil phase matrix comprises a mixture of fatty acid glycerides (stearin), cetyl alcohol, mono- and di-stearyl glycerides, white petrolatum, glyceryl behenate, isopropyl myristate, and stearic acid, preferably satisfying one or more of the following conditions: (1) The oil phase matrix is ​​composed of mixed fatty acid glycerides (stearin), cetyl alcohol, mono- and di-stearyl glycerides, white petrolatum, behenic acid glycerides, isopropyl myristate and stearic acid; (2) The mixed fatty acid glycerides (stearin) account for 2-25% of the mass of the oil phase matrix; for example, 4.7-20.0%; for another example, 10.3-11.5%; and for yet another example, 4.8%, 10.9% or 20%; (3) The hexadecyl alcohol accounts for 1.5-40% of the mass of the oil phase matrix; for example, 2.8-38.1%; for example, 6.9-7.7%; and for example, 2.9%, 7.3% or 38.1%; (4) The mass ratio of the mono- and di-stearyl glycerides to the oil phase matrix is ​​5-20%; for example, 7.1-17.1%; or for example, 13.7-15.3%; or for example, 7.1%, 14.5% or 17.1%; (5) The white petrolatum accounts for 1.5-30% of the mass of the oil phase matrix; for example, 9.5-28.6%; for another example, 24.2-26.8%; and for yet another example, 9.5%, 25.5% or 28.6%; (6) The behenicol glyceride accounts for 1.5-35% of the mass of the oil phase matrix; for example, 2.8-28.6%; for example, 17.2-19.2%; and for example, 2.9%, 18.2% or 28.6%; (7) The isopropyl myristate accounts for 3-18% of the oil phase matrix by mass; for example, 4.7-14.3%; for another example, 10.3-11.5%; and for yet another example, 4.8%, 10.9% or 14.3%; (8) The stearic acid accounts for 4-20% of the mass of the oil phase matrix; for example, 7.1-14.3%; or for example, 12.0-13.4%; or for example, 7.1%, 12.7% or 14.3%; Preferably, the mass ratio of behenicol to the mixed fatty acid glycerides (stearin) can be 1:(0.5-0.7); for example, 1:0.6; the mass ratio of behenicol to cetyl alcohol can be 1:(0.3-0.5); for example, 1:0.4; the mass ratio of behenicol to mono- and di-stearic acid glycerides can be 1:(0.9-1); for example, 1:0.8; the mass ratio of behenicol to white petrolatum can be 1:(1.3-1.5); for example, 1:1.4; the mass ratio of behenicol to isopropyl myristate can be 1:(0.5-0.7); for example, 1:0.6; and the mass ratio of behenicol to stearic acid can be 1:(0.6-0.8); for example, 1:0.

7.

7. The cream as described in claim 1, characterized in that, It meets one of the following conditions: (1) The cream comprises the brivudine, the organic solvent, the emulsifier, the oil phase matrix, the antibacterial agent, the antioxidant, and the water; (2) The cream is composed of the bromfudin, the organic solvent, the emulsifier, the oil phase matrix, the antibacterial agent, the antioxidant and the water; (3) The cream comprises an oil phase, the brombutin, the organic solvent, and the water; the oil phase comprises the oil phase matrix, the emulsifier, the antibacterial agent, and the antioxidant; (4) The cream is composed of an oil phase, the bromfudin, the organic solvent, and the water; the oil phase is composed of the oil phase matrix, the emulsifier, the antibacterial agent, and the antioxidant. (5) The cream comprises the following components by mass fraction: 0.1-1% bivvudine, 10-35% organic solvent, 0.5-6% emulsifier, 21-35% oil phase matrix, 0.05-0.5% antibacterial agent, 0.02-0.3% antioxidant and 25-65% water; the cream is an oil-in-water type cream. (6) The cream comprises the following components by mass fraction: 0.4-0.6% bivvudine, 18-22% organic solvent, 3.5-4.5% emulsifier, 26-29% oil phase matrix, 0.18-0.22% antibacterial agent, 0.09-0.11% antioxidant and 44-52% water; the cream is an oil-in-water type cream. (7) In the cream, the organic solvent is propylene glycol, the emulsifier is polyethylene glycol 15-hydroxystearate, the oil phase matrix is ​​a mixture of mixed fatty acid glycerides (stear), cetyl alcohol, mono- and di-stearyl glycerides, white petrolatum, glyceryl behenate, isopropyl myristate and stearic acid; the antibacterial agent is ethylparaben; the antioxidant is butylated hydroxytoluene; (8) The cream comprises the following components by mass fraction: 0.4-0.6% bivvudine, 18-22% organic solvent, 3.5-4.5% emulsifier, 26-29% oil phase matrix, 0.18-0.22% antibacterial agent, 0.09-0.11% antioxidant and 44-52% water; the cream is an oil-in-water type cream. In the cream, the organic solvent is propylene glycol, the emulsifier is polyethylene glycol 15-hydroxystearate, the oil phase matrix is ​​a mixture of mixed fatty acid glycerides (stear), cetyl alcohol, glyceryl mono- and distearates, white petrolatum, glyceryl behenate, isopropyl myristate, and stearic acid; the antibacterial agent is ethylparaben; and the antioxidant is butylated hydroxytoluene. For example, the cream is any of the following formulations: Formula 1: 0.5% brivudine, 20% propylene glycol, 4% polyethylene glycol 15-hydroxystearate, 3% mixed fatty acid glycerides (stear), 2% cetyl alcohol, 4% mono- and di-stearyl glycerides, 7% white petrolatum, 5% glyceryl behenate, 3% isopropyl myristate, 3.5% stearic acid, 0.2% ethylparaben, 0.1% butylated hydroxytoluene, and the balance being purified water; Formula 2: 0.5% brivudine, 10% propylene glycol, 6% polyethylene glycol 15-hydroxystearate, 1% mixed fatty acid glycerides (stear), 8% cetyl alcohol, 1.5% mono- and di-stearyl glycerides, 2% white petrolatum, 6% glyceryl behenate, 1% isopropyl myristate, 1.5% stearic acid, 0.05% ethylparaben, 0.02% butylated hydroxytoluene, and the balance being purified water; Formula 3: 0.5% brivudine, 35% propylene glycol, 0.5% 15-hydroxystearic acid polyethylene glycol ester, 7% mixed fatty acid glycerides (stear), 1% cetyl alcohol, 6% mono- and di-stearic acid glycerides, 10% white petrolatum, 1% behenate glyceride, 5% isopropyl myristate, 5% stearic acid, 0.5% ethylparaben, 0.3% butylated hydroxytoluene, and the balance being purified water; Formula 4: 0.5% bromhexine, 20% propylene glycol, 5% polysorbate 80, 1% mixed fatty acid glycerides (stearin), 5% stearyl alcohol, 2% cetyl alcohol, 2% paraffin wax, 3% behenicol, 4% ethyl oleate, 8% silicone oil, 0.18% methylparaben, 0.02% propylparaben, 0.05% butylated hydroxytoluene, and the balance being purified water; Formula 5: 0.5% bromhexine, 20% propylene glycol, 4% 15-hydroxystearic acid polyethylene glycol ester, 2% mixed fatty acid glycerides (stearic acid), 5% octadecyl alcohol, 2% polyoxyethylene (50) stearate, 8% white beeswax, 5% polyoxyethylene (40) stearate, 3% liquid paraffin, 5% palmitic acid, 0.2% potassium sorbate, 0.1% butylated hydroxytoluene and the balance being purified water; Formula 6: 0.5% brivudine, 20% propylene glycol, 5% polyethylene glycol 15-hydroxystearate, 1.5% mixed fatty acid glycerides (stearate), 5% lanolin, 5% mono- and di-stearates, 8% yellow petrolatum, 5% behenate glycerides, 4% liquid paraffin, 3% stearyl alcohol, 0.2% ethylparaben, 0.1% butylated hydroxytoluene, and the balance being purified water; Formula 7: 0.5% bromhexine, 20% propylene glycol, 5% polyethylene glycol 15-hydroxystearate, 2% menthol, 6% cetearyl alcohol, 5% ethyl acetate, 5% liquid paraffin, 2% glyceryl behenate, 5% ethyl oleate, 2% hydrogenated castor oil, 0.2% ethylparaben, 0.1% butylated hydroxytoluene, and the balance being purified water; Formula Nine: 0.5% bromhexine, 20% propylene carbonate, 5% isopropanol, 1% sodium lauryl sulfate, 1% mixed fatty acid glycerides (stearin), 5% cetyl alcohol, 2% mono- and di-stearyl glycerides, 5% white petrolatum, 6% behenicol, 2% ethyl oleate, 4% stearic acid, 0.15% ethylparaben, 0.05% butylated hydroxytoluene, and the balance being purified water.

8. A method for preparing a cream, comprising the following steps: The raw materials are mixed and homogenized by emulsification; the raw materials include brovodine, organic solvent, water, oil phase matrix and emulsifier; The definitions and amounts of the bromfudin, the organic solvent, the water, the oil phase matrix, and the emulsifier are as described in any one of claims 1-7.

9. The preparation method according to claim 8, characterized in that, It meets one or more of the following conditions: (1) The cream is an oil-in-water type cream; (2) The cream is a cream used to treat skin diseases caused by viral infections; the skin diseases caused by viral infections include skin diseases caused by varicella-zoster virus; the skin diseases caused by varicella-zoster virus may be chickenpox or shingles; for example, shingles; (3) The raw materials also include antibacterial agents and / or antioxidants; (4) The preparation method of the cream includes the following steps: mixing bromfumidine solution and cream base, homogenizing and emulsifying to obtain the product; The brovidine solution comprises brovidine and an organic solvent; the cream base is an oil-in-water cream base, comprising an aqueous phase and an oil phase; the aqueous phase comprises water; the oil phase comprises the oil phase base and the emulsifier. (5) The raw materials also include antibacterial agents and / or antioxidants, and the oil phase of the cream matrix includes the antibacterial agents and / or the antioxidants; (6) The temperature of the homogenization emulsification is 50~85℃; for example, 55~65℃; (7) The pressure of the homogenization emulsification is -0.01 to -0.08 MPa; for example, -0.03 to -0.06 MPa; For example, the preparation method also satisfies one or more of the following conditions: 1) The temperature of the aqueous phase is 60~85℃; for example, 70~80℃; 2) The oil phase is prepared in step S2; S2, preparing the oil phase: mixing the materials of the oil phase to obtain the oil phase; for example, in step S2, the mixing is hot melt mixing; preferably hot melt mixing at 60~85℃; for example, hot melt mixing at 70~80℃; 3) The cream matrix is ​​prepared in step S3; S3, preparing the cream matrix: mixing the oil phase and the aqueous phase, homogenizing and emulsifying, and cooling to obtain the cream matrix; for example, in step S3, the temperature of homogenization and emulsification is 60~85℃; for example, 70~80℃; for example, in step S3, the pressure of homogenization and emulsification is -0.03~-0.06MPa; for example, in step S3, the cooling is to 50~70℃; for example, 55~65℃.

10. A cream prepared according to the preparation method as described in claim 8 or 9.

11. The use of a cream as described in any one of claims 1-7 and 10 in the preparation of a medicament for treating skin diseases caused by viral infection; preferably, the skin disease caused by the viral infection is a skin disease caused by varicella-zoster virus; the skin disease caused by varicella-zoster virus may be chickenpox or shingles; for example, shingles.

12. The application of a behenicol glyceride or 15-hydroxystearic acid polyethylene glycol ester in improving the photostability of brovodine; For example, the mass ratio of the behenicol glyceride to the bromfumide is (2~12):1, such as 2:1, 4:1, 6:1, 10:1 or 12:1; For example, the mass ratio of the 15-hydroxystearic acid polyethylene glycol ester to the brovodine is (1~12):1, such as 1:1, 8:1, 10:1 or 12:

1.

13. The use of glyceryl behenate or polyethylene glycol 15-hydroxystearate in the preparation of brovostatin formulations; preferably, the formulation is a cream; for example, the cream of any one of claims 1-7 and 10; Preferably, the glyceryl behenate or polyethylene glycol 15-hydroxystearate plays a role in improving photostability in the bromofuc agent; The application can satisfy one or more of the following conditions: (1) When the application uses glyceryl behenate, the glyceryl behenate accounts for 0.5-10% of the mass of the bromofuran agent; such as 1-6%; for example, 1%, 5% or 6%; (2) The mass ratio of the behenicol glyceride to the bromfumide is (2~12):1, for example 2:1, 4:1, 6:1, 10:1 or 12:1; (3) When the application uses polyethylene 15-hydroxystearic acid, the polyethylene 15-hydroxystearic acid accounts for 0.1-10% of the mass of the bromofuran agent; such as 0.5-6%; for example 0.5%, 4% or 6%; The mass ratio of the 15-hydroxystearic acid polyethylene glycol ester to the bromfudin in (4) is (1~12):1, for example 1:1, 8:1, 10:1 or 12:1.

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